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Salvage Rendezvous Technique on Par With Precut Sphincterotomy for Tough Biliary Access
, new data suggest.
Selective deep cannulation of the common bile duct remains the key rate-limiting step in successful endoscopic retrograde cholangiopancreatography (ERCP), especially in benign biliary disease.
In cases of difficult cannulation, the traditional fallback has been precut sphincterotomy. Recently, EUS-RV has emerged as an alternative. However, head-to-head comparisons of these salvage techniques in homogeneous patient populations have been lacking, until now.
A team led by Arup Choudhury, MD, DM, with Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India, compared the two salvage techniques in a single-center, randomized controlled trial of 100 patients with benign biliary disease and difficult bile duct cannulation.
There were 50 patients in each group. When one technique failed, patients were crossed over to the other technique.
The technical success rate for achieving deep biliary, the primary outcome measure, was similar with EUS-RV and precut sphincterotomy (92% and 90%, respectively; P = 1.00; relative risk [RR], 1.02), the authors reported in Annals of Internal Medicine.
Median procedure time was also comparable (10.1 minutes with EUS-RV and 9.75 minutes with precut sphincterotomy). As expected, radiation exposure was notably higher in the EUS-RV group (median, 200.2 vs 67.8 mGy).
There was no difference in overall complication rates (12% and 10%, respectively; RR, 1.20).
Five patients in each group (10%) developed post-ERCP pancreatitis (PEP); one patient in the EUS-RV had moderately severe pancreatitis, whereas the rest had mild pancreatitis.
In an exploratory analysis of the subcohort of 72 patients who did not have 1 or more inadvertent pancreatic duct cannulation, two (5.6%) patients in the precut sphincterotomy group had PEP, whereas none of the patients in the EUS-RV had PEP (RR, 0.21). The investigators caution that a larger, multicenter, randomized controlled trial would be required to evaluate the “probable benefit” of lower PEP in the EUS-RV approach.
None of the patients had bleeding or perforation, but two (4%) patients in the EUS-RV group had an infection after the intervention. One required repeated ERCP due to post procedure cholangitis, whereas the other developed lower respiratory tract infection with transient acute lung injury and sputum showing gram-negative organism. None of the patients required surgical intervention.
“Interestingly,” said the investigators, on crossover from one salvage technique to the other, all of the cases could be successfully cannulated, suggesting the two salvage techniques are “complementary to each other and can help achieve successful cannulation in all cases when used in any sequence.”
Summing up, they said it appears from this head-to-head comparison that both EUS-RV and precut sphincterotomy can be considered effective salvage techniques in expert centers with similar safety and success profiles.
Limitations included the single-center design with both procedures performed by expert operators. EUS-RV entailed additional cost of needle and use of a separate scope, and a cost-efficacy analysis was not done.
This study had no specific funding. Disclosures for the authors are available with the original article.
A version of this article appeared on Medscape.com.
, new data suggest.
Selective deep cannulation of the common bile duct remains the key rate-limiting step in successful endoscopic retrograde cholangiopancreatography (ERCP), especially in benign biliary disease.
In cases of difficult cannulation, the traditional fallback has been precut sphincterotomy. Recently, EUS-RV has emerged as an alternative. However, head-to-head comparisons of these salvage techniques in homogeneous patient populations have been lacking, until now.
A team led by Arup Choudhury, MD, DM, with Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India, compared the two salvage techniques in a single-center, randomized controlled trial of 100 patients with benign biliary disease and difficult bile duct cannulation.
There were 50 patients in each group. When one technique failed, patients were crossed over to the other technique.
The technical success rate for achieving deep biliary, the primary outcome measure, was similar with EUS-RV and precut sphincterotomy (92% and 90%, respectively; P = 1.00; relative risk [RR], 1.02), the authors reported in Annals of Internal Medicine.
Median procedure time was also comparable (10.1 minutes with EUS-RV and 9.75 minutes with precut sphincterotomy). As expected, radiation exposure was notably higher in the EUS-RV group (median, 200.2 vs 67.8 mGy).
There was no difference in overall complication rates (12% and 10%, respectively; RR, 1.20).
Five patients in each group (10%) developed post-ERCP pancreatitis (PEP); one patient in the EUS-RV had moderately severe pancreatitis, whereas the rest had mild pancreatitis.
In an exploratory analysis of the subcohort of 72 patients who did not have 1 or more inadvertent pancreatic duct cannulation, two (5.6%) patients in the precut sphincterotomy group had PEP, whereas none of the patients in the EUS-RV had PEP (RR, 0.21). The investigators caution that a larger, multicenter, randomized controlled trial would be required to evaluate the “probable benefit” of lower PEP in the EUS-RV approach.
None of the patients had bleeding or perforation, but two (4%) patients in the EUS-RV group had an infection after the intervention. One required repeated ERCP due to post procedure cholangitis, whereas the other developed lower respiratory tract infection with transient acute lung injury and sputum showing gram-negative organism. None of the patients required surgical intervention.
“Interestingly,” said the investigators, on crossover from one salvage technique to the other, all of the cases could be successfully cannulated, suggesting the two salvage techniques are “complementary to each other and can help achieve successful cannulation in all cases when used in any sequence.”
Summing up, they said it appears from this head-to-head comparison that both EUS-RV and precut sphincterotomy can be considered effective salvage techniques in expert centers with similar safety and success profiles.
Limitations included the single-center design with both procedures performed by expert operators. EUS-RV entailed additional cost of needle and use of a separate scope, and a cost-efficacy analysis was not done.
This study had no specific funding. Disclosures for the authors are available with the original article.
A version of this article appeared on Medscape.com.
, new data suggest.
Selective deep cannulation of the common bile duct remains the key rate-limiting step in successful endoscopic retrograde cholangiopancreatography (ERCP), especially in benign biliary disease.
In cases of difficult cannulation, the traditional fallback has been precut sphincterotomy. Recently, EUS-RV has emerged as an alternative. However, head-to-head comparisons of these salvage techniques in homogeneous patient populations have been lacking, until now.
A team led by Arup Choudhury, MD, DM, with Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India, compared the two salvage techniques in a single-center, randomized controlled trial of 100 patients with benign biliary disease and difficult bile duct cannulation.
There were 50 patients in each group. When one technique failed, patients were crossed over to the other technique.
The technical success rate for achieving deep biliary, the primary outcome measure, was similar with EUS-RV and precut sphincterotomy (92% and 90%, respectively; P = 1.00; relative risk [RR], 1.02), the authors reported in Annals of Internal Medicine.
Median procedure time was also comparable (10.1 minutes with EUS-RV and 9.75 minutes with precut sphincterotomy). As expected, radiation exposure was notably higher in the EUS-RV group (median, 200.2 vs 67.8 mGy).
There was no difference in overall complication rates (12% and 10%, respectively; RR, 1.20).
Five patients in each group (10%) developed post-ERCP pancreatitis (PEP); one patient in the EUS-RV had moderately severe pancreatitis, whereas the rest had mild pancreatitis.
In an exploratory analysis of the subcohort of 72 patients who did not have 1 or more inadvertent pancreatic duct cannulation, two (5.6%) patients in the precut sphincterotomy group had PEP, whereas none of the patients in the EUS-RV had PEP (RR, 0.21). The investigators caution that a larger, multicenter, randomized controlled trial would be required to evaluate the “probable benefit” of lower PEP in the EUS-RV approach.
None of the patients had bleeding or perforation, but two (4%) patients in the EUS-RV group had an infection after the intervention. One required repeated ERCP due to post procedure cholangitis, whereas the other developed lower respiratory tract infection with transient acute lung injury and sputum showing gram-negative organism. None of the patients required surgical intervention.
“Interestingly,” said the investigators, on crossover from one salvage technique to the other, all of the cases could be successfully cannulated, suggesting the two salvage techniques are “complementary to each other and can help achieve successful cannulation in all cases when used in any sequence.”
Summing up, they said it appears from this head-to-head comparison that both EUS-RV and precut sphincterotomy can be considered effective salvage techniques in expert centers with similar safety and success profiles.
Limitations included the single-center design with both procedures performed by expert operators. EUS-RV entailed additional cost of needle and use of a separate scope, and a cost-efficacy analysis was not done.
This study had no specific funding. Disclosures for the authors are available with the original article.
A version of this article appeared on Medscape.com.
Clinicians Should Have Private Spaces for Telehealth According to VA Memo
US Department of Veterans Affairs (VA) officials are insisting that when remote telehealth clinicians return to an office setting, they must have private workspaces “that foster trusted, confidential, and therapeutic relationships with veterans,” according to an April internal memo reported on by NPR.
The return-to-office mandate followed a Trump Administration executive order in February indicated that mental health clinicians at the US Department of Veterans Affairs (VA) must physically return to their workplace by May 5. For some, the deadline came as early as April 14; however, that order, like many others, may now be being revised or reconsidered due to concerns that have been raised. Many mental health clinicians were hired specifically to work remotely. They worried there would simply not be enough space for them, particularly to provide confidential counseling.
Millions of veterans use telehealth to access VA care. More than 98% of VA mental health clinicians have conducted ≥ 1 video visit to screen and treat patients for anxiety, depression, posttraumatic stress disorder, and more. Telehealth has been particularly important for veterans living in rural communities.
The April VA memo stipulated that “spaces used to deliver synchronous telehealth services should offer the same level of privacy and therapeutic environment applicable to an in-person visit in the same space.”
Therapists, patients, advocacy groups, and lawmakers have expressed concern about the potential impacts the policy change could have on patient care for veterans and, above all, about what it could mean for privacy. On Mar. 27, the American Psychological Association issued a statement noting that the change “resulted in providers being asked to conduct sensitive therapy sessions in open office environments, cubicles, or shared spaces that fail to meet basic confidentiality and privacy requirements for the delivery of mental health care services.”
Twenty Democrats in the House of Representatives sent a letter to VA Secretary Doug Collins expressing concern with the return to office policy. According to the letter a VA social worker supervisor reported managing their caseload while sharing a 100 ft2 shower space with another supervisor. It also reported that Clinical Resource Hub employees were being told to report to buildings where federal employees from other agencies work. “We have heard from countless stakeholders, veterans, and Department of Veterans Affairs (VA) employees that by carrying out President Trump’s blanket return-to-office policy your administration is damaging veteran and employee trust in VA, disrupting and impeding veterans’ access to care, and creating untenable and inefficient conditions for both veterans and the VA workforce,” the letter stated.
“This is a clear violation of veterans’ privacy and VA’s obligation to protect veterans’ private health information, and risks violation of the Health Insurance Portability and Accountability Act (HIPAA),” the letter added.
The lawmakers noted that, as of March 10, the VA was exempting Veterans Crisis Line workers, most of whom had been working remotely for the past 5 years, responding to more than 10 million calls, texts, and chats. That move, they said, indicated “that you understand there will be negative impacts to veterans’ care due to the return-to-office order and that these must be mitigated.”
VA spokesperson Peter Kasperowicz called the privacy concerns “nonsensical” and blamed “fear mongering from the media.” The VA, he said, “is no longer a place where the status quo for employees is to simply phone it in from home.” He also claimed that “the small number of employees who are desperate to avoid returning to the office will do more to drive away staff and patients than VA’s commonsense return-to-office policy ever will.”
VA care, he said, would continue uninterrupted and the “VA will ensure that employees have a workspace that is appropriate for the work they do.”
US Department of Veterans Affairs (VA) officials are insisting that when remote telehealth clinicians return to an office setting, they must have private workspaces “that foster trusted, confidential, and therapeutic relationships with veterans,” according to an April internal memo reported on by NPR.
The return-to-office mandate followed a Trump Administration executive order in February indicated that mental health clinicians at the US Department of Veterans Affairs (VA) must physically return to their workplace by May 5. For some, the deadline came as early as April 14; however, that order, like many others, may now be being revised or reconsidered due to concerns that have been raised. Many mental health clinicians were hired specifically to work remotely. They worried there would simply not be enough space for them, particularly to provide confidential counseling.
Millions of veterans use telehealth to access VA care. More than 98% of VA mental health clinicians have conducted ≥ 1 video visit to screen and treat patients for anxiety, depression, posttraumatic stress disorder, and more. Telehealth has been particularly important for veterans living in rural communities.
The April VA memo stipulated that “spaces used to deliver synchronous telehealth services should offer the same level of privacy and therapeutic environment applicable to an in-person visit in the same space.”
Therapists, patients, advocacy groups, and lawmakers have expressed concern about the potential impacts the policy change could have on patient care for veterans and, above all, about what it could mean for privacy. On Mar. 27, the American Psychological Association issued a statement noting that the change “resulted in providers being asked to conduct sensitive therapy sessions in open office environments, cubicles, or shared spaces that fail to meet basic confidentiality and privacy requirements for the delivery of mental health care services.”
Twenty Democrats in the House of Representatives sent a letter to VA Secretary Doug Collins expressing concern with the return to office policy. According to the letter a VA social worker supervisor reported managing their caseload while sharing a 100 ft2 shower space with another supervisor. It also reported that Clinical Resource Hub employees were being told to report to buildings where federal employees from other agencies work. “We have heard from countless stakeholders, veterans, and Department of Veterans Affairs (VA) employees that by carrying out President Trump’s blanket return-to-office policy your administration is damaging veteran and employee trust in VA, disrupting and impeding veterans’ access to care, and creating untenable and inefficient conditions for both veterans and the VA workforce,” the letter stated.
“This is a clear violation of veterans’ privacy and VA’s obligation to protect veterans’ private health information, and risks violation of the Health Insurance Portability and Accountability Act (HIPAA),” the letter added.
The lawmakers noted that, as of March 10, the VA was exempting Veterans Crisis Line workers, most of whom had been working remotely for the past 5 years, responding to more than 10 million calls, texts, and chats. That move, they said, indicated “that you understand there will be negative impacts to veterans’ care due to the return-to-office order and that these must be mitigated.”
VA spokesperson Peter Kasperowicz called the privacy concerns “nonsensical” and blamed “fear mongering from the media.” The VA, he said, “is no longer a place where the status quo for employees is to simply phone it in from home.” He also claimed that “the small number of employees who are desperate to avoid returning to the office will do more to drive away staff and patients than VA’s commonsense return-to-office policy ever will.”
VA care, he said, would continue uninterrupted and the “VA will ensure that employees have a workspace that is appropriate for the work they do.”
US Department of Veterans Affairs (VA) officials are insisting that when remote telehealth clinicians return to an office setting, they must have private workspaces “that foster trusted, confidential, and therapeutic relationships with veterans,” according to an April internal memo reported on by NPR.
The return-to-office mandate followed a Trump Administration executive order in February indicated that mental health clinicians at the US Department of Veterans Affairs (VA) must physically return to their workplace by May 5. For some, the deadline came as early as April 14; however, that order, like many others, may now be being revised or reconsidered due to concerns that have been raised. Many mental health clinicians were hired specifically to work remotely. They worried there would simply not be enough space for them, particularly to provide confidential counseling.
Millions of veterans use telehealth to access VA care. More than 98% of VA mental health clinicians have conducted ≥ 1 video visit to screen and treat patients for anxiety, depression, posttraumatic stress disorder, and more. Telehealth has been particularly important for veterans living in rural communities.
The April VA memo stipulated that “spaces used to deliver synchronous telehealth services should offer the same level of privacy and therapeutic environment applicable to an in-person visit in the same space.”
Therapists, patients, advocacy groups, and lawmakers have expressed concern about the potential impacts the policy change could have on patient care for veterans and, above all, about what it could mean for privacy. On Mar. 27, the American Psychological Association issued a statement noting that the change “resulted in providers being asked to conduct sensitive therapy sessions in open office environments, cubicles, or shared spaces that fail to meet basic confidentiality and privacy requirements for the delivery of mental health care services.”
Twenty Democrats in the House of Representatives sent a letter to VA Secretary Doug Collins expressing concern with the return to office policy. According to the letter a VA social worker supervisor reported managing their caseload while sharing a 100 ft2 shower space with another supervisor. It also reported that Clinical Resource Hub employees were being told to report to buildings where federal employees from other agencies work. “We have heard from countless stakeholders, veterans, and Department of Veterans Affairs (VA) employees that by carrying out President Trump’s blanket return-to-office policy your administration is damaging veteran and employee trust in VA, disrupting and impeding veterans’ access to care, and creating untenable and inefficient conditions for both veterans and the VA workforce,” the letter stated.
“This is a clear violation of veterans’ privacy and VA’s obligation to protect veterans’ private health information, and risks violation of the Health Insurance Portability and Accountability Act (HIPAA),” the letter added.
The lawmakers noted that, as of March 10, the VA was exempting Veterans Crisis Line workers, most of whom had been working remotely for the past 5 years, responding to more than 10 million calls, texts, and chats. That move, they said, indicated “that you understand there will be negative impacts to veterans’ care due to the return-to-office order and that these must be mitigated.”
VA spokesperson Peter Kasperowicz called the privacy concerns “nonsensical” and blamed “fear mongering from the media.” The VA, he said, “is no longer a place where the status quo for employees is to simply phone it in from home.” He also claimed that “the small number of employees who are desperate to avoid returning to the office will do more to drive away staff and patients than VA’s commonsense return-to-office policy ever will.”
VA care, he said, would continue uninterrupted and the “VA will ensure that employees have a workspace that is appropriate for the work they do.”
Auto-Brewery Syndrome Explained: New Patient Cohort Identifies Culprit Bacteria, Fermentation
WASHINGTON — When a published case of auto-brewery syndrome (ABS) in China — caused by Klebsiella pneumoniae — received widespread publicity in 2019, patients reacted, sending emails to lead author Jing Yuan, in Beijing, China. Many of these inquiries were from patients in the United States who believed they might have ABS.
“Can you check to see if I have ABS?” patients asked Yuan.
For help, Yuan contacted Bernd Schnabl, MD, AGAF, at the University of California, San Diego, whose research was addressing alcohol-associated liver disease and who was also interested in the gut-liver axis and the role of gut microbiome–derived ethanol in metabolic dysfunction–associated steatotic liver disease (MASLD).
