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Consider cultural differences in IBD diet planning
AURORA, COLO. – Inflammatory bowel disease doesn’t respect international borders, and
“Many patients are in an environment that they’re not used to, an environment where most people speak English and their customs and their language may differ from the individual providing care to them. They’re often told, in addition, to eat foods that they may not even have heard of. It can really be a scary situation for many of these patients,” said Neha D. Shah, MPH, RD, CNSC, a dietitian at University of California San Francisco Health.
“Put yourself in their shoes. [Consider] what would make you feel more comfortable in that environment, and then apply that perspective to the care of your patient,” she advised colleagues at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
Ms. Shah explained that by incorporating understanding of cultural differences and food culture into the care of persons with IBD, clinicians can help patients from different ethnic backgrounds accept diets that both contain familiar foods and also help to ameliorate their gastrointestinal symptoms.
Food culture and acculturation
As of 2016, the estimated prevalence of IBD among pediatric patients in the United States was 77 per 100,000, and the prevalence in adults was estimated at 478.4 per 100,000. In a 2021 study of the effects of race and ethnicity on the diagnosis and management of IBD, the authors estimated that the prevalence of IBD in the United States was about 3.1 million persons, or 1.3% of the population, with an increase in prevalence in non-White persons and ethnicities, she noted.
Some of the increasing prevalence among minority populations may be attributable to diet acculturation, when members of a particular group partially or completely adopt the eating patterns and/or food choices of the host country.
Culturally appropriate foods
The term “food culture” refers to “the sociocultural aspect of eating, and include[s] the beliefs, values, and attitudes a community may accept around food,” she said.
Ms. Shah provided examples of culturally appropriate foods that may be tolerated by patients with IBD, such as beans, tortillas, chicken with rice, guacamole, mangos, and tomatoes in persons from South America, or lentils, breads, rice, oats, spinach, and tea among patients from the Indian subcontinent.
By understanding and respecting cultural differences, learning how to best communicate with persons of other cultures, and by being aware of one’s own biases, clinicians can better help patients create diet plans that fit within their expectations and lifestyles, she said.
For example, patients can be encouraged to incorporate more culturally familiar plant-based foods such as legumes to manage active disease and maintain remissions.
Patients with active disease should have at least one-half cup of one form of culturally appropriate fiber at each meal. The dietitian should consider recommending blending fiber into other foods or serving it cooked, mashed, or minced, depending upon the patient’s level of tolerance.
During the transition phase, patients can reintroduce an additional half cup of fiber at one meal, then at two meals, and finally at three daily meals. Patients can see whether they can tolerate more raw or whole high-fiber foods at this stage.
During remissions, patients should be advised to add two to three foods containing culturally appropriate fiber at each meal, she said.
‘Eye-opening’ realization
“I think it’s really eye-opening for us to think about how we have to have culturally sensitive discussions with our patients,” commented Sandra Kim, MD, from the University of Pittsburgh Medical Center, who moderated the session.
Dr. Kim asked Ms. Shah what advice she’d give to pediatric gastroenterologists about engaging patients and their families.
The clinician should ask both patients and parents about what the child eats and what the challenges of eating under certain circumstances are, and have culturally appropriate resources on hand.
Ms. Shah did not report a funding source for her work. She disclosed compensation as editor of the Journal of Practical Gastroeneterology and as GI on Demand–consultant for a joint virtual platform from the American College of Gastroenterology and Gastro Girl. She also serves as treasurer and director of operations for the South Asian IBD Alliance.
AURORA, COLO. – Inflammatory bowel disease doesn’t respect international borders, and
“Many patients are in an environment that they’re not used to, an environment where most people speak English and their customs and their language may differ from the individual providing care to them. They’re often told, in addition, to eat foods that they may not even have heard of. It can really be a scary situation for many of these patients,” said Neha D. Shah, MPH, RD, CNSC, a dietitian at University of California San Francisco Health.
“Put yourself in their shoes. [Consider] what would make you feel more comfortable in that environment, and then apply that perspective to the care of your patient,” she advised colleagues at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
Ms. Shah explained that by incorporating understanding of cultural differences and food culture into the care of persons with IBD, clinicians can help patients from different ethnic backgrounds accept diets that both contain familiar foods and also help to ameliorate their gastrointestinal symptoms.
Food culture and acculturation
As of 2016, the estimated prevalence of IBD among pediatric patients in the United States was 77 per 100,000, and the prevalence in adults was estimated at 478.4 per 100,000. In a 2021 study of the effects of race and ethnicity on the diagnosis and management of IBD, the authors estimated that the prevalence of IBD in the United States was about 3.1 million persons, or 1.3% of the population, with an increase in prevalence in non-White persons and ethnicities, she noted.