“She asked me, ‘Are you interested in looking into ABS?” Schnabl recalled at the Gut Microbiota for Health (GMFH) World Summit 2025. He dug in and formed what may be the largest research cohort thus far of patients with ABS — a group of 22 patients with their diagnosis confirmed through observed glucose challenge.
His soon-to-be-published
ABS is considered a rare condition, but “I’d argue that it’s rarely diagnosed because many physicians don’t know of the diagnosis, and many are actually very skeptical about the disease,” Schnabl said at the meeting, convened by AGA and the European Society of Neurogastroenterology and Motility.
Patients experience symptoms of intoxication when ethanol produced by dysregulated gut microbiota exceeds the capacity of the liver to metabolize it and accumulates in the blood, he explained.
“Patients constantly talk about brain fog; they can’t concentrate, and it can be very severe,” he said. “They don’t get a firm diagnosis and go from one medical center to another, and they also suffer from complications of alcohol use disorder including serious family, social, and legal problems.”
Advancing Knowledge, Findings From the Cohort
The phenomenon of ethanol production by gut microbiota has been known for over a century, Schnabl wrote with two co-authors in a 2024 review in Nature Reviews Gastroenterology & Hepatology of “endogenous ethanol production in health and disease.”
And in recent decades, he said at the meeting, research has linked endogenous ethanol production to MASLD, positioning it as a potential contributor to disease pathogenesis. In one of the most recently published studies, patients with MASLD had higher concentrations of ethanol in their systemic circulation after a mixed meal test than did healthy controls — and even higher ethanol concentrations in their portal vein blood, “suggesting that this ethanol is coming from the gut microbiome,” Schnabl said.
The paper from China that led Schnabl to establish his cohort was spurred on by a patient with both ABS and MASLD cirrhosis. The patient was found to have strains of high alcohol–producing K pneumoniae in the gut microbiome. When the researchers transplanted these strains into mice via fecal microbiota transplantation (FMT), the mice developed MASLD.
Schnabl’s study focused just on ABS, which is alternatively sometimes called gut fermentation syndrome. The 22 patients in his ABS cohort — each of whom provided stool samples corresponding to remission or flare of ABS symptoms — had a median age of 45 years and were predominantly men, slightly overweight and not obese, and without liver disease. (About 48 patients with suspected ABS were screened, and 20 were excluded after an observed glucose challenge failed to establish a diagnosis; 6 withdrew from the study.)
During remission (no symptoms), patients’ mean blood alcohol content (BAC) level was zero, but during a flare, the mean BAC level was 136 mg/dL. “To put it into perspective, the legal limit for driving in the US is 80 mg/dL,” Schnabl said. Within a mean of 4 hours after the oral glucose load used for diagnosis, patients’ mean BAC level was 73 mg/dL, he noted.
To assess ethanol production by the patients’ microbiota, Schnabl and his team cultured the stool samples — anaerobically adding glucose and measuring ethanol production — and compared the results with findings from stool samples collected from household partners who generally were of the opposite sex. Among their findings: cultures of stool from patients experiencing a flare produced significantly more ethanol than stool from household partners and samples from patients in remission.
To assess whether ethanol was produced by bacteria or fungi, the researchers measured ethanol production in cultures treated with either the antifungal amphotericin B or the antibiotic chloramphenicol. “Chloramphenicol clearly decreased the ethanol production,” Schnabl said. “So at least in this culture test, bacteria produced most of the alcohol in our patients.”
Taxonomic profiling, moreover, revealed “significantly elevated levels” of proteobacteria — with relative abundance of Escherichia coli and K pneumoniae — in patients who were flaring, he said. And functional profiling of the fecal microbiota showed much higher activity of fermentation pathways during patients’ flares than in household partners or healthy controls. (Healthy controls were incorporated into the taxonomic and functional profiling parts of the research.)
A Clinical Approach to ABS
Schnabl said at the meeting that stool cultures of both household partners and patients in long-term remission “all produced some low amount of ethanol, which was initially puzzling to us” but became less surprising as he and his colleagues reviewed more of the literature.
Asked during a discussion period whether ABS could explain chronic fatigue, a commonly reported chronic symptom in populations, Schnabl said it’s possible. And in an interview after the meeting, he elaborated. “The literature clearly says ABS is a rare disease, but I argue that more patients may have ABS; they just don’t know it. And I suspect some may have mild symptoms, like brain fog, feeling tired,” he said. “But at this point, this is complete speculation.”
Physicians should “be aware that if a patient has unexplained symptoms that could be aligned with ABS, checking the blood alcohol level” may be warranted, he said in the interview. A PEth (phosphatidylethanol) test — a biomarker test used to check for longer-term alcohol consumption — is an option, but it is important to appreciate it will not discriminate between exogenous alcohol drinking and endogenous ethanol production.
There are no standardized diagnostic tests for ABS, but at the meeting, Schnabl outlined a clinical approach, starting with a standardized oral glucose tolerance challenge test to detect elevated ethanol concentrations.
A fecal yeast test is warranted for diagnosed patients on the basis of some case reports in which ABS symptoms have improved with antifungal treatments. When the fecal yeast test is negative, “ideally you want to identify the ethanol-producing intestinal bacteria in the patient,” he said, using cultures and fecal metagenomics sequencing.
Treatment could then be tailored to the identified microbial strain, with options being selective antibiotics, probiotics and/or prebiotics, and — likely in the future — phages or FMT, he said. (These options, all aimed at restoring gut homeostasis, are also discussed in his 2024 review.)
Schnabl and his team recently performed FMT in a patient with ABS in whom E coli was determined to be producing excessive ethanol. The FMT, performed after antibiotic pretreatment, resulted in decreases in the relative abundance of proteobacteria and E coli levels, lower blood alcohol levels and fermentation enrichment pathways, and normalized liver enzymes.
After 6 months, however, the patient relapsed, and the measurements reversed. “We decided to do FMT every month, and we treated the patient for 6 months,” Schnabl said, noting that ABS had rendered the patient dysfunctional and unable to work. “He has been out of treatment for over a year now and is not flaring any longer.”
Schnabl and Elizabeth Hohmann, MD, at Massachusetts General Hospital, Boston, are currently recruiting patients with confirmed ABS for a National Institutes of Health–funded phase 1 safety and tolerability study of FMT for ABS.
Schnabl disclosed serving as an external scientific advisor/consultant to Ambys Medicines, Boehringer Ingelheim, Gelesis, Mabwell Therapeutics, Surrozen, and Takeda; and as the founder/BOD/BEO of Nterica Bio.
A version of this article appeared on Medscape.com.
WASHINGTON — When a published case of auto-brewery syndrome (ABS) in China — caused by Klebsiella pneumoniae — received widespread publicity in 2019, patients reacted, sending emails to lead author Jing Yuan, in Beijing, China. Many of these inquiries were from patients in the United States who believed they might have ABS.
“Can you check to see if I have ABS?” patients asked Yuan.
For help, Yuan contacted Bernd Schnabl, MD, AGAF, at the University of California, San Diego, whose research was addressing alcohol-associated liver disease and who was also interested in the gut-liver axis and the role of gut microbiome–derived ethanol in metabolic dysfunction–associated steatotic liver disease (MASLD).
“She asked me, ‘Are you interested in looking into ABS?” Schnabl recalled at the Gut Microbiota for Health (GMFH) World Summit 2025. He dug in and formed what may be the largest research cohort thus far of patients with ABS — a group of 22 patients with their diagnosis confirmed through observed glucose challenge.
His soon-to-be-published
ABS is considered a rare condition, but “I’d argue that it’s rarely diagnosed because many physicians don’t know of the diagnosis, and many are actually very skeptical about the disease,” Schnabl said at the meeting, convened by AGA and the European Society of Neurogastroenterology and Motility.
Patients experience symptoms of intoxication when ethanol produced by dysregulated gut microbiota exceeds the capacity of the liver to metabolize it and accumulates in the blood, he explained.
“Patients constantly talk about brain fog; they can’t concentrate, and it can be very severe,” he said. “They don’t get a firm diagnosis and go from one medical center to another, and they also suffer from complications of alcohol use disorder including serious family, social, and legal problems.”
Advancing Knowledge, Findings From the Cohort
The phenomenon of ethanol production by gut microbiota has been known for over a century, Schnabl wrote with two co-authors in a 2024 review in Nature Reviews Gastroenterology & Hepatology of “endogenous ethanol production in health and disease.”
And in recent decades, he said at the meeting, research has linked endogenous ethanol production to MASLD, positioning it as a potential contributor to disease pathogenesis. In one of the most recently published studies, patients with MASLD had higher concentrations of ethanol in their systemic circulation after a mixed meal test than did healthy controls — and even higher ethanol concentrations in their portal vein blood, “suggesting that this ethanol is coming from the gut microbiome,” Schnabl said.
The paper from China that led Schnabl to establish his cohort was spurred on by a patient with both ABS and MASLD cirrhosis. The patient was found to have strains of high alcohol–producing K pneumoniae in the gut microbiome. When the researchers transplanted these strains into mice via fecal microbiota transplantation (FMT), the mice developed MASLD.
Schnabl’s study focused just on ABS, which is alternatively sometimes called gut fermentation syndrome. The 22 patients in his ABS cohort — each of whom provided stool samples corresponding to remission or flare of ABS symptoms — had a median age of 45 years and were predominantly men, slightly overweight and not obese, and without liver disease. (About 48 patients with suspected ABS were screened, and 20 were excluded after an observed glucose challenge failed to establish a diagnosis; 6 withdrew from the study.)
During remission (no symptoms), patients’ mean blood alcohol content (BAC) level was zero, but during a flare, the mean BAC level was 136 mg/dL. “To put it into perspective, the legal limit for driving in the US is 80 mg/dL,” Schnabl said. Within a mean of 4 hours after the oral glucose load used for diagnosis, patients’ mean BAC level was 73 mg/dL, he noted.
To assess ethanol production by the patients’ microbiota, Schnabl and his team cultured the stool samples — anaerobically adding glucose and measuring ethanol production — and compared the results with findings from stool samples collected from household partners who generally were of the opposite sex. Among their findings: cultures of stool from patients experiencing a flare produced significantly more ethanol than stool from household partners and samples from patients in remission.
To assess whether ethanol was produced by bacteria or fungi, the researchers measured ethanol production in cultures treated with either the antifungal amphotericin B or the antibiotic chloramphenicol. “Chloramphenicol clearly decreased the ethanol production,” Schnabl said. “So at least in this culture test, bacteria produced most of the alcohol in our patients.”
Taxonomic profiling, moreover, revealed “significantly elevated levels” of proteobacteria — with relative abundance of Escherichia coli and K pneumoniae — in patients who were flaring, he said. And functional profiling of the fecal microbiota showed much higher activity of fermentation pathways during patients’ flares than in household partners or healthy controls. (Healthy controls were incorporated into the taxonomic and functional profiling parts of the research.)
A Clinical Approach to ABS
Schnabl said at the meeting that stool cultures of both household partners and patients in long-term remission “all produced some low amount of ethanol, which was initially puzzling to us” but became less surprising as he and his colleagues reviewed more of the literature.
Asked during a discussion period whether ABS could explain chronic fatigue, a commonly reported chronic symptom in populations, Schnabl said it’s possible. And in an interview after the meeting, he elaborated. “The literature clearly says ABS is a rare disease, but I argue that more patients may have ABS; they just don’t know it. And I suspect some may have mild symptoms, like brain fog, feeling tired,” he said. “But at this point, this is complete speculation.”
Physicians should “be aware that if a patient has unexplained symptoms that could be aligned with ABS, checking the blood alcohol level” may be warranted, he said in the interview. A PEth (phosphatidylethanol) test — a biomarker test used to check for longer-term alcohol consumption — is an option, but it is important to appreciate it will not discriminate between exogenous alcohol drinking and endogenous ethanol production.
There are no standardized diagnostic tests for ABS, but at the meeting, Schnabl outlined a clinical approach, starting with a standardized oral glucose tolerance challenge test to detect elevated ethanol concentrations.
A fecal yeast test is warranted for diagnosed patients on the basis of some case reports in which ABS symptoms have improved with antifungal treatments. When the fecal yeast test is negative, “ideally you want to identify the ethanol-producing intestinal bacteria in the patient,” he said, using cultures and fecal metagenomics sequencing.
Treatment could then be tailored to the identified microbial strain, with options being selective antibiotics, probiotics and/or prebiotics, and — likely in the future — phages or FMT, he said. (These options, all aimed at restoring gut homeostasis, are also discussed in his 2024 review.)
Schnabl and his team recently performed FMT in a patient with ABS in whom E coli was determined to be producing excessive ethanol. The FMT, performed after antibiotic pretreatment, resulted in decreases in the relative abundance of proteobacteria and E coli levels, lower blood alcohol levels and fermentation enrichment pathways, and normalized liver enzymes.
After 6 months, however, the patient relapsed, and the measurements reversed. “We decided to do FMT every month, and we treated the patient for 6 months,” Schnabl said, noting that ABS had rendered the patient dysfunctional and unable to work. “He has been out of treatment for over a year now and is not flaring any longer.”
Schnabl and Elizabeth Hohmann, MD, at Massachusetts General Hospital, Boston, are currently recruiting patients with confirmed ABS for a National Institutes of Health–funded phase 1 safety and tolerability study of FMT for ABS.
Schnabl disclosed serving as an external scientific advisor/consultant to Ambys Medicines, Boehringer Ingelheim, Gelesis, Mabwell Therapeutics, Surrozen, and Takeda; and as the founder/BOD/BEO of Nterica Bio.
A version of this article appeared on Medscape.com.
WASHINGTON — When a published case of auto-brewery syndrome (ABS) in China — caused by Klebsiella pneumoniae — received widespread publicity in 2019, patients reacted, sending emails to lead author Jing Yuan, in Beijing, China. Many of these inquiries were from patients in the United States who believed they might have ABS.
“Can you check to see if I have ABS?” patients asked Yuan.
For help, Yuan contacted Bernd Schnabl, MD, AGAF, at the University of California, San Diego, whose research was addressing alcohol-associated liver disease and who was also interested in the gut-liver axis and the role of gut microbiome–derived ethanol in metabolic dysfunction–associated steatotic liver disease (MASLD).
“She asked me, ‘Are you interested in looking into ABS?” Schnabl recalled at the Gut Microbiota for Health (GMFH) World Summit 2025. He dug in and formed what may be the largest research cohort thus far of patients with ABS — a group of 22 patients with their diagnosis confirmed through observed glucose challenge.
His soon-to-be-published
ABS is considered a rare condition, but “I’d argue that it’s rarely diagnosed because many physicians don’t know of the diagnosis, and many are actually very skeptical about the disease,” Schnabl said at the meeting, convened by AGA and the European Society of Neurogastroenterology and Motility.
Patients experience symptoms of intoxication when ethanol produced by dysregulated gut microbiota exceeds the capacity of the liver to metabolize it and accumulates in the blood, he explained.
“Patients constantly talk about brain fog; they can’t concentrate, and it can be very severe,” he said. “They don’t get a firm diagnosis and go from one medical center to another, and they also suffer from complications of alcohol use disorder including serious family, social, and legal problems.”
Advancing Knowledge, Findings From the Cohort
The phenomenon of ethanol production by gut microbiota has been known for over a century, Schnabl wrote with two co-authors in a 2024 review in Nature Reviews Gastroenterology & Hepatology of “endogenous ethanol production in health and disease.”
And in recent decades, he said at the meeting, research has linked endogenous ethanol production to MASLD, positioning it as a potential contributor to disease pathogenesis. In one of the most recently published studies, patients with MASLD had higher concentrations of ethanol in their systemic circulation after a mixed meal test than did healthy controls — and even higher ethanol concentrations in their portal vein blood, “suggesting that this ethanol is coming from the gut microbiome,” Schnabl said.
The paper from China that led Schnabl to establish his cohort was spurred on by a patient with both ABS and MASLD cirrhosis. The patient was found to have strains of high alcohol–producing K pneumoniae in the gut microbiome. When the researchers transplanted these strains into mice via fecal microbiota transplantation (FMT), the mice developed MASLD.
Schnabl’s study focused just on ABS, which is alternatively sometimes called gut fermentation syndrome. The 22 patients in his ABS cohort — each of whom provided stool samples corresponding to remission or flare of ABS symptoms — had a median age of 45 years and were predominantly men, slightly overweight and not obese, and without liver disease. (About 48 patients with suspected ABS were screened, and 20 were excluded after an observed glucose challenge failed to establish a diagnosis; 6 withdrew from the study.)
During remission (no symptoms), patients’ mean blood alcohol content (BAC) level was zero, but during a flare, the mean BAC level was 136 mg/dL. “To put it into perspective, the legal limit for driving in the US is 80 mg/dL,” Schnabl said. Within a mean of 4 hours after the oral glucose load used for diagnosis, patients’ mean BAC level was 73 mg/dL, he noted.
To assess ethanol production by the patients’ microbiota, Schnabl and his team cultured the stool samples — anaerobically adding glucose and measuring ethanol production — and compared the results with findings from stool samples collected from household partners who generally were of the opposite sex. Among their findings: cultures of stool from patients experiencing a flare produced significantly more ethanol than stool from household partners and samples from patients in remission.
To assess whether ethanol was produced by bacteria or fungi, the researchers measured ethanol production in cultures treated with either the antifungal amphotericin B or the antibiotic chloramphenicol. “Chloramphenicol clearly decreased the ethanol production,” Schnabl said. “So at least in this culture test, bacteria produced most of the alcohol in our patients.”
Taxonomic profiling, moreover, revealed “significantly elevated levels” of proteobacteria — with relative abundance of Escherichia coli and K pneumoniae — in patients who were flaring, he said. And functional profiling of the fecal microbiota showed much higher activity of fermentation pathways during patients’ flares than in household partners or healthy controls. (Healthy controls were incorporated into the taxonomic and functional profiling parts of the research.)
A Clinical Approach to ABS
Schnabl said at the meeting that stool cultures of both household partners and patients in long-term remission “all produced some low amount of ethanol, which was initially puzzling to us” but became less surprising as he and his colleagues reviewed more of the literature.
Asked during a discussion period whether ABS could explain chronic fatigue, a commonly reported chronic symptom in populations, Schnabl said it’s possible. And in an interview after the meeting, he elaborated. “The literature clearly says ABS is a rare disease, but I argue that more patients may have ABS; they just don’t know it. And I suspect some may have mild symptoms, like brain fog, feeling tired,” he said. “But at this point, this is complete speculation.”
Physicians should “be aware that if a patient has unexplained symptoms that could be aligned with ABS, checking the blood alcohol level” may be warranted, he said in the interview. A PEth (phosphatidylethanol) test — a biomarker test used to check for longer-term alcohol consumption — is an option, but it is important to appreciate it will not discriminate between exogenous alcohol drinking and endogenous ethanol production.
There are no standardized diagnostic tests for ABS, but at the meeting, Schnabl outlined a clinical approach, starting with a standardized oral glucose tolerance challenge test to detect elevated ethanol concentrations.
A fecal yeast test is warranted for diagnosed patients on the basis of some case reports in which ABS symptoms have improved with antifungal treatments. When the fecal yeast test is negative, “ideally you want to identify the ethanol-producing intestinal bacteria in the patient,” he said, using cultures and fecal metagenomics sequencing.
Treatment could then be tailored to the identified microbial strain, with options being selective antibiotics, probiotics and/or prebiotics, and — likely in the future — phages or FMT, he said. (These options, all aimed at restoring gut homeostasis, are also discussed in his 2024 review.)
Schnabl and his team recently performed FMT in a patient with ABS in whom E coli was determined to be producing excessive ethanol. The FMT, performed after antibiotic pretreatment, resulted in decreases in the relative abundance of proteobacteria and E coli levels, lower blood alcohol levels and fermentation enrichment pathways, and normalized liver enzymes.
After 6 months, however, the patient relapsed, and the measurements reversed. “We decided to do FMT every month, and we treated the patient for 6 months,” Schnabl said, noting that ABS had rendered the patient dysfunctional and unable to work. “He has been out of treatment for over a year now and is not flaring any longer.”
Schnabl and Elizabeth Hohmann, MD, at Massachusetts General Hospital, Boston, are currently recruiting patients with confirmed ABS for a National Institutes of Health–funded phase 1 safety and tolerability study of FMT for ABS.
Schnabl disclosed serving as an external scientific advisor/consultant to Ambys Medicines, Boehringer Ingelheim, Gelesis, Mabwell Therapeutics, Surrozen, and Takeda; and as the founder/BOD/BEO of Nterica Bio.
A version of this article appeared on Medscape.com.
FROM GMFH 2025
Early Warning Signs: Catching Gastric Cancer in Time
Hello. I’m Dr. David Johnson, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School and Old Dominion University in Norfolk, Virginia.
The American College of Gastroenterology (ACG) recently issued a clinical guideline on the diagnosis and management of gastric premalignant conditions.
Coincidentally, earlier this year, the ACG and the American Society for Gastrointestinal Endoscopy (ASGE) collaborated to issue recommendations on quality indicators for upper endoscopy.
In this overview, I’ll focus on gastric premalignant conditions while drawing upon some of the quality indicators from ACG/ASGE. Together, these publications highlight several things that we may be overlooking and clearly need to do better at addressing, given the emerging data in this area.
Gastric Premalignant Conditions: Increased Risk for Progression
Gastric premalignant conditions are common and include atrophic gastritis, gastric intestinal metaplasia, dysplasia, and certain gastric epithelial polyps.
The increased risk for progression to gastric adenocarcinoma in the United States is quite striking. It also reveals an important cancer disparity in certain high-risk groups.
The incidence rates of gastric cancer are two- to 13-fold greater in non-White individuals, particularly among immigrants from high-risk areas. The rates exceed those for esophageal cancer and approach those for colorectal cancer. We have had a dramatic oversight in recognizing the risk for gastric carcinoma in underserved areas.
Gastric carcinoma is not a good diagnosis. The 5-year survival rate is 36%. Approximately 40% of cases are metastatic at the time of diagnosis; only about 15% are caught at a curable early stage.
These rates are in far contrast to Asia and areas that do programmatic screening, where the numbers are dramatically reduced. However, in the United States, we’re simply not there yet.
Endoscopic Evaluation
There are three phases of endoscopic evaluation for gastric premalignant conditions on which I’d like to focus: pre-endoscopy, intra-endoscopy, and post-endoscopy.
Pre-endoscopy — that is, before you even put in the endoscope — it’s important to assess patients’ potential risk for certain conditions, regardless of the reason for performing the endoscopy.
Gastric carcinoma is in the top eight leading causes of cancer death in the United States, with the risk being particularly high in Hispanics and Asians.
According to 2020 data, 40 million people living in the United States were born in another country, with over 70% coming from areas that have a high incidence of gastric carcinoma.
Accounting for the increased risk in these groups will become even more important. By 2065, it is projected that Asian and Hispanic individuals — the immigrant groups with the highest risk for gastric cancer — will comprise 70% of the US population. Therefore, we need to do a better job on pre-endoscopic assessment if we want to address this major cancer disparity in the United States.
However, it’s a potentially fixable problem because, in most cases, gastric carcinoma is preceded by a typical asymptomatic precancerous cascade known as the “Correa’s cascade.” It is analogous to what we see in Barrett’s esophagus or even in colorectal neoplasia as it evolves.
This histologic cascade is important to recognize in patients before they get to the stage of progression. Doing so is highly dependent on the assessment prior to the endoscopy.
You should also be thinking about high-risk groups before a pre-endoscopy evaluation.
During intra-endoscopy, it’s important to plan your actions while performing the procedure, even if you are not specifically screening for gastric carcinoma. We must be held accountable to established recommendations, standards, and best practices for accurately defining observations, determining appropriate actions, and effectively implementing screening protocols.
A high-quality evaluation of the gastric mucosa is critically important, as an estimated 5%-11% of neoplastic lesions are missed on upper endoscopy completed within 3 years of a gastric cancer diagnosis. With less-experienced endoscopists, the rate of missed neoplastic lesions may be as high as 25%.
A quality endoscopy begins (as it would in the colon) with mucosal cleaning. This may not be achieved by water alone and requires the use of mucolytic and defoaming agents, such as simethicone or N-acetylcysteine, which can be inordinately helpful.
Complete mucosal evaluation entails using insufflation to adequately distend the gastric folds.
Atrophic gastritis is observed in a high percentage of patients, and I’m always on the lookout for it when performing endoscopies. One way to identify atrophic gastritis is to look for the loss of gastric folds, which has an approximate sensitivity of 67% and specificity of 85%. The increased visibility of the submucosal venules is another sign of atrophic gastritis, although its sensitivity and specificity are relatively lower at 48% and 87%, respectively.
Full photo documentation of the gastric mucosa should be included. It is an important part of the intra-endoscopy procedure and also is mentioned as part of the recently published quality indicators for upper endoscopy from ACG/ASGE.
Recognizing which patients require a biopsy is important. Appropriate biopsy samples should be obtained in patients with recognizable abnormalities. We’re often looking for changes that may be quite subtle. Dysplasia and even adenocarcinoma in the stomach sometimes just cannot be appreciated based on pure endoscopic evaluation.
When it comes to the biopsy protocol, the recommendation is to follow the Sydney system, which was developed in the 1990s. Simply put, this protocol calls for the biopsy samples to be obtained and placed in two separate jars. You look at the greater and lesser curvature of the antrum and the incisura (jar one), and the greater and lesser curvature of the corpus (jar two) in any identified incidental focused biopsy. This is what we do in the colon and the esophagus.
You should do this after you appropriately clean the mucosa and distend the gastric lumen, ideally using CO2, to avoid the retention of gas.
Time is another important quality measure. This is similar to the colon, where we see that withdrawal times have increased from 6 minutes to 8-9 minutes. In the stomach, there were initial data about a minimum of 2-3 minutes. However, more recent data in the ACG guideline and the ACG/ASGE quality indicators indicate that detection rates increase after mucosal clearance and dissension when the gastric evaluation is 6-7 minutes. These are numbers we need to pay attention to. The ACG guideline notes that a 2- to 3-minute withdrawal time for upper endoscopy is substandard and not acceptable. If you’re still at that level, then you’re below the standard of care.
Again, consider time and photo documentation while examining four to six specific areas of both the greater and lesser curvature of the antrum and corpus, and the incisura angularis. It is ideal to use high-definition endoscopy along with the available virtual imaging enhancers. This is the basic requirement for achieving high-quality assessments.
When it comes to post-endoscopy, it’s essential to talk to your pathologist about using validated instruments of reporting what gastric precancerous lesions involve. There are two different systems: the Operative Link for Gastritis Assessment (OLGA) and the Operative Link on Gastric Intestinal Metaplasia (OLGIM). Although not routinely used in the United States, they are the best recommendations we have for validated histologic scoring systems.
Your pathologist needs to be up to speed on understanding how to report the extent of intestinal metaplasia (complete, incomplete, and mixed) and identifying the areas of focality or abnormalities. It defines what the subsequent surveillance recommendations should be.
Know What’s Required
Let’s review what’s required when it comes to diagnosing and managing gastric premalignant conditions.
First, pre-endoscopy must involve the assessment of risk. Before we put in the endoscope, it’s critical to know, regardless of why the patient is there, who needs to be assessed for gastric premalignant conditions.
Second, during the intra-endoscopy phase, don’t forget the assessments and documentation. If you’re assessing for gastric intestinal metaplasia, use the Sydney system.
Time is a big component. Withdrawal times are discussed much more frequently now, with the takeaway being that longer is better. Aiming for 6-7 minutes is best, according to recommendations from international endoscopy societies and quality measures from the United States. The ACG guideline says that withdrawal times of 2-3 minutes are not best practice and fall short of standard of care.
For post-endoscopy, talk to your pathologist to ensure better communication and understanding. Make sure that you have a quality gastrointestinal pathologist interpreting these lesions so patients can either enter surveillance or discontinue surveillance after potentially two exams negative for evidence of progressive change.
To do better, we need to understand these guidelines, which are all applicable now.
I’m Dr. David Johnson. Thanks for listening. See you next time.
David A. Johnson, MD, a regular contributor to Medscape, is professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia, and a past president of the American College of Gastroenterology. His primary focus is the clinical practice of gastroenterology. He has published extensively in the internal medicine/gastroenterology literature, with principal research interests in esophageal and colon disease, and more recently in sleep and microbiome effects on gastrointestinal health and disease.
He has disclosed the relevant financial relationships: Advisor to ISOTHRIVE.
A version of this article first appeared on Medscape.com.
Hello. I’m Dr. David Johnson, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School and Old Dominion University in Norfolk, Virginia.
The American College of Gastroenterology (ACG) recently issued a clinical guideline on the diagnosis and management of gastric premalignant conditions.
Coincidentally, earlier this year, the ACG and the American Society for Gastrointestinal Endoscopy (ASGE) collaborated to issue recommendations on quality indicators for upper endoscopy.
In this overview, I’ll focus on gastric premalignant conditions while drawing upon some of the quality indicators from ACG/ASGE. Together, these publications highlight several things that we may be overlooking and clearly need to do better at addressing, given the emerging data in this area.
Gastric Premalignant Conditions: Increased Risk for Progression
Gastric premalignant conditions are common and include atrophic gastritis, gastric intestinal metaplasia, dysplasia, and certain gastric epithelial polyps.
The increased risk for progression to gastric adenocarcinoma in the United States is quite striking. It also reveals an important cancer disparity in certain high-risk groups.
The incidence rates of gastric cancer are two- to 13-fold greater in non-White individuals, particularly among immigrants from high-risk areas. The rates exceed those for esophageal cancer and approach those for colorectal cancer. We have had a dramatic oversight in recognizing the risk for gastric carcinoma in underserved areas.
Gastric carcinoma is not a good diagnosis. The 5-year survival rate is 36%. Approximately 40% of cases are metastatic at the time of diagnosis; only about 15% are caught at a curable early stage.
These rates are in far contrast to Asia and areas that do programmatic screening, where the numbers are dramatically reduced. However, in the United States, we’re simply not there yet.
Endoscopic Evaluation
There are three phases of endoscopic evaluation for gastric premalignant conditions on which I’d like to focus: pre-endoscopy, intra-endoscopy, and post-endoscopy.
Pre-endoscopy — that is, before you even put in the endoscope — it’s important to assess patients’ potential risk for certain conditions, regardless of the reason for performing the endoscopy.
Gastric carcinoma is in the top eight leading causes of cancer death in the United States, with the risk being particularly high in Hispanics and Asians.
According to 2020 data, 40 million people living in the United States were born in another country, with over 70% coming from areas that have a high incidence of gastric carcinoma.
Accounting for the increased risk in these groups will become even more important. By 2065, it is projected that Asian and Hispanic individuals — the immigrant groups with the highest risk for gastric cancer — will comprise 70% of the US population. Therefore, we need to do a better job on pre-endoscopic assessment if we want to address this major cancer disparity in the United States.
However, it’s a potentially fixable problem because, in most cases, gastric carcinoma is preceded by a typical asymptomatic precancerous cascade known as the “Correa’s cascade.” It is analogous to what we see in Barrett’s esophagus or even in colorectal neoplasia as it evolves.
This histologic cascade is important to recognize in patients before they get to the stage of progression. Doing so is highly dependent on the assessment prior to the endoscopy.
You should also be thinking about high-risk groups before a pre-endoscopy evaluation.
During intra-endoscopy, it’s important to plan your actions while performing the procedure, even if you are not specifically screening for gastric carcinoma. We must be held accountable to established recommendations, standards, and best practices for accurately defining observations, determining appropriate actions, and effectively implementing screening protocols.
A high-quality evaluation of the gastric mucosa is critically important, as an estimated 5%-11% of neoplastic lesions are missed on upper endoscopy completed within 3 years of a gastric cancer diagnosis. With less-experienced endoscopists, the rate of missed neoplastic lesions may be as high as 25%.
A quality endoscopy begins (as it would in the colon) with mucosal cleaning. This may not be achieved by water alone and requires the use of mucolytic and defoaming agents, such as simethicone or N-acetylcysteine, which can be inordinately helpful.
Complete mucosal evaluation entails using insufflation to adequately distend the gastric folds.
Atrophic gastritis is observed in a high percentage of patients, and I’m always on the lookout for it when performing endoscopies. One way to identify atrophic gastritis is to look for the loss of gastric folds, which has an approximate sensitivity of 67% and specificity of 85%. The increased visibility of the submucosal venules is another sign of atrophic gastritis, although its sensitivity and specificity are relatively lower at 48% and 87%, respectively.
Full photo documentation of the gastric mucosa should be included. It is an important part of the intra-endoscopy procedure and also is mentioned as part of the recently published quality indicators for upper endoscopy from ACG/ASGE.
Recognizing which patients require a biopsy is important. Appropriate biopsy samples should be obtained in patients with recognizable abnormalities. We’re often looking for changes that may be quite subtle. Dysplasia and even adenocarcinoma in the stomach sometimes just cannot be appreciated based on pure endoscopic evaluation.
When it comes to the biopsy protocol, the recommendation is to follow the Sydney system, which was developed in the 1990s. Simply put, this protocol calls for the biopsy samples to be obtained and placed in two separate jars. You look at the greater and lesser curvature of the antrum and the incisura (jar one), and the greater and lesser curvature of the corpus (jar two) in any identified incidental focused biopsy. This is what we do in the colon and the esophagus.
You should do this after you appropriately clean the mucosa and distend the gastric lumen, ideally using CO2, to avoid the retention of gas.
Time is another important quality measure. This is similar to the colon, where we see that withdrawal times have increased from 6 minutes to 8-9 minutes. In the stomach, there were initial data about a minimum of 2-3 minutes. However, more recent data in the ACG guideline and the ACG/ASGE quality indicators indicate that detection rates increase after mucosal clearance and dissension when the gastric evaluation is 6-7 minutes. These are numbers we need to pay attention to. The ACG guideline notes that a 2- to 3-minute withdrawal time for upper endoscopy is substandard and not acceptable. If you’re still at that level, then you’re below the standard of care.
Again, consider time and photo documentation while examining four to six specific areas of both the greater and lesser curvature of the antrum and corpus, and the incisura angularis. It is ideal to use high-definition endoscopy along with the available virtual imaging enhancers. This is the basic requirement for achieving high-quality assessments.
When it comes to post-endoscopy, it’s essential to talk to your pathologist about using validated instruments of reporting what gastric precancerous lesions involve. There are two different systems: the Operative Link for Gastritis Assessment (OLGA) and the Operative Link on Gastric Intestinal Metaplasia (OLGIM). Although not routinely used in the United States, they are the best recommendations we have for validated histologic scoring systems.
Your pathologist needs to be up to speed on understanding how to report the extent of intestinal metaplasia (complete, incomplete, and mixed) and identifying the areas of focality or abnormalities. It defines what the subsequent surveillance recommendations should be.
Know What’s Required
Let’s review what’s required when it comes to diagnosing and managing gastric premalignant conditions.
First, pre-endoscopy must involve the assessment of risk. Before we put in the endoscope, it’s critical to know, regardless of why the patient is there, who needs to be assessed for gastric premalignant conditions.
Second, during the intra-endoscopy phase, don’t forget the assessments and documentation. If you’re assessing for gastric intestinal metaplasia, use the Sydney system.
Time is a big component. Withdrawal times are discussed much more frequently now, with the takeaway being that longer is better. Aiming for 6-7 minutes is best, according to recommendations from international endoscopy societies and quality measures from the United States. The ACG guideline says that withdrawal times of 2-3 minutes are not best practice and fall short of standard of care.
For post-endoscopy, talk to your pathologist to ensure better communication and understanding. Make sure that you have a quality gastrointestinal pathologist interpreting these lesions so patients can either enter surveillance or discontinue surveillance after potentially two exams negative for evidence of progressive change.