Some of the increasing prevalence among minority populations may be attributable to diet acculturation, when members of a particular group partially or completely adopt the eating patterns and/or food choices of the host country.
Culturally appropriate foods
The term “food culture” refers to “the sociocultural aspect of eating, and include[s] the beliefs, values, and attitudes a community may accept around food,” she said.
Ms. Shah provided examples of culturally appropriate foods that may be tolerated by patients with IBD, such as beans, tortillas, chicken with rice, guacamole, mangos, and tomatoes in persons from South America, or lentils, breads, rice, oats, spinach, and tea among patients from the Indian subcontinent.
By understanding and respecting cultural differences, learning how to best communicate with persons of other cultures, and by being aware of one’s own biases, clinicians can better help patients create diet plans that fit within their expectations and lifestyles, she said.
For example, patients can be encouraged to incorporate more culturally familiar plant-based foods such as legumes to manage active disease and maintain remissions.
Patients with active disease should have at least one-half cup of one form of culturally appropriate fiber at each meal. The dietitian should consider recommending blending fiber into other foods or serving it cooked, mashed, or minced, depending upon the patient’s level of tolerance.
During the transition phase, patients can reintroduce an additional half cup of fiber at one meal, then at two meals, and finally at three daily meals. Patients can see whether they can tolerate more raw or whole high-fiber foods at this stage.
During remissions, patients should be advised to add two to three foods containing culturally appropriate fiber at each meal, she said.
‘Eye-opening’ realization
“I think it’s really eye-opening for us to think about how we have to have culturally sensitive discussions with our patients,” commented Sandra Kim, MD, from the University of Pittsburgh Medical Center, who moderated the session.
Dr. Kim asked Ms. Shah what advice she’d give to pediatric gastroenterologists about engaging patients and their families.
The clinician should ask both patients and parents about what the child eats and what the challenges of eating under certain circumstances are, and have culturally appropriate resources on hand.
Ms. Shah did not report a funding source for her work. She disclosed compensation as editor of the Journal of Practical Gastroeneterology and as GI on Demand–consultant for a joint virtual platform from the American College of Gastroenterology and Gastro Girl. She also serves as treasurer and director of operations for the South Asian IBD Alliance.
AURORA, COLO. – Inflammatory bowel disease doesn’t respect international borders, and
“Many patients are in an environment that they’re not used to, an environment where most people speak English and their customs and their language may differ from the individual providing care to them. They’re often told, in addition, to eat foods that they may not even have heard of. It can really be a scary situation for many of these patients,” said Neha D. Shah, MPH, RD, CNSC, a dietitian at University of California San Francisco Health.
“Put yourself in their shoes. [Consider] what would make you feel more comfortable in that environment, and then apply that perspective to the care of your patient,” she advised colleagues at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
Ms. Shah explained that by incorporating understanding of cultural differences and food culture into the care of persons with IBD, clinicians can help patients from different ethnic backgrounds accept diets that both contain familiar foods and also help to ameliorate their gastrointestinal symptoms.
Food culture and acculturation
As of 2016, the estimated prevalence of IBD among pediatric patients in the United States was 77 per 100,000, and the prevalence in adults was estimated at 478.4 per 100,000. In a 2021 study of the effects of race and ethnicity on the diagnosis and management of IBD, the authors estimated that the prevalence of IBD in the United States was about 3.1 million persons, or 1.3% of the population, with an increase in prevalence in non-White persons and ethnicities, she noted.
Some of the increasing prevalence among minority populations may be attributable to diet acculturation, when members of a particular group partially or completely adopt the eating patterns and/or food choices of the host country.
Culturally appropriate foods
The term “food culture” refers to “the sociocultural aspect of eating, and include[s] the beliefs, values, and attitudes a community may accept around food,” she said.
Ms. Shah provided examples of culturally appropriate foods that may be tolerated by patients with IBD, such as beans, tortillas, chicken with rice, guacamole, mangos, and tomatoes in persons from South America, or lentils, breads, rice, oats, spinach, and tea among patients from the Indian subcontinent.
By understanding and respecting cultural differences, learning how to best communicate with persons of other cultures, and by being aware of one’s own biases, clinicians can better help patients create diet plans that fit within their expectations and lifestyles, she said.
For example, patients can be encouraged to incorporate more culturally familiar plant-based foods such as legumes to manage active disease and maintain remissions.