To do better, we need to understand these guidelines, which are all applicable now.
I’m Dr. David Johnson. Thanks for listening. See you next time.
David A. Johnson, MD, a regular contributor to Medscape, is professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia, and a past president of the American College of Gastroenterology. His primary focus is the clinical practice of gastroenterology. He has published extensively in the internal medicine/gastroenterology literature, with principal research interests in esophageal and colon disease, and more recently in sleep and microbiome effects on gastrointestinal health and disease.
He has disclosed the relevant financial relationships: Advisor to ISOTHRIVE.
A version of this article first appeared on Medscape.com.
Hello. I’m Dr. David Johnson, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School and Old Dominion University in Norfolk, Virginia.
The American College of Gastroenterology (ACG) recently issued a clinical guideline on the diagnosis and management of gastric premalignant conditions.
Coincidentally, earlier this year, the ACG and the American Society for Gastrointestinal Endoscopy (ASGE) collaborated to issue recommendations on quality indicators for upper endoscopy.
In this overview, I’ll focus on gastric premalignant conditions while drawing upon some of the quality indicators from ACG/ASGE. Together, these publications highlight several things that we may be overlooking and clearly need to do better at addressing, given the emerging data in this area.
Gastric Premalignant Conditions: Increased Risk for Progression
Gastric premalignant conditions are common and include atrophic gastritis, gastric intestinal metaplasia, dysplasia, and certain gastric epithelial polyps.
The increased risk for progression to gastric adenocarcinoma in the United States is quite striking. It also reveals an important cancer disparity in certain high-risk groups.
The incidence rates of gastric cancer are two- to 13-fold greater in non-White individuals, particularly among immigrants from high-risk areas. The rates exceed those for esophageal cancer and approach those for colorectal cancer. We have had a dramatic oversight in recognizing the risk for gastric carcinoma in underserved areas.
Gastric carcinoma is not a good diagnosis. The 5-year survival rate is 36%. Approximately 40% of cases are metastatic at the time of diagnosis; only about 15% are caught at a curable early stage.
These rates are in far contrast to Asia and areas that do programmatic screening, where the numbers are dramatically reduced. However, in the United States, we’re simply not there yet.
Endoscopic Evaluation
There are three phases of endoscopic evaluation for gastric premalignant conditions on which I’d like to focus: pre-endoscopy, intra-endoscopy, and post-endoscopy.
Pre-endoscopy — that is, before you even put in the endoscope — it’s important to assess patients’ potential risk for certain conditions, regardless of the reason for performing the endoscopy.
Gastric carcinoma is in the top eight leading causes of cancer death in the United States, with the risk being particularly high in Hispanics and Asians.
According to 2020 data, 40 million people living in the United States were born in another country, with over 70% coming from areas that have a high incidence of gastric carcinoma.
Accounting for the increased risk in these groups will become even more important. By 2065, it is projected that Asian and Hispanic individuals — the immigrant groups with the highest risk for gastric cancer — will comprise 70% of the US population. Therefore, we need to do a better job on pre-endoscopic assessment if we want to address this major cancer disparity in the United States.
However, it’s a potentially fixable problem because, in most cases, gastric carcinoma is preceded by a typical asymptomatic precancerous cascade known as the “Correa’s cascade.” It is analogous to what we see in Barrett’s esophagus or even in colorectal neoplasia as it evolves.
This histologic cascade is important to recognize in patients before they get to the stage of progression. Doing so is highly dependent on the assessment prior to the endoscopy.
You should also be thinking about high-risk groups before a pre-endoscopy evaluation.
During intra-endoscopy, it’s important to plan your actions while performing the procedure, even if you are not specifically screening for gastric carcinoma. We must be held accountable to established recommendations, standards, and best practices for accurately defining observations, determining appropriate actions, and effectively implementing screening protocols.
A high-quality evaluation of the gastric mucosa is critically important, as an estimated 5%-11% of neoplastic lesions are missed on upper endoscopy completed within 3 years of a gastric cancer diagnosis. With less-experienced endoscopists, the rate of missed neoplastic lesions may be as high as 25%.
A quality endoscopy begins (as it would in the colon) with mucosal cleaning. This may not be achieved by water alone and requires the use of mucolytic and defoaming agents, such as simethicone or N-acetylcysteine, which can be inordinately helpful.
Complete mucosal evaluation entails using insufflation to adequately distend the gastric folds.
Atrophic gastritis is observed in a high percentage of patients, and I’m always on the lookout for it when performing endoscopies. One way to identify atrophic gastritis is to look for the loss of gastric folds, which has an approximate sensitivity of 67% and specificity of 85%. The increased visibility of the submucosal venules is another sign of atrophic gastritis, although its sensitivity and specificity are relatively lower at 48% and 87%, respectively.
Full photo documentation of the gastric mucosa should be included. It is an important part of the intra-endoscopy procedure and also is mentioned as part of the recently published quality indicators for upper endoscopy from ACG/ASGE.
Recognizing which patients require a biopsy is important. Appropriate biopsy samples should be obtained in patients with recognizable abnormalities. We’re often looking for changes that may be quite subtle. Dysplasia and even adenocarcinoma in the stomach sometimes just cannot be appreciated based on pure endoscopic evaluation.
When it comes to the biopsy protocol, the recommendation is to follow the Sydney system, which was developed in the 1990s. Simply put, this protocol calls for the biopsy samples to be obtained and placed in two separate jars. You look at the greater and lesser curvature of the antrum and the incisura (jar one), and the greater and lesser curvature of the corpus (jar two) in any identified incidental focused biopsy. This is what we do in the colon and the esophagus.
You should do this after you appropriately clean the mucosa and distend the gastric lumen, ideally using CO2, to avoid the retention of gas.
Time is another important quality measure. This is similar to the colon, where we see that withdrawal times have increased from 6 minutes to 8-9 minutes. In the stomach, there were initial data about a minimum of 2-3 minutes. However, more recent data in the ACG guideline and the ACG/ASGE quality indicators indicate that detection rates increase after mucosal clearance and dissension when the gastric evaluation is 6-7 minutes. These are numbers we need to pay attention to. The ACG guideline notes that a 2- to 3-minute withdrawal time for upper endoscopy is substandard and not acceptable. If you’re still at that level, then you’re below the standard of care.
Again, consider time and photo documentation while examining four to six specific areas of both the greater and lesser curvature of the antrum and corpus, and the incisura angularis. It is ideal to use high-definition endoscopy along with the available virtual imaging enhancers. This is the basic requirement for achieving high-quality assessments.
When it comes to post-endoscopy, it’s essential to talk to your pathologist about using validated instruments of reporting what gastric precancerous lesions involve. There are two different systems: the Operative Link for Gastritis Assessment (OLGA) and the Operative Link on Gastric Intestinal Metaplasia (OLGIM). Although not routinely used in the United States, they are the best recommendations we have for validated histologic scoring systems.
Your pathologist needs to be up to speed on understanding how to report the extent of intestinal metaplasia (complete, incomplete, and mixed) and identifying the areas of focality or abnormalities. It defines what the subsequent surveillance recommendations should be.
Know What’s Required
Let’s review what’s required when it comes to diagnosing and managing gastric premalignant conditions.
First, pre-endoscopy must involve the assessment of risk. Before we put in the endoscope, it’s critical to know, regardless of why the patient is there, who needs to be assessed for gastric premalignant conditions.
Second, during the intra-endoscopy phase, don’t forget the assessments and documentation. If you’re assessing for gastric intestinal metaplasia, use the Sydney system.
Time is a big component. Withdrawal times are discussed much more frequently now, with the takeaway being that longer is better. Aiming for 6-7 minutes is best, according to recommendations from international endoscopy societies and quality measures from the United States. The ACG guideline says that withdrawal times of 2-3 minutes are not best practice and fall short of standard of care.
For post-endoscopy, talk to your pathologist to ensure better communication and understanding. Make sure that you have a quality gastrointestinal pathologist interpreting these lesions so patients can either enter surveillance or discontinue surveillance after potentially two exams negative for evidence of progressive change.
To do better, we need to understand these guidelines, which are all applicable now.
I’m Dr. David Johnson. Thanks for listening. See you next time.
David A. Johnson, MD, a regular contributor to Medscape, is professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia, and a past president of the American College of Gastroenterology. His primary focus is the clinical practice of gastroenterology. He has published extensively in the internal medicine/gastroenterology literature, with principal research interests in esophageal and colon disease, and more recently in sleep and microbiome effects on gastrointestinal health and disease.
He has disclosed the relevant financial relationships: Advisor to ISOTHRIVE.
A version of this article first appeared on Medscape.com.
Can a Polygenic Risk Score Turn the Tide on Prostate Cancer Screening?
Incorporating a polygenic risk score into prostate cancer screening could enhance the detection of clinically significant prostate cancer that conventional screening may miss, according to results of the BARCODE 1 clinical trial conducted in the United Kingdom.
The study found that about 72% of participants with high polygenic risk scores were diagnosed with clinically significant prostate cancers, which would not have been detected with prostate-specific antigen (PSA) testing or MRI.
“With this test, it could be possible to turn the tide on prostate cancer,” study author Ros Eeles, PhD, professor of oncogenetics at The Institute of Cancer Research, London, England, said in a statement following the publication of the analysis in The New England Journal of Medicine.
Prostate cancer remains the second most commonly diagnosed cancer among men. As a screening tool, PSA testing has been criticized for leading to a high rate of false positive results and overdiagnosis — defined as a screen-detected cancer that would take longer to progress to clinical cancer than the patient’s lifetime. Both issues can result in overtreatment.
Given prostate cancer’s high heritability and the proliferation of genome-wide association studies identifying common genetic variants, there has been growing interest in using polygenic risk scores to improve risk stratification and guide screening.
“Building on decades of research into the genetic markers of prostate cancer, our study shows that the theory does work in practice — we can identify men at risk of aggressive cancers who need further tests and spare the men who are at lower risk from unnecessary treatments,” said Eeles.
An Adjunct to Screening?
The BARCODE 1 study, conducted in the United Kingdom, tested the clinical utility of a polygenic risk score as an adjunct to screening.
The researchers recruited men aged 55-69 years from primary care centers in the United Kingdom. Using germline DNA extracted from saliva, they derived polygenic risk scores from 130 genetic variants known to be associated with an increased risk for prostate cancer.
Among a total of 6393 men who had their scores calculated, 745 (12%) had a score in the top 10% of genetic risk (≥ 90th percentile) and were invited to undergo further screening.
Of these, 468 (63%) accepted the invite and underwent multiparametric MRI and transperineal prostate biopsy, irrespective of the PSA level. Overall, 187 (40%) were diagnosed with prostate cancer following biopsy. Of the 187 men with prostate cancer, 55% (n = 103) had disease classified as intermediate or high risk (Gleason score ≥ 7) per National Comprehensive Cancer Network criteria and therefore warranted further treatment.
Researchers then compared screening that incorporated polygenic risk scores with standard screening with PSA levels and MRI.
When participants’ risk was stratified by their polygenic risk score, 103 patients (55%) with prostate cancer could be classified as intermediate or higher risk, thus warranting treatment. Overall, 74 (71.8%) of those cancers would have been missed using the standard diagnostic pathway in the United Kingdom, which requires patients to have a high PSA level (> 3.0 μg/L) as well as a positive MRI result. These 74 patients either had PSA levels ≤ 3.0 μg/L or negative MRIs, which would mean these patients would typically fall below the action threshold for further testing.
Of the 103 participants warranting treatment, 40 of these men would have been classified as unfavorable intermediate, high, or very high risk, which would require radical treatment. Among this group, roughly 43% would have been missed using the UK diagnostic pathway.
However, the investigators estimated a rate of overdiagnosis with the use of polygenic risk scores of 16%-21%, similar to the overdiagnosis estimates in two prior PSA-based screening studies, signaling that the addition of polygenic risk scores does not necessarily reduce the risk for overdiagnosis.
Overall, “this study is the strongest evidence to date on the clinical utility of a polygenic score for prostate cancer screening,” commented Michael Inouye, professor of systems genomics & population health, University of Cambridge, Cambridge, England, in a statement from the UK nonprofit Science Media Centre (SMC).
“I suspect we will look back on this as a landmark study that really made the clinical case for polygenic scores as a new tool that moved health systems from disease management to early detection and prevention,” said Inouye, who was not involved in the study.
However, other experts were more cautious about the findings.
Dusko Ilic, MD, professor of stem cell sciences, King’s College London, London, England, said the results are “promising, especially in identifying significant cancers that would otherwise be missed,” but cautioned that “there is no direct evidence yet that using [polygenic risk scores] improves long-term outcomes such as mortality or quality-adjusted life years.”
“Modeling suggests benefit, but empirical confirmation is needed,” Ilic said in the SMC statement.
The hope is that the recently launched TRANSFORM trial will help answer some of these outstanding questions.
The current study suggests that polygenic risk scores for prostate cancer “would be a useful component of a multimodality screening program that assesses age, family history of prostate cancer, PSA, and MRI results as triage tools before biopsy is recommended,” David Hunter, MPH, ScD, with Harvard T. H. Chan School of Public Health, Boston, and University of Oxford, Oxford, England, wrote in an editorial accompanying the study.
“To make this integrated program a reality, however, changes to infrastructure would be needed to make running and analyzing a regulated genome array as easy as requesting a PSA level or ordering an MRI. Clearly, we are far from that future,” Hunter cautioned.
“A possible first step that would require less infrastructure could be to order a polygenic risk score only for men with a positive PSA result, then use the polygenic risk score to determine who should undergo an MRI, and then use all the information to determine whether biopsy is recommended,” Hunter said.
In his view, the current study is a “first step on a long road to evaluating new components of any disease screening pathway.”
The research received funding from the European Research Council, the Bob Willis Fund, Cancer Research UK, the Peacock Trust, and the National Institute for Health and Care Research Biomedical Research Centre at The Royal Marsden and The Institute of Cancer Research. Disclosures for authors and editorialists are available with the original article. Inouye and Ilic reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
Incorporating a polygenic risk score into prostate cancer screening could enhance the detection of clinically significant prostate cancer that conventional screening may miss, according to results of the BARCODE 1 clinical trial conducted in the United Kingdom.
The study found that about 72% of participants with high polygenic risk scores were diagnosed with clinically significant prostate cancers, which would not have been detected with prostate-specific antigen (PSA) testing or MRI.
“With this test, it could be possible to turn the tide on prostate cancer,” study author Ros Eeles, PhD, professor of oncogenetics at The Institute of Cancer Research, London, England, said in a statement following the publication of the analysis in The New England Journal of Medicine.
Prostate cancer remains the second most commonly diagnosed cancer among men. As a screening tool, PSA testing has been criticized for leading to a high rate of false positive results and overdiagnosis — defined as a screen-detected cancer that would take longer to progress to clinical cancer than the patient’s lifetime. Both issues can result in overtreatment.
Given prostate cancer’s high heritability and the proliferation of genome-wide association studies identifying common genetic variants, there has been growing interest in using polygenic risk scores to improve risk stratification and guide screening.
“Building on decades of research into the genetic markers of prostate cancer, our study shows that the theory does work in practice — we can identify men at risk of aggressive cancers who need further tests and spare the men who are at lower risk from unnecessary treatments,” said Eeles.
An Adjunct to Screening?
The BARCODE 1 study, conducted in the United Kingdom, tested the clinical utility of a polygenic risk score as an adjunct to screening.
The researchers recruited men aged 55-69 years from primary care centers in the United Kingdom. Using germline DNA extracted from saliva, they derived polygenic risk scores from 130 genetic variants known to be associated with an increased risk for prostate cancer.
Among a total of 6393 men who had their scores calculated, 745 (12%) had a score in the top 10% of genetic risk (≥ 90th percentile) and were invited to undergo further screening.
Of these, 468 (63%) accepted the invite and underwent multiparametric MRI and transperineal prostate biopsy, irrespective of the PSA level. Overall, 187 (40%) were diagnosed with prostate cancer following biopsy. Of the 187 men with prostate cancer, 55% (n = 103) had disease classified as intermediate or high risk (Gleason score ≥ 7) per National Comprehensive Cancer Network criteria and therefore warranted further treatment.
Researchers then compared screening that incorporated polygenic risk scores with standard screening with PSA levels and MRI.
When participants’ risk was stratified by their polygenic risk score, 103 patients (55%) with prostate cancer could be classified as intermediate or higher risk, thus warranting treatment. Overall, 74 (71.8%) of those cancers would have been missed using the standard diagnostic pathway in the United Kingdom, which requires patients to have a high PSA level (> 3.0 μg/L) as well as a positive MRI result. These 74 patients either had PSA levels ≤ 3.0 μg/L or negative MRIs, which would mean these patients would typically fall below the action threshold for further testing.
Of the 103 participants warranting treatment, 40 of these men would have been classified as unfavorable intermediate, high, or very high risk, which would require radical treatment. Among this group, roughly 43% would have been missed using the UK diagnostic pathway.
However, the investigators estimated a rate of overdiagnosis with the use of polygenic risk scores of 16%-21%, similar to the overdiagnosis estimates in two prior PSA-based screening studies, signaling that the addition of polygenic risk scores does not necessarily reduce the risk for overdiagnosis.
Overall, “this study is the strongest evidence to date on the clinical utility of a polygenic score for prostate cancer screening,” commented Michael Inouye, professor of systems genomics & population health, University of Cambridge, Cambridge, England, in a statement from the UK nonprofit Science Media Centre (SMC).
“I suspect we will look back on this as a landmark study that really made the clinical case for polygenic scores as a new tool that moved health systems from disease management to early detection and prevention,” said Inouye, who was not involved in the study.
However, other experts were more cautious about the findings.
Dusko Ilic, MD, professor of stem cell sciences, King’s College London, London, England, said the results are “promising, especially in identifying significant cancers that would otherwise be missed,” but cautioned that “there is no direct evidence yet that using [polygenic risk scores] improves long-term outcomes such as mortality or quality-adjusted life years.”