Patients with active disease should have at least one-half cup of one form of culturally appropriate fiber at each meal. The dietitian should consider recommending blending fiber into other foods or serving it cooked, mashed, or minced, depending upon the patient’s level of tolerance.
During the transition phase, patients can reintroduce an additional half cup of fiber at one meal, then at two meals, and finally at three daily meals. Patients can see whether they can tolerate more raw or whole high-fiber foods at this stage.
During remissions, patients should be advised to add two to three foods containing culturally appropriate fiber at each meal, she said.
‘Eye-opening’ realization
“I think it’s really eye-opening for us to think about how we have to have culturally sensitive discussions with our patients,” commented Sandra Kim, MD, from the University of Pittsburgh Medical Center, who moderated the session.
Dr. Kim asked Ms. Shah what advice she’d give to pediatric gastroenterologists about engaging patients and their families.
The clinician should ask both patients and parents about what the child eats and what the challenges of eating under certain circumstances are, and have culturally appropriate resources on hand.
Ms. Shah did not report a funding source for her work. She disclosed compensation as editor of the Journal of Practical Gastroeneterology and as GI on Demand–consultant for a joint virtual platform from the American College of Gastroenterology and Gastro Girl. She also serves as treasurer and director of operations for the South Asian IBD Alliance.
AT THE CROHN’S & COLITIS CONGRESS
Herbal combination tames active UC in small study
AURORA, COLO. –
Among 42 patients randomized on a 2:1 basis to receive either an enteric-coated pill containing 3 g of curcumin and qing-dai (CurQD) or placebo for 8 weeks, 43% of those assigned to receive the combination met the co-primary endpoint of a significant reduction in disease activity and objective evidence of response, compared with 8% of those assigned to placebo, reported Shomron Ben-Horin, MD, of Sheba Medical Center in Tel Aviv, Israel, and colleagues.
“In this randomized multicenter placebo-controlled trial, combination CurQD was found effective for inducing remission in active UC patients, including biologic-experienced patients,” they wrote in a scientific poster presented at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
Nice spice
Curcumin is a polyphenolic compound derived from the spice turmeric that has been shown to have antioxidative and anti-inflammatory properties. Qing-dai (QD), also known as indigo naturalis, has been used in traditional Chinese medicine as an anti-inflammatory. Both agents are available over the counter in the United States, and have been on the market in Israel as a combination since 2016, said coauthor Nir Salomon, a certified herbalist at Sheba Medical Center.
“What we have here is a combination of these two compounds that are specifically sourced – the gut-directed curcumin, which we developed, and the specifically-sourced QD, and we use them in a specific protocol with a formulation suitable for moderate to severe disease,” he said in an interview.
Mr. Salomon and colleagues in Israel and in Athens, Greece, tested CurQD in a two-part trial. The first part was a 4-week open-label study of CurQD in 10 patients with active UC defined by a Simple Clinical Colitis Activity Index (SCCAI) score of 5 or greater and a modified Mayo endoscopic subscore of 2 or greater.
Part 2 was the placebo-controlled trial described before, with 42 patients with active UC. For 49% of these patients immunomodulatory and/or biologic therapies had failed to induce or maintain remissions.
A total of 43% of patients assigned to CurQD met the primary combined endpoint of a reduction in SCCAI of at least 3 points and objective evidence of response, consisting of either a Mayo endoscopic subscore improvement of 1 or greater, or at least 50% reduction in calprotectin.
In all, 85.7% of patients assigned to CurQD had a clinical response, compared with 30.7% of those assigned to placebo (P < .001).
In addition, 75% of patients on CurQD had endoscopic improvement, compared with 20% on placebo (P = .036), and more patients on the combined supplement had at least 50% reductions in calprotectin levels (46.4% vs. 15.4%, respectively), although the difference did not reach statistical significance.
Patients randomized to CurQD had significantly better resolution of rectal bleeding by day 12 (P value not shown).
Eight additional weeks of maintenance on curcumin alone resulted in 93% retention at week 16 of clinical response, 80% retention of remissions, and 40% maintenance of clinical biomarker responses.
CurQD, but not placebo, was associated with activation of the aryl-hydrocarbon receptor (AhR) pathway. AhR is a nuclear receptor that has been implicated as a mediator of inflammatory bowel disease.
“Induction of AhR merits further study as [a] potential treatment target in active UC,” the investigators wrote.
Small molecule
“This is a very promising and nicely conducted trial. Previously there are separate trials both determining potential mechanisms of action as well as efficacy of curcumin and Qing Dai separately in this population. This is a nice study that uses the combination in patients with mild to moderate UC,” said Ashwin N. Ananthakrishnan, MBBS, MPH, a gastroenterology physician and researcher at Massachusetts General Hospital in Boston.
“Immunosuppressive treatments are very effective in our patients with IBD but there remains concern (particularly for patients) about the consequences of immunosuppression including risk of treatment associated cancer. Thus, there is a lot of interest in rigorous studies of nonimmunosuppressive treatments that may still be effective in relieving objective inflammation (apart from just symptomatic improvement). This study provides a nice evidence base for that. There remain multiple limitations including small sample size, potential generalizability to other populations, and importantly whether the efficacy is driven by curcumin or Qing Dai,” he said in reply to a request for independent commentary.
Dr. Ananthakrishnan was not involved in the study.
“This is great work! We are also studying Qing Dai/indigo naturalis and have developed a single small molecule that works similarly to this therapy,” Matt Davidson, PhD, of Azora Therapeutics in Encino, Calif., said in an online chat section of the meeting website.
In a separate scientific poster presented at the meeting, Dr. Davidson and Julie Saiki, PhD, also from Azora, reported that their company is developing a novel synthetic small molecule prodrug of indirubin, an AhR agonist derived from indigo that is purported to maximize colonic exposure while minimizing systemic exposure.
In mouse models of colitis, oral administration of the prodrug significantly reduced Disease Activity Index and weight loss similar in magnitude to the active compound indirubin, they reported.
The study was supported by Sheba Medical Center. Mr. Salomon disclosed speaking fees from various companies and has received consulting fees and has an equity position in EvNature, the manufacturer of CurQD. Dr. Ananthakrishnan reported having no disclosures relative to the study. Dr. Davidson is CEO and cofounder of Avora Therapeutics.
AURORA, COLO. –
Among 42 patients randomized on a 2:1 basis to receive either an enteric-coated pill containing 3 g of curcumin and qing-dai (CurQD) or placebo for 8 weeks, 43% of those assigned to receive the combination met the co-primary endpoint of a significant reduction in disease activity and objective evidence of response, compared with 8% of those assigned to placebo, reported Shomron Ben-Horin, MD, of Sheba Medical Center in Tel Aviv, Israel, and colleagues.
“In this randomized multicenter placebo-controlled trial, combination CurQD was found effective for inducing remission in active UC patients, including biologic-experienced patients,” they wrote in a scientific poster presented at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
Nice spice
Curcumin is a polyphenolic compound derived from the spice turmeric that has been shown to have antioxidative and anti-inflammatory properties. Qing-dai (QD), also known as indigo naturalis, has been used in traditional Chinese medicine as an anti-inflammatory. Both agents are available over the counter in the United States, and have been on the market in Israel as a combination since 2016, said coauthor Nir Salomon, a certified herbalist at Sheba Medical Center.
“What we have here is a combination of these two compounds that are specifically sourced – the gut-directed curcumin, which we developed, and the specifically-sourced QD, and we use them in a specific protocol with a formulation suitable for moderate to severe disease,” he said in an interview.
Mr. Salomon and colleagues in Israel and in Athens, Greece, tested CurQD in a two-part trial. The first part was a 4-week open-label study of CurQD in 10 patients with active UC defined by a Simple Clinical Colitis Activity Index (SCCAI) score of 5 or greater and a modified Mayo endoscopic subscore of 2 or greater.
Part 2 was the placebo-controlled trial described before, with 42 patients with active UC. For 49% of these patients immunomodulatory and/or biologic therapies had failed to induce or maintain remissions.
A total of 43% of patients assigned to CurQD met the primary combined endpoint of a reduction in SCCAI of at least 3 points and objective evidence of response, consisting of either a Mayo endoscopic subscore improvement of 1 or greater, or at least 50% reduction in calprotectin.
In all, 85.7% of patients assigned to CurQD had a clinical response, compared with 30.7% of those assigned to placebo (P < .001).
In addition, 75% of patients on CurQD had endoscopic improvement, compared with 20% on placebo (P = .036), and more patients on the combined supplement had at least 50% reductions in calprotectin levels (46.4% vs. 15.4%, respectively), although the difference did not reach statistical significance.
Patients randomized to CurQD had significantly better resolution of rectal bleeding by day 12 (P value not shown).
Eight additional weeks of maintenance on curcumin alone resulted in 93% retention at week 16 of clinical response, 80% retention of remissions, and 40% maintenance of clinical biomarker responses.
CurQD, but not placebo, was associated with activation of the aryl-hydrocarbon receptor (AhR) pathway. AhR is a nuclear receptor that has been implicated as a mediator of inflammatory bowel disease.