“Modeling suggests benefit, but empirical confirmation is needed,” Ilic said in the SMC statement.
The hope is that the recently launched TRANSFORM trial will help answer some of these outstanding questions.
The current study suggests that polygenic risk scores for prostate cancer “would be a useful component of a multimodality screening program that assesses age, family history of prostate cancer, PSA, and MRI results as triage tools before biopsy is recommended,” David Hunter, MPH, ScD, with Harvard T. H. Chan School of Public Health, Boston, and University of Oxford, Oxford, England, wrote in an editorial accompanying the study.
“To make this integrated program a reality, however, changes to infrastructure would be needed to make running and analyzing a regulated genome array as easy as requesting a PSA level or ordering an MRI. Clearly, we are far from that future,” Hunter cautioned.
“A possible first step that would require less infrastructure could be to order a polygenic risk score only for men with a positive PSA result, then use the polygenic risk score to determine who should undergo an MRI, and then use all the information to determine whether biopsy is recommended,” Hunter said.
In his view, the current study is a “first step on a long road to evaluating new components of any disease screening pathway.”
The research received funding from the European Research Council, the Bob Willis Fund, Cancer Research UK, the Peacock Trust, and the National Institute for Health and Care Research Biomedical Research Centre at The Royal Marsden and The Institute of Cancer Research. Disclosures for authors and editorialists are available with the original article. Inouye and Ilic reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
Incorporating a polygenic risk score into prostate cancer screening could enhance the detection of clinically significant prostate cancer that conventional screening may miss, according to results of the BARCODE 1 clinical trial conducted in the United Kingdom.
The study found that about 72% of participants with high polygenic risk scores were diagnosed with clinically significant prostate cancers, which would not have been detected with prostate-specific antigen (PSA) testing or MRI.
“With this test, it could be possible to turn the tide on prostate cancer,” study author Ros Eeles, PhD, professor of oncogenetics at The Institute of Cancer Research, London, England, said in a statement following the publication of the analysis in The New England Journal of Medicine.
Prostate cancer remains the second most commonly diagnosed cancer among men. As a screening tool, PSA testing has been criticized for leading to a high rate of false positive results and overdiagnosis — defined as a screen-detected cancer that would take longer to progress to clinical cancer than the patient’s lifetime. Both issues can result in overtreatment.
Given prostate cancer’s high heritability and the proliferation of genome-wide association studies identifying common genetic variants, there has been growing interest in using polygenic risk scores to improve risk stratification and guide screening.
“Building on decades of research into the genetic markers of prostate cancer, our study shows that the theory does work in practice — we can identify men at risk of aggressive cancers who need further tests and spare the men who are at lower risk from unnecessary treatments,” said Eeles.
An Adjunct to Screening?
The BARCODE 1 study, conducted in the United Kingdom, tested the clinical utility of a polygenic risk score as an adjunct to screening.
The researchers recruited men aged 55-69 years from primary care centers in the United Kingdom. Using germline DNA extracted from saliva, they derived polygenic risk scores from 130 genetic variants known to be associated with an increased risk for prostate cancer.
Among a total of 6393 men who had their scores calculated, 745 (12%) had a score in the top 10% of genetic risk (≥ 90th percentile) and were invited to undergo further screening.
Of these, 468 (63%) accepted the invite and underwent multiparametric MRI and transperineal prostate biopsy, irrespective of the PSA level. Overall, 187 (40%) were diagnosed with prostate cancer following biopsy. Of the 187 men with prostate cancer, 55% (n = 103) had disease classified as intermediate or high risk (Gleason score ≥ 7) per National Comprehensive Cancer Network criteria and therefore warranted further treatment.
Researchers then compared screening that incorporated polygenic risk scores with standard screening with PSA levels and MRI.
When participants’ risk was stratified by their polygenic risk score, 103 patients (55%) with prostate cancer could be classified as intermediate or higher risk, thus warranting treatment. Overall, 74 (71.8%) of those cancers would have been missed using the standard diagnostic pathway in the United Kingdom, which requires patients to have a high PSA level (> 3.0 μg/L) as well as a positive MRI result. These 74 patients either had PSA levels ≤ 3.0 μg/L or negative MRIs, which would mean these patients would typically fall below the action threshold for further testing.
Of the 103 participants warranting treatment, 40 of these men would have been classified as unfavorable intermediate, high, or very high risk, which would require radical treatment. Among this group, roughly 43% would have been missed using the UK diagnostic pathway.
However, the investigators estimated a rate of overdiagnosis with the use of polygenic risk scores of 16%-21%, similar to the overdiagnosis estimates in two prior PSA-based screening studies, signaling that the addition of polygenic risk scores does not necessarily reduce the risk for overdiagnosis.
Overall, “this study is the strongest evidence to date on the clinical utility of a polygenic score for prostate cancer screening,” commented Michael Inouye, professor of systems genomics & population health, University of Cambridge, Cambridge, England, in a statement from the UK nonprofit Science Media Centre (SMC).
“I suspect we will look back on this as a landmark study that really made the clinical case for polygenic scores as a new tool that moved health systems from disease management to early detection and prevention,” said Inouye, who was not involved in the study.
However, other experts were more cautious about the findings.
Dusko Ilic, MD, professor of stem cell sciences, King’s College London, London, England, said the results are “promising, especially in identifying significant cancers that would otherwise be missed,” but cautioned that “there is no direct evidence yet that using [polygenic risk scores] improves long-term outcomes such as mortality or quality-adjusted life years.”
“Modeling suggests benefit, but empirical confirmation is needed,” Ilic said in the SMC statement.
The hope is that the recently launched TRANSFORM trial will help answer some of these outstanding questions.
The current study suggests that polygenic risk scores for prostate cancer “would be a useful component of a multimodality screening program that assesses age, family history of prostate cancer, PSA, and MRI results as triage tools before biopsy is recommended,” David Hunter, MPH, ScD, with Harvard T. H. Chan School of Public Health, Boston, and University of Oxford, Oxford, England, wrote in an editorial accompanying the study.
“To make this integrated program a reality, however, changes to infrastructure would be needed to make running and analyzing a regulated genome array as easy as requesting a PSA level or ordering an MRI. Clearly, we are far from that future,” Hunter cautioned.
“A possible first step that would require less infrastructure could be to order a polygenic risk score only for men with a positive PSA result, then use the polygenic risk score to determine who should undergo an MRI, and then use all the information to determine whether biopsy is recommended,” Hunter said.
In his view, the current study is a “first step on a long road to evaluating new components of any disease screening pathway.”
The research received funding from the European Research Council, the Bob Willis Fund, Cancer Research UK, the Peacock Trust, and the National Institute for Health and Care Research Biomedical Research Centre at The Royal Marsden and The Institute of Cancer Research. Disclosures for authors and editorialists are available with the original article. Inouye and Ilic reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
Older Adults Face Higher Cancer Risk From Alcohol, Even at Low or Moderate Levels
This transcript has been edited for clarity.
Hello. I’m Maurie Markman, from City of Hope. I want to briefly discuss a very interesting paper that is probably a bit controversial, but nevertheless, I want to point out the data. The paper is “Alcohol Consumption Patterns and Mortality Among Older Adults With Health-Related or Socioeconomic Risk Factors,” published in JAMA Network Open.
This involved a little over 135,000 individual participants in a large, multiyear [research project] in the UK; it’s part of the UK Biobank. This is a population-based cohort that they were looking at here and is only a small part of this huge effort in the UK.
The particular participants that they were looking at here were 60 years or older and defined as current drinkers; that could be occasional all the way up to heavy. Again, that’s the 135,000 individuals I’m referring to.
The data were analyzed from September 2023 to May 2024. They divided the population into four groups, including what they call occasional drinkers, which I guess are social drinkers; it was not clear how they defined that. Then they defined three other categories, which were low risk, moderate risk, and high risk, which was much more clearly defined as it was stated in the paper the amount of alcohol consumption each individual had per day.
The question there was about the relationship between how much alcohol an individual stated they drank compared with the occasional drinker, and the risk for cancer in each group. The answer is that there was no protection from cancer by only being a low-risk or a low-level drinker.
All of the populations had a higher risk for cancer compared with the occasional drinkers. The low-risk group was not protected. The high-risk group had a hazard ratio of 1.39, which is a 39% increase. For the moderate-risk group, the hazard ratio was 1.15, and for the low-risk group, 1.11.
The risk was higher the more an individual drank. However, the point to be made is that if someone says, “Oh, I drink a certain amount each day, but there’s no impact on my risk for cancer,” these data do not support that conclusion.
There is much more to be discussed about this topic. It’s an interesting, large population-based, very carefully controlled analysis being done here, but an important point for future conversation.
Thank you for your attention.
Maurie Markman, MD, has disclosed the following relevant financial relationships: Received income in an amount equal to or greater than $250 from: GlaxoSmithKline; AstraZeneca.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
Hello. I’m Maurie Markman, from City of Hope. I want to briefly discuss a very interesting paper that is probably a bit controversial, but nevertheless, I want to point out the data. The paper is “Alcohol Consumption Patterns and Mortality Among Older Adults With Health-Related or Socioeconomic Risk Factors,” published in JAMA Network Open.
This involved a little over 135,000 individual participants in a large, multiyear [research project] in the UK; it’s part of the UK Biobank. This is a population-based cohort that they were looking at here and is only a small part of this huge effort in the UK.
The particular participants that they were looking at here were 60 years or older and defined as current drinkers; that could be occasional all the way up to heavy. Again, that’s the 135,000 individuals I’m referring to.
The data were analyzed from September 2023 to May 2024. They divided the population into four groups, including what they call occasional drinkers, which I guess are social drinkers; it was not clear how they defined that. Then they defined three other categories, which were low risk, moderate risk, and high risk, which was much more clearly defined as it was stated in the paper the amount of alcohol consumption each individual had per day.
The question there was about the relationship between how much alcohol an individual stated they drank compared with the occasional drinker, and the risk for cancer in each group. The answer is that there was no protection from cancer by only being a low-risk or a low-level drinker.
All of the populations had a higher risk for cancer compared with the occasional drinkers. The low-risk group was not protected. The high-risk group had a hazard ratio of 1.39, which is a 39% increase. For the moderate-risk group, the hazard ratio was 1.15, and for the low-risk group, 1.11.
The risk was higher the more an individual drank. However, the point to be made is that if someone says, “Oh, I drink a certain amount each day, but there’s no impact on my risk for cancer,” these data do not support that conclusion.
There is much more to be discussed about this topic. It’s an interesting, large population-based, very carefully controlled analysis being done here, but an important point for future conversation.
Thank you for your attention.
Maurie Markman, MD, has disclosed the following relevant financial relationships: Received income in an amount equal to or greater than $250 from: GlaxoSmithKline; AstraZeneca.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
Hello. I’m Maurie Markman, from City of Hope. I want to briefly discuss a very interesting paper that is probably a bit controversial, but nevertheless, I want to point out the data. The paper is “Alcohol Consumption Patterns and Mortality Among Older Adults With Health-Related or Socioeconomic Risk Factors,” published in JAMA Network Open.
This involved a little over 135,000 individual participants in a large, multiyear [research project] in the UK; it’s part of the UK Biobank. This is a population-based cohort that they were looking at here and is only a small part of this huge effort in the UK.
The particular participants that they were looking at here were 60 years or older and defined as current drinkers; that could be occasional all the way up to heavy. Again, that’s the 135,000 individuals I’m referring to.
The data were analyzed from September 2023 to May 2024. They divided the population into four groups, including what they call occasional drinkers, which I guess are social drinkers; it was not clear how they defined that. Then they defined three other categories, which were low risk, moderate risk, and high risk, which was much more clearly defined as it was stated in the paper the amount of alcohol consumption each individual had per day.
The question there was about the relationship between how much alcohol an individual stated they drank compared with the occasional drinker, and the risk for cancer in each group. The answer is that there was no protection from cancer by only being a low-risk or a low-level drinker.
All of the populations had a higher risk for cancer compared with the occasional drinkers. The low-risk group was not protected. The high-risk group had a hazard ratio of 1.39, which is a 39% increase. For the moderate-risk group, the hazard ratio was 1.15, and for the low-risk group, 1.11.
The risk was higher the more an individual drank. However, the point to be made is that if someone says, “Oh, I drink a certain amount each day, but there’s no impact on my risk for cancer,” these data do not support that conclusion.
There is much more to be discussed about this topic. It’s an interesting, large population-based, very carefully controlled analysis being done here, but an important point for future conversation.
Thank you for your attention.
Maurie Markman, MD, has disclosed the following relevant financial relationships: Received income in an amount equal to or greater than $250 from: GlaxoSmithKline; AstraZeneca.
A version of this article first appeared on Medscape.com.
Computer-Aided Colonoscopy Not Ready for Prime Time: AGA Clinical Practice Guideline
, the third most common cause of cancer mortality in the United States.
The systematic data review is a collaboration between AGA and The BMJ’s MAGIC Rapid Recommendations. The BMJ issued a separate recommendation against CADe shortly after the AGA guideline was published.
Led by Shahnaz S. Sultan, MD, MHSc, AGAF, of the Division of Gastroenterology, Hepatology, and Nutrition at University of Minnesota, Minneapolis, and recently published in Gastroenterology, found only very low certainty of GRADE-based evidence for several critical long-term outcomes, both desirable and undesirable. These included the following: 11 fewer CRCs per 10,000 individuals and two fewer CRC deaths per 10,000 individuals, an increased burden of more intensive surveillance colonoscopies (635 more per 10,000 individuals), and cost and resource implications.
This technology did, however, yield an 8% (95% CI, 6-10) absolute increase in the adenoma detection rate (ADR) and a 2% (95% CI, 0-4) increase in the detection rate of advanced adenomas and/or sessile serrated lesions. “How this translates into a reduction in CRC incidence or death is where we were uncertain,” Sultan said. “Our best effort at trying to translate the ADR and other endoscopy outcomes to CRC incidence and CRC death relied on the modeling study, which included a lot of assumptions, which also contributed to our overall lower certainty.”
The systematic and meta-analysis included 41 randomized controlled trials with more than 32,108 participants who underwent CADe-assisted colonoscopy. This technology was associated with a higher polyp detection rate than standard colonoscopy: 56.1% vs 47.9% (relative risk [RR], 1.22, 95% CI, 1.15-1.28). It also had a higher ADR: 44.8% vs 37.4% (RR, 1.22; 95% CI, 1.16-1.29).
But although CADe-assisted colonoscopy may increase ADR, it carries a risk for overdiagnosis, as most polyps detected during colonoscopy are diminutive (< 5 mm) and of low malignant potential, the panel noted. Approximately 25% of lesions are missed at colonoscopy. More than 15 million colonoscopies are performed annually in the United States, but studies have demonstrated variable quality of colonoscopies across key quality indicators.
“Artificial intelligence [AI] is revolutionizing medicine and healthcare in the field of GI [gastroenterology], and CADe in colonoscopy has been brought to commercialization,” Sultan told GI & Hepatology News. “Unlike many areas of endoscopic research where we often have a finite number of clinical trial data, CADe-assisted colonoscopy intervention has been studied in over 44 randomized controlled trials and numerous nonrandomized, real-world studies. The question of whether or not to adopt this intervention at a health system or practice level is an important question that was prioritized to be addressed as guidance was needed.”
Commenting on the guideline but not involved in its formulation, Larry S. Kim, MD, MBA, AGAF, a gastroenterologist at South Denver Gastroenterology in Denver, Colorado, said his practice group has used the GI Genius AI system in its affiliated hospitals but has so far chosen not to implement the technology at its endoscopy centers. “At the hospital, our physicians have the ability to utilize the system for select patients or not at all,” he told GI & Hepatology News.
The fact that The BMJ reached a different conclusion based on the same data, evidence-grading system, and microsimulation, Kim added, “highlights the point that when evidence for benefit is uncertain, underlying values are critical.” In declining to make a recommendation, the AGA panel balanced the benefit of improved detection of potentially precancerous adenomas vs increased resource utilization in the face of unclear benefit. “With different priorities, other bodies could reasonably decide to recommend either for or against CADe.”
The Future
According to Sultan, gastroenterologists need a better understanding of patient values and preferences and the value placed on increased adenoma detection, which may also lead to more lifetime colonoscopies without reducing the risk for CRC. “We need better intermediate- and long-term data on the impact of adenoma detection on interval cancers and CRC incidence,” she said. “We need data on detection of polyps that are more clinically significant such as those 6-10 mm in size, as well as serrated sessile lesions. We also need to understand at the population or health system level what the impact is on resources, cost, and access.”
Ultimately, the living guideline underscores the trade-off between desirable and undesirable effects and the limitations of current evidence to support a recommendation, but CADe has to improve as an iterative AI application with further validation and better training.
With the anticipated improvement in software accuracy as AI machine learning reads increasing numbers of images, Sultan added, “the next version of the software may perform better, especially for polyps that are more clinically significant or for flat sessile serrated polyps, which are harder to detect. We plan to revisit the question in the next year or two and potentially revise the guideline.”
These guidelines were fully funded by the AGA Institute with no funding from any outside agency or industry.
Sultan is supported by the US Food and Drug Administration. Co-authors Shazia Mehmood Siddique, Dennis L. Shung, and Benjamin Lebwohl are supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases. Theodore R. Levin is supported by the Permanente Medical Group Delivery Science and Applied Research Program. Cesare Hassan is a consultant for Fujifilm and Olympus. Peter S. Liang reported doing research work for Freenome and advisory board work for Guardant Health and Natera.
Kim is the AGA president-elect. He disclosed no competing interests relevant to his comments.
A version of this article appeared on Medscape.com.
, the third most common cause of cancer mortality in the United States.
The systematic data review is a collaboration between AGA and The BMJ’s MAGIC Rapid Recommendations. The BMJ issued a separate recommendation against CADe shortly after the AGA guideline was published.
Led by Shahnaz S. Sultan, MD, MHSc, AGAF, of the Division of Gastroenterology, Hepatology, and Nutrition at University of Minnesota, Minneapolis, and recently published in Gastroenterology, found only very low certainty of GRADE-based evidence for several critical long-term outcomes, both desirable and undesirable. These included the following: 11 fewer CRCs per 10,000 individuals and two fewer CRC deaths per 10,000 individuals, an increased burden of more intensive surveillance colonoscopies (635 more per 10,000 individuals), and cost and resource implications.
This technology did, however, yield an 8% (95% CI, 6-10) absolute increase in the adenoma detection rate (ADR) and a 2% (95% CI, 0-4) increase in the detection rate of advanced adenomas and/or sessile serrated lesions. “How this translates into a reduction in CRC incidence or death is where we were uncertain,” Sultan said. “Our best effort at trying to translate the ADR and other endoscopy outcomes to CRC incidence and CRC death relied on the modeling study, which included a lot of assumptions, which also contributed to our overall lower certainty.”
The systematic and meta-analysis included 41 randomized controlled trials with more than 32,108 participants who underwent CADe-assisted colonoscopy. This technology was associated with a higher polyp detection rate than standard colonoscopy: 56.1% vs 47.9% (relative risk [RR], 1.22, 95% CI, 1.15-1.28). It also had a higher ADR: 44.8% vs 37.4% (RR, 1.22; 95% CI, 1.16-1.29).
But although CADe-assisted colonoscopy may increase ADR, it carries a risk for overdiagnosis, as most polyps detected during colonoscopy are diminutive (< 5 mm) and of low malignant potential, the panel noted. Approximately 25% of lesions are missed at colonoscopy. More than 15 million colonoscopies are performed annually in the United States, but studies have demonstrated variable quality of colonoscopies across key quality indicators.
“Artificial intelligence [AI] is revolutionizing medicine and healthcare in the field of GI [gastroenterology], and CADe in colonoscopy has been brought to commercialization,” Sultan told GI & Hepatology News. “Unlike many areas of endoscopic research where we often have a finite number of clinical trial data, CADe-assisted colonoscopy intervention has been studied in over 44 randomized controlled trials and numerous nonrandomized, real-world studies. The question of whether or not to adopt this intervention at a health system or practice level is an important question that was prioritized to be addressed as guidance was needed.”
Commenting on the guideline but not involved in its formulation, Larry S. Kim, MD, MBA, AGAF, a gastroenterologist at South Denver Gastroenterology in Denver, Colorado, said his practice group has used the GI Genius AI system in its affiliated hospitals but has so far chosen not to implement the technology at its endoscopy centers. “At the hospital, our physicians have the ability to utilize the system for select patients or not at all,” he told GI & Hepatology News.
The fact that The BMJ reached a different conclusion based on the same data, evidence-grading system, and microsimulation, Kim added, “highlights the point that when evidence for benefit is uncertain, underlying values are critical.” In declining to make a recommendation, the AGA panel balanced the benefit of improved detection of potentially precancerous adenomas vs increased resource utilization in the face of unclear benefit. “With different priorities, other bodies could reasonably decide to recommend either for or against CADe.”
The Future
According to Sultan, gastroenterologists need a better understanding of patient values and preferences and the value placed on increased adenoma detection, which may also lead to more lifetime colonoscopies without reducing the risk for CRC. “We need better intermediate- and long-term data on the impact of adenoma detection on interval cancers and CRC incidence,” she said. “We need data on detection of polyps that are more clinically significant such as those 6-10 mm in size, as well as serrated sessile lesions. We also need to understand at the population or health system level what the impact is on resources, cost, and access.”
Ultimately, the living guideline underscores the trade-off between desirable and undesirable effects and the limitations of current evidence to support a recommendation, but CADe has to improve as an iterative AI application with further validation and better training.
With the anticipated improvement in software accuracy as AI machine learning reads increasing numbers of images, Sultan added, “the next version of the software may perform better, especially for polyps that are more clinically significant or for flat sessile serrated polyps, which are harder to detect. We plan to revisit the question in the next year or two and potentially revise the guideline.”
These guidelines were fully funded by the AGA Institute with no funding from any outside agency or industry.
Sultan is supported by the US Food and Drug Administration. Co-authors Shazia Mehmood Siddique, Dennis L. Shung, and Benjamin Lebwohl are supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases. Theodore R. Levin is supported by the Permanente Medical Group Delivery Science and Applied Research Program. Cesare Hassan is a consultant for Fujifilm and Olympus. Peter S. Liang reported doing research work for Freenome and advisory board work for Guardant Health and Natera.
Kim is the AGA president-elect. He disclosed no competing interests relevant to his comments.
A version of this article appeared on Medscape.com.
, the third most common cause of cancer mortality in the United States.
The systematic data review is a collaboration between AGA and The BMJ’s MAGIC Rapid Recommendations. The BMJ issued a separate recommendation against CADe shortly after the AGA guideline was published.
Led by Shahnaz S. Sultan, MD, MHSc, AGAF, of the Division of Gastroenterology, Hepatology, and Nutrition at University of Minnesota, Minneapolis, and recently published in Gastroenterology, found only very low certainty of GRADE-based evidence for several critical long-term outcomes, both desirable and undesirable. These included the following: 11 fewer CRCs per 10,000 individuals and two fewer CRC deaths per 10,000 individuals, an increased burden of more intensive surveillance colonoscopies (635 more per 10,000 individuals), and cost and resource implications.
This technology did, however, yield an 8% (95% CI, 6-10) absolute increase in the adenoma detection rate (ADR) and a 2% (95% CI, 0-4) increase in the detection rate of advanced adenomas and/or sessile serrated lesions. “How this translates into a reduction in CRC incidence or death is where we were uncertain,” Sultan said. “Our best effort at trying to translate the ADR and other endoscopy outcomes to CRC incidence and CRC death relied on the modeling study, which included a lot of assumptions, which also contributed to our overall lower certainty.”
The systematic and meta-analysis included 41 randomized controlled trials with more than 32,108 participants who underwent CADe-assisted colonoscopy. This technology was associated with a higher polyp detection rate than standard colonoscopy: 56.1% vs 47.9% (relative risk [RR], 1.22, 95% CI, 1.15-1.28). It also had a higher ADR: 44.8% vs 37.4% (RR, 1.22; 95% CI, 1.16-1.29).
But although CADe-assisted colonoscopy may increase ADR, it carries a risk for overdiagnosis, as most polyps detected during colonoscopy are diminutive (< 5 mm) and of low malignant potential, the panel noted. Approximately 25% of lesions are missed at colonoscopy. More than 15 million colonoscopies are performed annually in the United States, but studies have demonstrated variable quality of colonoscopies across key quality indicators.
“Artificial intelligence [AI] is revolutionizing medicine and healthcare in the field of GI [gastroenterology], and CADe in colonoscopy has been brought to commercialization,” Sultan told GI & Hepatology News. “Unlike many areas of endoscopic research where we often have a finite number of clinical trial data, CADe-assisted colonoscopy intervention has been studied in over 44 randomized controlled trials and numerous nonrandomized, real-world studies. The question of whether or not to adopt this intervention at a health system or practice level is an important question that was prioritized to be addressed as guidance was needed.”
Commenting on the guideline but not involved in its formulation, Larry S. Kim, MD, MBA, AGAF, a gastroenterologist at South Denver Gastroenterology in Denver, Colorado, said his practice group has used the GI Genius AI system in its affiliated hospitals but has so far chosen not to implement the technology at its endoscopy centers. “At the hospital, our physicians have the ability to utilize the system for select patients or not at all,” he told GI & Hepatology News.
The fact that The BMJ reached a different conclusion based on the same data, evidence-grading system, and microsimulation, Kim added, “highlights the point that when evidence for benefit is uncertain, underlying values are critical.” In declining to make a recommendation, the AGA panel balanced the benefit of improved detection of potentially precancerous adenomas vs increased resource utilization in the face of unclear benefit. “With different priorities, other bodies could reasonably decide to recommend either for or against CADe.”
The Future
According to Sultan, gastroenterologists need a better understanding of patient values and preferences and the value placed on increased adenoma detection, which may also lead to more lifetime colonoscopies without reducing the risk for CRC. “We need better intermediate- and long-term data on the impact of adenoma detection on interval cancers and CRC incidence,” she said. “We need data on detection of polyps that are more clinically significant such as those 6-10 mm in size, as well as serrated sessile lesions. We also need to understand at the population or health system level what the impact is on resources, cost, and access.”
Ultimately, the living guideline underscores the trade-off between desirable and undesirable effects and the limitations of current evidence to support a recommendation, but CADe has to improve as an iterative AI application with further validation and better training.
With the anticipated improvement in software accuracy as AI machine learning reads increasing numbers of images, Sultan added, “the next version of the software may perform better, especially for polyps that are more clinically significant or for flat sessile serrated polyps, which are harder to detect. We plan to revisit the question in the next year or two and potentially revise the guideline.”
These guidelines were fully funded by the AGA Institute with no funding from any outside agency or industry.
Sultan is supported by the US Food and Drug Administration. Co-authors Shazia Mehmood Siddique, Dennis L. Shung, and Benjamin Lebwohl are supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases. Theodore R. Levin is supported by the Permanente Medical Group Delivery Science and Applied Research Program. Cesare Hassan is a consultant for Fujifilm and Olympus. Peter S. Liang reported doing research work for Freenome and advisory board work for Guardant Health and Natera.
Kim is the AGA president-elect. He disclosed no competing interests relevant to his comments.
A version of this article appeared on Medscape.com.
FROM GASTROENTEROLOGY
Elemental Diet Eases Symptoms in Microbiome Gastro Disorders
, according to a new study.
“Elemental diets have long shown promise for treating gastrointestinal disorders like Crohn’s disease, eosinophilic esophagitis, SIBO (small intestinal bacterial overgrowth), and IMO (intestinal methanogen overgrowth), but poor palatability has limited their use,” lead author Ali Rezaie, MD, medical director of the Gastrointestinal (GI) Motility Program and director of Bioinformatics at Cedars-Sinai Medical Center, Los Angeles, told GI & Hepatology News.
Elemental diets are specialized formulas tailored to meet an individual’s specific nutritional needs and daily requirements for vitamins, minerals, fat, free amino acids, and carbohydrates.
In SIBO and IMO specifically, only about half the patients respond to antibiotics, and many require repeat treatments, which underscores the need for effective nonantibiotic alternatives, said Rezaie. “This is the first prospective trial using a PED, aiming to make this approach both viable and accessible for patients,” he noted.
Assessing a Novel Diet in IMO and SIBO
In the study, which was recently published in Clinical Gastroenterology and Hepatology, Rezaie and colleagues enrolled 30 adults with IMO (40%), SIBO (20%), or both (40%). The mean participant age was 45 years, and 63% were women.
All participants completed 2 weeks of a PED, transitioned to 2-3 days of a bland diet, and then resumed their regular diets for 2 weeks.
The diet consisted of multiple 300-calorie packets, adjusted for individual caloric needs. Participants could consume additional packets for hunger but were prohibited from eating other foods. There was no restriction on water intake.
The primary endpoint was changes in stool microbiome after the PED and reintroduction of regular food. Secondary endpoints included lactose breath test normalization to determine bacterial overgrowth in the gut, symptom response, and adverse events.
Researchers collected 29 stool samples at baseline, 27 post-PED, and 27 at study conclusion (2 weeks post-diet).
Key Outcomes
Although the stool samples’ alpha diversity decreased after the PED, the difference was not statistically significant at the end of the study. However, 30 bacterial families showed significant differences in relative abundance post-PED.
Daily symptom severity improved significantly during the second week of the diet compared with baseline, with reduction in abdominal discomfort, bloating, distention, constipation, and flatulence. Further significant improvements in measures such as abdominal pain, diarrhea, fatigue, urgency, and brain fog were observed after reintroducing regular food.
“We observed 73% breath test normalization and 83% global symptom relief — with 100% adherence and tolerance to 2 weeks of exclusive PED,” Rezaie told GI & Hepatology News. No serious adverse events occurred during the study, he added.
Lactose breath test normalization rates post-PED were 58% in patients with IMO, 100% in patients with SIBO, and 75% in those with both conditions.
The extent of patient response to PED was notable, given that 83% had failed prior treatments, Rezaie said.
“While we expected benefit based on palatability improvements and prior retrospective data, the rapid reduction in methane and hydrogen gas — and the sustained microbiome modulation even after reintroducing a regular diet — exceeded expectations,” he said. A significant reduction in visceral fat was another novel finding.
“This study reinforces the power of diet as a therapeutic tool,” Rezaie said, adding that the results show that elemental diets can be palatable, thereby improving patient adherence, tolerance, and, eventually, effectiveness. This is particularly valuable for patients with SIBO and IMO who do not tolerate or respond to antibiotics, prefer nonpharmacologic options, or experience recurrent symptoms after antibiotic treatment.
Limitations and Next Steps
Study limitations included the lack of a placebo group with a sham diet, the short follow-up after reintroducing a regular diet, and the inability to assess microbial gene function.
However, the results support the safety, tolerance, and benefit of a PED in patients with IMO/SIBO. Personalized dietary interventions that support the growth of beneficial bacteria may be an effective approach to treating these disorders, Rezaie and colleagues noted in their publication.
Although the current study is a promising first step, longer-term studies are needed to evaluate the durability of microbiome and symptom improvements, Rezaie said.
Making the Most of Microbiome Manipulation
Elemental diets may help modulate the gut microbiome while reducing immune activation, making them attractive for microbiome-targeted gastrointestinal therapies, Jatin Roper, MD, a gastroenterologist at Duke University, Durham, North Carolina, told GI & Hepatology News.
“Antibiotics are only effective in half of SIBO cases and often require retreatment, so better therapies are needed,” said Roper, who was not affiliated with the study. He added that its findings confirmed the researchers’ hypothesis that a PED can be both safe and effective in patients with SIBO.
Roper noted the 83% symptom improvement as the study’s most unexpected and encouraging finding, as it represents a substantial improvement compared with standard antibiotic therapy. “It is also surprising that the tolerance rate of the elemental diet in this study was 100%,” he said.
However, diet palatability remains a major barrier in real-world practice.
“Adherence rates are likely to be far lower than in trials in which patients are closely monitored, and this challenge will not be easily overcome,” he added.
The study’s limitations, including the lack of metagenomic analysis and a placebo group, are important to address in future research, Roper said. In particular, controlled trials of elemental diets are needed to determine whether microbiome changes are directly responsible for symptom improvement.
The study was supported in part by Good LFE and the John and Geraldine Cusenza Foundation. Rezaie disclosed serving as a consultant/speaker for Bausch Health and having equity in Dieta Health, Gemelli Biotech, and Good LFE. Roper had no financial conflicts to disclose.
A version of this article first appeared on Medscape.com.
, according to a new study.
“Elemental diets have long shown promise for treating gastrointestinal disorders like Crohn’s disease, eosinophilic esophagitis, SIBO (small intestinal bacterial overgrowth), and IMO (intestinal methanogen overgrowth), but poor palatability has limited their use,” lead author Ali Rezaie, MD, medical director of the Gastrointestinal (GI) Motility Program and director of Bioinformatics at Cedars-Sinai Medical Center, Los Angeles, told GI & Hepatology News.
Elemental diets are specialized formulas tailored to meet an individual’s specific nutritional needs and daily requirements for vitamins, minerals, fat, free amino acids, and carbohydrates.
In SIBO and IMO specifically, only about half the patients respond to antibiotics, and many require repeat treatments, which underscores the need for effective nonantibiotic alternatives, said Rezaie. “This is the first prospective trial using a PED, aiming to make this approach both viable and accessible for patients,” he noted.
Assessing a Novel Diet in IMO and SIBO
In the study, which was recently published in Clinical Gastroenterology and Hepatology, Rezaie and colleagues enrolled 30 adults with IMO (40%), SIBO (20%), or both (40%). The mean participant age was 45 years, and 63% were women.
All participants completed 2 weeks of a PED, transitioned to 2-3 days of a bland diet, and then resumed their regular diets for 2 weeks.
The diet consisted of multiple 300-calorie packets, adjusted for individual caloric needs. Participants could consume additional packets for hunger but were prohibited from eating other foods. There was no restriction on water intake.
The primary endpoint was changes in stool microbiome after the PED and reintroduction of regular food. Secondary endpoints included lactose breath test normalization to determine bacterial overgrowth in the gut, symptom response, and adverse events.
Researchers collected 29 stool samples at baseline, 27 post-PED, and 27 at study conclusion (2 weeks post-diet).
Key Outcomes
Although the stool samples’ alpha diversity decreased after the PED, the difference was not statistically significant at the end of the study. However, 30 bacterial families showed significant differences in relative abundance post-PED.
Daily symptom severity improved significantly during the second week of the diet compared with baseline, with reduction in abdominal discomfort, bloating, distention, constipation, and flatulence. Further significant improvements in measures such as abdominal pain, diarrhea, fatigue, urgency, and brain fog were observed after reintroducing regular food.
“We observed 73% breath test normalization and 83% global symptom relief — with 100% adherence and tolerance to 2 weeks of exclusive PED,” Rezaie told GI & Hepatology News. No serious adverse events occurred during the study, he added.
Lactose breath test normalization rates post-PED were 58% in patients with IMO, 100% in patients with SIBO, and 75% in those with both conditions.
The extent of patient response to PED was notable, given that 83% had failed prior treatments, Rezaie said.
“While we expected benefit based on palatability improvements and prior retrospective data, the rapid reduction in methane and hydrogen gas — and the sustained microbiome modulation even after reintroducing a regular diet — exceeded expectations,” he said. A significant reduction in visceral fat was another novel finding.
“This study reinforces the power of diet as a therapeutic tool,” Rezaie said, adding that the results show that elemental diets can be palatable, thereby improving patient adherence, tolerance, and, eventually, effectiveness. This is particularly valuable for patients with SIBO and IMO who do not tolerate or respond to antibiotics, prefer nonpharmacologic options, or experience recurrent symptoms after antibiotic treatment.
Limitations and Next Steps
Study limitations included the lack of a placebo group with a sham diet, the short follow-up after reintroducing a regular diet, and the inability to assess microbial gene function.
However, the results support the safety, tolerance, and benefit of a PED in patients with IMO/SIBO. Personalized dietary interventions that support the growth of beneficial bacteria may be an effective approach to treating these disorders, Rezaie and colleagues noted in their publication.
Although the current study is a promising first step, longer-term studies are needed to evaluate the durability of microbiome and symptom improvements, Rezaie said.
Making the Most of Microbiome Manipulation
Elemental diets may help modulate the gut microbiome while reducing immune activation, making them attractive for microbiome-targeted gastrointestinal therapies, Jatin Roper, MD, a gastroenterologist at Duke University, Durham, North Carolina, told GI & Hepatology News.
“Antibiotics are only effective in half of SIBO cases and often require retreatment, so better therapies are needed,” said Roper, who was not affiliated with the study. He added that its findings confirmed the researchers’ hypothesis that a PED can be both safe and effective in patients with SIBO.
Roper noted the 83% symptom improvement as the study’s most unexpected and encouraging finding, as it represents a substantial improvement compared with standard antibiotic therapy. “It is also surprising that the tolerance rate of the elemental diet in this study was 100%,” he said.
However, diet palatability remains a major barrier in real-world practice.
“Adherence rates are likely to be far lower than in trials in which patients are closely monitored, and this challenge will not be easily overcome,” he added.
The study’s limitations, including the lack of metagenomic analysis and a placebo group, are important to address in future research, Roper said. In particular, controlled trials of elemental diets are needed to determine whether microbiome changes are directly responsible for symptom improvement.
The study was supported in part by Good LFE and the John and Geraldine Cusenza Foundation. Rezaie disclosed serving as a consultant/speaker for Bausch Health and having equity in Dieta Health, Gemelli Biotech, and Good LFE. Roper had no financial conflicts to disclose.
A version of this article first appeared on Medscape.com.
, according to a new study.
“Elemental diets have long shown promise for treating gastrointestinal disorders like Crohn’s disease, eosinophilic esophagitis, SIBO (small intestinal bacterial overgrowth), and IMO (intestinal methanogen overgrowth), but poor palatability has limited their use,” lead author Ali Rezaie, MD, medical director of the Gastrointestinal (GI) Motility Program and director of Bioinformatics at Cedars-Sinai Medical Center, Los Angeles, told GI & Hepatology News.
Elemental diets are specialized formulas tailored to meet an individual’s specific nutritional needs and daily requirements for vitamins, minerals, fat, free amino acids, and carbohydrates.
In SIBO and IMO specifically, only about half the patients respond to antibiotics, and many require repeat treatments, which underscores the need for effective nonantibiotic alternatives, said Rezaie. “This is the first prospective trial using a PED, aiming to make this approach both viable and accessible for patients,” he noted.
Assessing a Novel Diet in IMO and SIBO
In the study, which was recently published in Clinical Gastroenterology and Hepatology, Rezaie and colleagues enrolled 30 adults with IMO (40%), SIBO (20%), or both (40%). The mean participant age was 45 years, and 63% were women.
All participants completed 2 weeks of a PED, transitioned to 2-3 days of a bland diet, and then resumed their regular diets for 2 weeks.
The diet consisted of multiple 300-calorie packets, adjusted for individual caloric needs. Participants could consume additional packets for hunger but were prohibited from eating other foods. There was no restriction on water intake.
The primary endpoint was changes in stool microbiome after the PED and reintroduction of regular food. Secondary endpoints included lactose breath test normalization to determine bacterial overgrowth in the gut, symptom response, and adverse events.
Researchers collected 29 stool samples at baseline, 27 post-PED, and 27 at study conclusion (2 weeks post-diet).
Key Outcomes
Although the stool samples’ alpha diversity decreased after the PED, the difference was not statistically significant at the end of the study. However, 30 bacterial families showed significant differences in relative abundance post-PED.
Daily symptom severity improved significantly during the second week of the diet compared with baseline, with reduction in abdominal discomfort, bloating, distention, constipation, and flatulence. Further significant improvements in measures such as abdominal pain, diarrhea, fatigue, urgency, and brain fog were observed after reintroducing regular food.
“We observed 73% breath test normalization and 83% global symptom relief — with 100% adherence and tolerance to 2 weeks of exclusive PED,” Rezaie told GI & Hepatology News. No serious adverse events occurred during the study, he added.
Lactose breath test normalization rates post-PED were 58% in patients with IMO, 100% in patients with SIBO, and 75% in those with both conditions.
The extent of patient response to PED was notable, given that 83% had failed prior treatments, Rezaie said.
“While we expected benefit based on palatability improvements and prior retrospective data, the rapid reduction in methane and hydrogen gas — and the sustained microbiome modulation even after reintroducing a regular diet — exceeded expectations,” he said. A significant reduction in visceral fat was another novel finding.
“This study reinforces the power of diet as a therapeutic tool,” Rezaie said, adding that the results show that elemental diets can be palatable, thereby improving patient adherence, tolerance, and, eventually, effectiveness. This is particularly valuable for patients with SIBO and IMO who do not tolerate or respond to antibiotics, prefer nonpharmacologic options, or experience recurrent symptoms after antibiotic treatment.
Limitations and Next Steps
Study limitations included the lack of a placebo group with a sham diet, the short follow-up after reintroducing a regular diet, and the inability to assess microbial gene function.
However, the results support the safety, tolerance, and benefit of a PED in patients with IMO/SIBO. Personalized dietary interventions that support the growth of beneficial bacteria may be an effective approach to treating these disorders, Rezaie and colleagues noted in their publication.
Although the current study is a promising first step, longer-term studies are needed to evaluate the durability of microbiome and symptom improvements, Rezaie said.
Making the Most of Microbiome Manipulation
Elemental diets may help modulate the gut microbiome while reducing immune activation, making them attractive for microbiome-targeted gastrointestinal therapies, Jatin Roper, MD, a gastroenterologist at Duke University, Durham, North Carolina, told GI & Hepatology News.
“Antibiotics are only effective in half of SIBO cases and often require retreatment, so better therapies are needed,” said Roper, who was not affiliated with the study. He added that its findings confirmed the researchers’ hypothesis that a PED can be both safe and effective in patients with SIBO.
Roper noted the 83% symptom improvement as the study’s most unexpected and encouraging finding, as it represents a substantial improvement compared with standard antibiotic therapy. “It is also surprising that the tolerance rate of the elemental diet in this study was 100%,” he said.
However, diet palatability remains a major barrier in real-world practice.
“Adherence rates are likely to be far lower than in trials in which patients are closely monitored, and this challenge will not be easily overcome,” he added.
The study’s limitations, including the lack of metagenomic analysis and a placebo group, are important to address in future research, Roper said. In particular, controlled trials of elemental diets are needed to determine whether microbiome changes are directly responsible for symptom improvement.
The study was supported in part by Good LFE and the John and Geraldine Cusenza Foundation. Rezaie disclosed serving as a consultant/speaker for Bausch Health and having equity in Dieta Health, Gemelli Biotech, and Good LFE. Roper had no financial conflicts to disclose.
A version of this article first appeared on Medscape.com.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
The Extra-Bacterial Gut Ecosystem: The Influence of Phages and Fungi in the Microbiome
WASHINGTON, DC — Research on the gut microbiome — and clinical attention to it — has focused mainly on bacteria, but bacteriophages and fungi play critical roles as well, with significant influences on health and disease, experts said at the Gut Microbiota for Health (GMFH) World Summit 2025.
Fungi account for < 1% of the total genetic material in the microbiome but 1%-2% of its total biomass. “Despite their relative rarity, they have an important and outsized influence on gut health” — an impact that results from their unique interface with the immune system, said Kyla Ost, PhD, of the Anschutz Medical Campus, University of Colorado, in Denver, whose research focuses on this interface.
And bacteriophages — viruses that infect and kill bacteria — are highly abundant in the gut. “Bacteriophages begin to colonize our GI [gastrointestinal] tract at the same time we develop our own microbiome shortly after birth, and from that time on, they interact with the bacteria in our GI tract, shaping [and being shaped by] the bacterial species we carry with us,” said Robert (Chip) Schooley, MD, distinguished professor of medicine at the University of California San Diego School of Medicine.
“We’ve been talking about things that affect the gut microbiome — diet, genetics, immune response — but probably the biggest influence on what grows in the GI tract are bacteriophages,” said Schooley, co-director of the Center for Innovative Phage Applications and Therapeutics, in a session on the extra-bacterial gut ecosystem.
Among the current questions:
‘New life’ for Phage Therapy
Bacteriophages represent a promising approach for the treatment of multidrug resistant bacterial pathogens in an era of increasing resistance and a dried-up antibiotic discovery pipeline, Schooley said. (In 2019, an estimated 4.95 million deaths around the world were associated with bacterial antimicrobial resistance, and by 2050, it has been forecast that this number will rise to an estimated 8.22 million deaths.)
But in addition to suppressing bacterial pathogens causing direct morbidity, phage therapy has the potential to suppress bacteria believed to contribute to chronic diseases, he said. “We have proof-of-concept studies about the ability of phage to modulate bacteria in the digestive tract,” and an increasing number of clinical trials of the use of phages in GI and other diseases are underway, he said.
Phages were discovered just over a century ago, but phage therapy was widely abandoned once antibiotics were developed, except for in Russia and the former Eastern Bloc countries, where phage therapy continued to be used.
Phage therapy “got new life” in the West, Schooley said, about 10-15 years ago with an increasing number of detailed and high-profile case reports, including one in which a UC San Diego colleague, Tom Patterson, PhD, contracted a deadly multidrug resistant bacterial infection in Egypt and was eventually saved with bacteriophage therapy. (The case was the subject of the book The Perfect Predator).
Since then, as described in case reports and studies in the literature, “hundreds of people have been treated with bacteriophages here and in Europe,” most commonly for pulmonary infections and infections in implanted vascular and orthopedic devices, said Schooley, who coauthored a review in Cell in 2023 that describes phage biology and advances and future directions in phage therapy.
The use of bacteriophages to prevent systemic infections during high-risk periods — such as during chemotherapeutic regimens for hematological regimens — is an area of interest, he said at the meeting.
In research that is making its way to a clinical trial of patients undergoing allogeneic hematopoietic stem cell transplant (HSCT), researchers screened a library of phages to identify those with broad coverage of Escherichia coli. Using tail fiber engineering and CRISPR technology, they then engineered a combination of the four most complementary bacteriophages to selectively kill E coli — including fluoroquinolone-resistant strains that, in patients whose GI tracts are colonized with these strains, can translocate from the gut into the bloodstream, causing sepsis, during chemotherapeutic regimens for HSCT.
In a mouse model, the CRISPR-enhanced four-phage cocktail (SNIPR001) led to a steady reduction in the E coli colony counts in stool, “showing you can modulate these bacteria in the gut by using bacteriophages to kill them,” Schooley said. Moreover, the CRISPR enhancement strengthened the phages’ ability to break up biofilms, he said, showing “that you can engineer bacteriophages to make them better killers.” A phase 1b/2a study is being planned.
Other Niches for Therapeutic Phages, Challenges
Bacteriophages also could be used to target a gut bacterium that has been shown to attenuate alcoholic liver disease. Patients with alcoholic hepatitis “have a gut microbiome that is different in distribution,” Schooley said, often with increased numbers of Enterococcus faecalis that produce cytolysin, an exotoxin that exacerbates liver injury and is associated with increased mortality.
In published research led by investigators at UC San Diego, stool from cytolysin-positive patients with alcoholic hepatitis was found to exacerbate ethanol-induced liver disease in gnotobiotic mice, and phage therapy against cytolytic E faecalis was found to abolish it, Schooley shared.
Research is also exploring the potential of phage therapy to selectively target adherent invasive E coli in Crohn’s disease, and Klebsiella pneumoniae in the gut microbiome as an exacerbator of inflammatory bowel disease (IBD), he said.
And investigators in Japan, he noted, have reported that bacteriophage therapy against K pneumoniae can ameliorate liver inflammation and disease severity in primary sclerosing cholangitis.
Challenges in the therapeutic use of phages include the narrow host range of phages and an uncertain predictive value of in vitro phage susceptibility testing. “We don’t know yet how to do resistance testing as well as we do with antibiotics,” he said.
In addition, most phages tend to be acid labile, requiring strategies to mitigate inactivation by gastric acid, and there are “major knowledge gaps” relating to phage pharmacology. “We also know that adaptive immune responses to phages can but often doesn’t impact therapy, and we want to understand that better in clinical trials,” Schooley said.
Phages that have a “lysogenic” lifestyle — as opposed to lytic phages which are used therapeutically — can contribute to antibiotic resistance by facilitating the interchange of bacterial resistance genes, he noted.
A Window Into the Mycobiome
The human gut mycobiome is primarily composed of fungi in the Saccharomyces, Candida, and Malassezia genera, with Candida species dominating. Fungal cells harbor distinct immune-stimulatory molecules and activate distinct immune pathways compared with bacteria and other members of the microbiome, said Ost, assistant professor in the immunology and microbiology department of CU Anschutz.
Some fungi, including those in the Candida genus, activate adaptive and innate immune responses that promote metabolic health and protect against infection. A recently published study in Science, for instance, demonstrated that colonization with C dubliniensis in very young mice who had been exposed to broad-spectrum antibiotics promoted “the expansion and development of beta cells in the pancreas” in a macrophage dependent manner, improving metabolic health and reducing diabetes incidence, she shared.
On the one hand, fungi can “exacerbate and perpetuate the pathogenic inflammation that’s found in a growing list of inflammatory diseases” such as IBD. And “in fact, a lot of the benefits and detriments are driven by the exact same species of fungi,” said Ost. “This is particularly true of Candida,” which is a “lifelong colonizer of intestinal microbiota that rarely causes disease but can be quite pathogenic when it does.”
A 2023 review in Nature Reviews Gastroenterology & Hepatology coauthored by Ost describes the role of commensal fungi in intestinal diseases, including IBD, colorectal cancer, and pancreatic cancer.
The pathogenic potential of commensal fungi is largely dependent on its strain, its morphology and its expression of virulence factors, researchers are learning. Ost has studied C albicans, which has been associated with intestinal inflammation and IBD. Like some other Candida species, C albicans are “fascinating shape shifters,” she said, transitioning between a less pathogenic “yeast” morphology and an elongated, adhesive “hyphae” shape that is more pathogenic.
It turns out, according to research by Ost and others, that the C albicans hyphal morphotype — and the adhesins (sticky proteins that facilitate adherence to epithelial cells) and a cytolytic toxin it produces — are preferentially targeted and suppressed by immunoglobulin A (IgA) in the gut.
“Our gut is protected by a large quantity of IgA antibodies…and these IgA interact with the microbiota and play a big role in what microbes are there and the biology of the microbes,” Ost said. Indeed, symptomatic IgA deficiency in humans has been shown to be associated with C albicans overgrowth.
Leveraging the hyphal-specific IgA response to protect against disease seems possible, she said, referring to an experimental anti-Candida fungal vaccine (NDV-3A) designed to induce an adhesin-specific immune response. In a mouse model of colitis, the vaccine protected against C albicans-associated damage. “We saw an immediate IgA response that targeted C albicans in the intestinal contents,” Ost said.
C glabrata, which has also been associated with intestinal inflammation and IBD, does not form hyphae but — depending on the strain — may also induce intestinal IgA responses, she said in describing her recent research.
Ost reported having no disclosures. Schooley disclosed being a consultant for SNIPR Biome, BiomX, Locus, MicrobiotiX, Amazon Data Monitoring Committee: Merck.
A version of this article appeared on Medscape.com.
WASHINGTON, DC — Research on the gut microbiome — and clinical attention to it — has focused mainly on bacteria, but bacteriophages and fungi play critical roles as well, with significant influences on health and disease, experts said at the Gut Microbiota for Health (GMFH) World Summit 2025.
Fungi account for < 1% of the total genetic material in the microbiome but 1%-2% of its total biomass. “Despite their relative rarity, they have an important and outsized influence on gut health” — an impact that results from their unique interface with the immune system, said Kyla Ost, PhD, of the Anschutz Medical Campus, University of Colorado, in Denver, whose research focuses on this interface.
And bacteriophages — viruses that infect and kill bacteria — are highly abundant in the gut. “Bacteriophages begin to colonize our GI [gastrointestinal] tract at the same time we develop our own microbiome shortly after birth, and from that time on, they interact with the bacteria in our GI tract, shaping [and being shaped by] the bacterial species we carry with us,” said Robert (Chip) Schooley, MD, distinguished professor of medicine at the University of California San Diego School of Medicine.
“We’ve been talking about things that affect the gut microbiome — diet, genetics, immune response — but probably the biggest influence on what grows in the GI tract are bacteriophages,” said Schooley, co-director of the Center for Innovative Phage Applications and Therapeutics, in a session on the extra-bacterial gut ecosystem.
Among the current questions:
‘New life’ for Phage Therapy
Bacteriophages represent a promising approach for the treatment of multidrug resistant bacterial pathogens in an era of increasing resistance and a dried-up antibiotic discovery pipeline, Schooley said. (In 2019, an estimated 4.95 million deaths around the world were associated with bacterial antimicrobial resistance, and by 2050, it has been forecast that this number will rise to an estimated 8.22 million deaths.)
But in addition to suppressing bacterial pathogens causing direct morbidity, phage therapy has the potential to suppress bacteria believed to contribute to chronic diseases, he said. “We have proof-of-concept studies about the ability of phage to modulate bacteria in the digestive tract,” and an increasing number of clinical trials of the use of phages in GI and other diseases are underway, he said.
Phages were discovered just over a century ago, but phage therapy was widely abandoned once antibiotics were developed, except for in Russia and the former Eastern Bloc countries, where phage therapy continued to be used.
Phage therapy “got new life” in the West, Schooley said, about 10-15 years ago with an increasing number of detailed and high-profile case reports, including one in which a UC San Diego colleague, Tom Patterson, PhD, contracted a deadly multidrug resistant bacterial infection in Egypt and was eventually saved with bacteriophage therapy. (The case was the subject of the book The Perfect Predator).
Since then, as described in case reports and studies in the literature, “hundreds of people have been treated with bacteriophages here and in Europe,” most commonly for pulmonary infections and infections in implanted vascular and orthopedic devices, said Schooley, who coauthored a review in Cell in 2023 that describes phage biology and advances and future directions in phage therapy.
The use of bacteriophages to prevent systemic infections during high-risk periods — such as during chemotherapeutic regimens for hematological regimens — is an area of interest, he said at the meeting.
In research that is making its way to a clinical trial of patients undergoing allogeneic hematopoietic stem cell transplant (HSCT), researchers screened a library of phages to identify those with broad coverage of Escherichia coli. Using tail fiber engineering and CRISPR technology, they then engineered a combination of the four most complementary bacteriophages to selectively kill E coli — including fluoroquinolone-resistant strains that, in patients whose GI tracts are colonized with these strains, can translocate from the gut into the bloodstream, causing sepsis, during chemotherapeutic regimens for HSCT.
In a mouse model, the CRISPR-enhanced four-phage cocktail (SNIPR001) led to a steady reduction in the E coli colony counts in stool, “showing you can modulate these bacteria in the gut by using bacteriophages to kill them,” Schooley said. Moreover, the CRISPR enhancement strengthened the phages’ ability to break up biofilms, he said, showing “that you can engineer bacteriophages to make them better killers.” A phase 1b/2a study is being planned.
Other Niches for Therapeutic Phages, Challenges
Bacteriophages also could be used to target a gut bacterium that has been shown to attenuate alcoholic liver disease. Patients with alcoholic hepatitis “have a gut microbiome that is different in distribution,” Schooley said, often with increased numbers of Enterococcus faecalis that produce cytolysin, an exotoxin that exacerbates liver injury and is associated with increased mortality.
In published research led by investigators at UC San Diego, stool from cytolysin-positive patients with alcoholic hepatitis was found to exacerbate ethanol-induced liver disease in gnotobiotic mice, and phage therapy against cytolytic E faecalis was found to abolish it, Schooley shared.
Research is also exploring the potential of phage therapy to selectively target adherent invasive E coli in Crohn’s disease, and Klebsiella pneumoniae in the gut microbiome as an exacerbator of inflammatory bowel disease (IBD), he said.
And investigators in Japan, he noted, have reported that bacteriophage therapy against K pneumoniae can ameliorate liver inflammation and disease severity in primary sclerosing cholangitis.
Challenges in the therapeutic use of phages include the narrow host range of phages and an uncertain predictive value of in vitro phage susceptibility testing. “We don’t know yet how to do resistance testing as well as we do with antibiotics,” he said.
In addition, most phages tend to be acid labile, requiring strategies to mitigate inactivation by gastric acid, and there are “major knowledge gaps” relating to phage pharmacology. “We also know that adaptive immune responses to phages can but often doesn’t impact therapy, and we want to understand that better in clinical trials,” Schooley said.
Phages that have a “lysogenic” lifestyle — as opposed to lytic phages which are used therapeutically — can contribute to antibiotic resistance by facilitating the interchange of bacterial resistance genes, he noted.
A Window Into the Mycobiome
The human gut mycobiome is primarily composed of fungi in the Saccharomyces, Candida, and Malassezia genera, with Candida species dominating. Fungal cells harbor distinct immune-stimulatory molecules and activate distinct immune pathways compared with bacteria and other members of the microbiome, said Ost, assistant professor in the immunology and microbiology department of CU Anschutz.
Some fungi, including those in the Candida genus, activate adaptive and innate immune responses that promote metabolic health and protect against infection. A recently published study in Science, for instance, demonstrated that colonization with C dubliniensis in very young mice who had been exposed to broad-spectrum antibiotics promoted “the expansion and development of beta cells in the pancreas” in a macrophage dependent manner, improving metabolic health and reducing diabetes incidence, she shared.
On the one hand, fungi can “exacerbate and perpetuate the pathogenic inflammation that’s found in a growing list of inflammatory diseases” such as IBD. And “in fact, a lot of the benefits and detriments are driven by the exact same species of fungi,” said Ost. “This is particularly true of Candida,” which is a “lifelong colonizer of intestinal microbiota that rarely causes disease but can be quite pathogenic when it does.”
A 2023 review in Nature Reviews Gastroenterology & Hepatology coauthored by Ost describes the role of commensal fungi in intestinal diseases, including IBD, colorectal cancer, and pancreatic cancer.
The pathogenic potential of commensal fungi is largely dependent on its strain, its morphology and its expression of virulence factors, researchers are learning. Ost has studied C albicans, which has been associated with intestinal inflammation and IBD. Like some other Candida species, C albicans are “fascinating shape shifters,” she said, transitioning between a less pathogenic “yeast” morphology and an elongated, adhesive “hyphae” shape that is more pathogenic.
It turns out, according to research by Ost and others, that the C albicans hyphal morphotype — and the adhesins (sticky proteins that facilitate adherence to epithelial cells) and a cytolytic toxin it produces — are preferentially targeted and suppressed by immunoglobulin A (IgA) in the gut.
“Our gut is protected by a large quantity of IgA antibodies…and these IgA interact with the microbiota and play a big role in what microbes are there and the biology of the microbes,” Ost said. Indeed, symptomatic IgA deficiency in humans has been shown to be associated with C albicans overgrowth.
Leveraging the hyphal-specific IgA response to protect against disease seems possible, she said, referring to an experimental anti-Candida fungal vaccine (NDV-3A) designed to induce an adhesin-specific immune response. In a mouse model of colitis, the vaccine protected against C albicans-associated damage. “We saw an immediate IgA response that targeted C albicans in the intestinal contents,” Ost said.
C glabrata, which has also been associated with intestinal inflammation and IBD, does not form hyphae but — depending on the strain — may also induce intestinal IgA responses, she said in describing her recent research.
Ost reported having no disclosures. Schooley disclosed being a consultant for SNIPR Biome, BiomX, Locus, MicrobiotiX, Amazon Data Monitoring Committee: Merck.
A version of this article appeared on Medscape.com.
WASHINGTON, DC — Research on the gut microbiome — and clinical attention to it — has focused mainly on bacteria, but bacteriophages and fungi play critical roles as well, with significant influences on health and disease, experts said at the Gut Microbiota for Health (GMFH) World Summit 2025.
Fungi account for < 1% of the total genetic material in the microbiome but 1%-2% of its total biomass. “Despite their relative rarity, they have an important and outsized influence on gut health” — an impact that results from their unique interface with the immune system, said Kyla Ost, PhD, of the Anschutz Medical Campus, University of Colorado, in Denver, whose research focuses on this interface.
And bacteriophages — viruses that infect and kill bacteria — are highly abundant in the gut. “Bacteriophages begin to colonize our GI [gastrointestinal] tract at the same time we develop our own microbiome shortly after birth, and from that time on, they interact with the bacteria in our GI tract, shaping [and being shaped by] the bacterial species we carry with us,” said Robert (Chip) Schooley, MD, distinguished professor of medicine at the University of California San Diego School of Medicine.
“We’ve been talking about things that affect the gut microbiome — diet, genetics, immune response — but probably the biggest influence on what grows in the GI tract are bacteriophages,” said Schooley, co-director of the Center for Innovative Phage Applications and Therapeutics, in a session on the extra-bacterial gut ecosystem.
Among the current questions:
‘New life’ for Phage Therapy
Bacteriophages represent a promising approach for the treatment of multidrug resistant bacterial pathogens in an era of increasing resistance and a dried-up antibiotic discovery pipeline, Schooley said. (In 2019, an estimated 4.95 million deaths around the world were associated with bacterial antimicrobial resistance, and by 2050, it has been forecast that this number will rise to an estimated 8.22 million deaths.)
But in addition to suppressing bacterial pathogens causing direct morbidity, phage therapy has the potential to suppress bacteria believed to contribute to chronic diseases, he said. “We have proof-of-concept studies about the ability of phage to modulate bacteria in the digestive tract,” and an increasing number of clinical trials of the use of phages in GI and other diseases are underway, he said.
Phages were discovered just over a century ago, but phage therapy was widely abandoned once antibiotics were developed, except for in Russia and the former Eastern Bloc countries, where phage therapy continued to be used.
Phage therapy “got new life” in the West, Schooley said, about 10-15 years ago with an increasing number of detailed and high-profile case reports, including one in which a UC San Diego colleague, Tom Patterson, PhD, contracted a deadly multidrug resistant bacterial infection in Egypt and was eventually saved with bacteriophage therapy. (The case was the subject of the book The Perfect Predator).
Since then, as described in case reports and studies in the literature, “hundreds of people have been treated with bacteriophages here and in Europe,” most commonly for pulmonary infections and infections in implanted vascular and orthopedic devices, said Schooley, who coauthored a review in Cell in 2023 that describes phage biology and advances and future directions in phage therapy.
The use of bacteriophages to prevent systemic infections during high-risk periods — such as during chemotherapeutic regimens for hematological regimens — is an area of interest, he said at the meeting.
In research that is making its way to a clinical trial of patients undergoing allogeneic hematopoietic stem cell transplant (HSCT), researchers screened a library of phages to identify those with broad coverage of Escherichia coli. Using tail fiber engineering and CRISPR technology, they then engineered a combination of the four most complementary bacteriophages to selectively kill E coli — including fluoroquinolone-resistant strains that, in patients whose GI tracts are colonized with these strains, can translocate from the gut into the bloodstream, causing sepsis, during chemotherapeutic regimens for HSCT.
In a mouse model, the CRISPR-enhanced four-phage cocktail (SNIPR001) led to a steady reduction in the E coli colony counts in stool, “showing you can modulate these bacteria in the gut by using bacteriophages to kill them,” Schooley said. Moreover, the CRISPR enhancement strengthened the phages’ ability to break up biofilms, he said, showing “that you can engineer bacteriophages to make them better killers.” A phase 1b/2a study is being planned.
Other Niches for Therapeutic Phages, Challenges
Bacteriophages also could be used to target a gut bacterium that has been shown to attenuate alcoholic liver disease. Patients with alcoholic hepatitis “have a gut microbiome that is different in distribution,” Schooley said, often with increased numbers of Enterococcus faecalis that produce cytolysin, an exotoxin that exacerbates liver injury and is associated with increased mortality.
In published research led by investigators at UC San Diego, stool from cytolysin-positive patients with alcoholic hepatitis was found to exacerbate ethanol-induced liver disease in gnotobiotic mice, and phage therapy against cytolytic E faecalis was found to abolish it, Schooley shared.
Research is also exploring the potential of phage therapy to selectively target adherent invasive E coli in Crohn’s disease, and Klebsiella pneumoniae in the gut microbiome as an exacerbator of inflammatory bowel disease (IBD), he said.
And investigators in Japan, he noted, have reported that bacteriophage therapy against K pneumoniae can ameliorate liver inflammation and disease severity in primary sclerosing cholangitis.
Challenges in the therapeutic use of phages include the narrow host range of phages and an uncertain predictive value of in vitro phage susceptibility testing. “We don’t know yet how to do resistance testing as well as we do with antibiotics,” he said.
In addition, most phages tend to be acid labile, requiring strategies to mitigate inactivation by gastric acid, and there are “major knowledge gaps” relating to phage pharmacology. “We also know that adaptive immune responses to phages can but often doesn’t impact therapy, and we want to understand that better in clinical trials,” Schooley said.
Phages that have a “lysogenic” lifestyle — as opposed to lytic phages which are used therapeutically — can contribute to antibiotic resistance by facilitating the interchange of bacterial resistance genes, he noted.
A Window Into the Mycobiome
The human gut mycobiome is primarily composed of fungi in the Saccharomyces, Candida, and Malassezia genera, with Candida species dominating. Fungal cells harbor distinct immune-stimulatory molecules and activate distinct immune pathways compared with bacteria and other members of the microbiome, said Ost, assistant professor in the immunology and microbiology department of CU Anschutz.
Some fungi, including those in the Candida genus, activate adaptive and innate immune responses that promote metabolic health and protect against infection. A recently published study in Science, for instance, demonstrated that colonization with C dubliniensis in very young mice who had been exposed to broad-spectrum antibiotics promoted “the expansion and development of beta cells in the pancreas” in a macrophage dependent manner, improving metabolic health and reducing diabetes incidence, she shared.
On the one hand, fungi can “exacerbate and perpetuate the pathogenic inflammation that’s found in a growing list of inflammatory diseases” such as IBD. And “in fact, a lot of the benefits and detriments are driven by the exact same species of fungi,” said Ost. “This is particularly true of Candida,” which is a “lifelong colonizer of intestinal microbiota that rarely causes disease but can be quite pathogenic when it does.”
A 2023 review in Nature Reviews Gastroenterology & Hepatology coauthored by Ost describes the role of commensal fungi in intestinal diseases, including IBD, colorectal cancer, and pancreatic cancer.
The pathogenic potential of commensal fungi is largely dependent on its strain, its morphology and its expression of virulence factors, researchers are learning. Ost has studied C albicans, which has been associated with intestinal inflammation and IBD. Like some other Candida species, C albicans are “fascinating shape shifters,” she said, transitioning between a less pathogenic “yeast” morphology and an elongated, adhesive “hyphae” shape that is more pathogenic.
It turns out, according to research by Ost and others, that the C albicans hyphal morphotype — and the adhesins (sticky proteins that facilitate adherence to epithelial cells) and a cytolytic toxin it produces — are preferentially targeted and suppressed by immunoglobulin A (IgA) in the gut.
“Our gut is protected by a large quantity of IgA antibodies…and these IgA interact with the microbiota and play a big role in what microbes are there and the biology of the microbes,” Ost said. Indeed, symptomatic IgA deficiency in humans has been shown to be associated with C albicans overgrowth.
Leveraging the hyphal-specific IgA response to protect against disease seems possible, she said, referring to an experimental anti-Candida fungal vaccine (NDV-3A) designed to induce an adhesin-specific immune response. In a mouse model of colitis, the vaccine protected against C albicans-associated damage. “We saw an immediate IgA response that targeted C albicans in the intestinal contents,” Ost said.
C glabrata, which has also been associated with intestinal inflammation and IBD, does not form hyphae but — depending on the strain — may also induce intestinal IgA responses, she said in describing her recent research.
Ost reported having no disclosures. Schooley disclosed being a consultant for SNIPR Biome, BiomX, Locus, MicrobiotiX, Amazon Data Monitoring Committee: Merck.
A version of this article appeared on Medscape.com.
FROM GMFH 2025
FDA Approves Avastin Biosimilar Agent, Jobevne
The United States Food and Drug Administration (FDA) has approved bevacizumab-nwgd (Jobevne, Biocon Biologics Ltd), a biosimilar to bevacizumab (Avastin, Genentech), for intravenous use across multiple cancer types.
Approval was based on “a comprehensive package of comparative pharmacokinetic, safety, efficacy, nonclinical, structural, analytical and functional data, which confirmed the Jobevne is highly similar to Avastin,” according to a Biocon Biologics Ltd press release.
“The data demonstrated that there were no clinically meaningful differences between Jobevne and Avastin in terms of pharmacokinetics, safety, efficacy, and immunogenicity,” the company stated.
The biosimilar agent is indicated as part of various combinations for the treatment of metastatic colorectal cancer, certain types of non-squamous non–small cell lung cancer, recurrent glioblastoma, metastatic renal cell carcinoma, certain advanced cervical cancers, and epithelial ovarian, fallopian tube, or primary peritoneal cancers, the company noted.
The agent is not indicated for adjuvant treatment of colon cancer, according to the press release, which includes detailed information about the indications, as well as a list of warnings and precautions.
A version of this article first appeared on Medscape.com.
The United States Food and Drug Administration (FDA) has approved bevacizumab-nwgd (Jobevne, Biocon Biologics Ltd), a biosimilar to bevacizumab (Avastin, Genentech), for intravenous use across multiple cancer types.
Approval was based on “a comprehensive package of comparative pharmacokinetic, safety, efficacy, nonclinical, structural, analytical and functional data, which confirmed the Jobevne is highly similar to Avastin,” according to a Biocon Biologics Ltd press release.
“The data demonstrated that there were no clinically meaningful differences between Jobevne and Avastin in terms of pharmacokinetics, safety, efficacy, and immunogenicity,” the company stated.
The biosimilar agent is indicated as part of various combinations for the treatment of metastatic colorectal cancer, certain types of non-squamous non–small cell lung cancer, recurrent glioblastoma, metastatic renal cell carcinoma, certain advanced cervical cancers, and epithelial ovarian, fallopian tube, or primary peritoneal cancers, the company noted.
The agent is not indicated for adjuvant treatment of colon cancer, according to the press release, which includes detailed information about the indications, as well as a list of warnings and precautions.
A version of this article first appeared on Medscape.com.
The United States Food and Drug Administration (FDA) has approved bevacizumab-nwgd (Jobevne, Biocon Biologics Ltd), a biosimilar to bevacizumab (Avastin, Genentech), for intravenous use across multiple cancer types.
Approval was based on “a comprehensive package of comparative pharmacokinetic, safety, efficacy, nonclinical, structural, analytical and functional data, which confirmed the Jobevne is highly similar to Avastin,” according to a Biocon Biologics Ltd press release.
“The data demonstrated that there were no clinically meaningful differences between Jobevne and Avastin in terms of pharmacokinetics, safety, efficacy, and immunogenicity,” the company stated.
The biosimilar agent is indicated as part of various combinations for the treatment of metastatic colorectal cancer, certain types of non-squamous non–small cell lung cancer, recurrent glioblastoma, metastatic renal cell carcinoma, certain advanced cervical cancers, and epithelial ovarian, fallopian tube, or primary peritoneal cancers, the company noted.
The agent is not indicated for adjuvant treatment of colon cancer, according to the press release, which includes detailed information about the indications, as well as a list of warnings and precautions.
A version of this article first appeared on Medscape.com.