“Induction of AhR merits further study as [a] potential treatment target in active UC,” the investigators wrote.
Small molecule
“This is a very promising and nicely conducted trial. Previously there are separate trials both determining potential mechanisms of action as well as efficacy of curcumin and Qing Dai separately in this population. This is a nice study that uses the combination in patients with mild to moderate UC,” said Ashwin N. Ananthakrishnan, MBBS, MPH, a gastroenterology physician and researcher at Massachusetts General Hospital in Boston.
“Immunosuppressive treatments are very effective in our patients with IBD but there remains concern (particularly for patients) about the consequences of immunosuppression including risk of treatment associated cancer. Thus, there is a lot of interest in rigorous studies of nonimmunosuppressive treatments that may still be effective in relieving objective inflammation (apart from just symptomatic improvement). This study provides a nice evidence base for that. There remain multiple limitations including small sample size, potential generalizability to other populations, and importantly whether the efficacy is driven by curcumin or Qing Dai,” he said in reply to a request for independent commentary.
Dr. Ananthakrishnan was not involved in the study.
“This is great work! We are also studying Qing Dai/indigo naturalis and have developed a single small molecule that works similarly to this therapy,” Matt Davidson, PhD, of Azora Therapeutics in Encino, Calif., said in an online chat section of the meeting website.
In a separate scientific poster presented at the meeting, Dr. Davidson and Julie Saiki, PhD, also from Azora, reported that their company is developing a novel synthetic small molecule prodrug of indirubin, an AhR agonist derived from indigo that is purported to maximize colonic exposure while minimizing systemic exposure.
In mouse models of colitis, oral administration of the prodrug significantly reduced Disease Activity Index and weight loss similar in magnitude to the active compound indirubin, they reported.
The study was supported by Sheba Medical Center. Mr. Salomon disclosed speaking fees from various companies and has received consulting fees and has an equity position in EvNature, the manufacturer of CurQD. Dr. Ananthakrishnan reported having no disclosures relative to the study. Dr. Davidson is CEO and cofounder of Avora Therapeutics.
AURORA, COLO. –
Among 42 patients randomized on a 2:1 basis to receive either an enteric-coated pill containing 3 g of curcumin and qing-dai (CurQD) or placebo for 8 weeks, 43% of those assigned to receive the combination met the co-primary endpoint of a significant reduction in disease activity and objective evidence of response, compared with 8% of those assigned to placebo, reported Shomron Ben-Horin, MD, of Sheba Medical Center in Tel Aviv, Israel, and colleagues.
“In this randomized multicenter placebo-controlled trial, combination CurQD was found effective for inducing remission in active UC patients, including biologic-experienced patients,” they wrote in a scientific poster presented at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
Nice spice
Curcumin is a polyphenolic compound derived from the spice turmeric that has been shown to have antioxidative and anti-inflammatory properties. Qing-dai (QD), also known as indigo naturalis, has been used in traditional Chinese medicine as an anti-inflammatory. Both agents are available over the counter in the United States, and have been on the market in Israel as a combination since 2016, said coauthor Nir Salomon, a certified herbalist at Sheba Medical Center.
“What we have here is a combination of these two compounds that are specifically sourced – the gut-directed curcumin, which we developed, and the specifically-sourced QD, and we use them in a specific protocol with a formulation suitable for moderate to severe disease,” he said in an interview.
Mr. Salomon and colleagues in Israel and in Athens, Greece, tested CurQD in a two-part trial. The first part was a 4-week open-label study of CurQD in 10 patients with active UC defined by a Simple Clinical Colitis Activity Index (SCCAI) score of 5 or greater and a modified Mayo endoscopic subscore of 2 or greater.
Part 2 was the placebo-controlled trial described before, with 42 patients with active UC. For 49% of these patients immunomodulatory and/or biologic therapies had failed to induce or maintain remissions.
A total of 43% of patients assigned to CurQD met the primary combined endpoint of a reduction in SCCAI of at least 3 points and objective evidence of response, consisting of either a Mayo endoscopic subscore improvement of 1 or greater, or at least 50% reduction in calprotectin.
In all, 85.7% of patients assigned to CurQD had a clinical response, compared with 30.7% of those assigned to placebo (P < .001).
In addition, 75% of patients on CurQD had endoscopic improvement, compared with 20% on placebo (P = .036), and more patients on the combined supplement had at least 50% reductions in calprotectin levels (46.4% vs. 15.4%, respectively), although the difference did not reach statistical significance.
Patients randomized to CurQD had significantly better resolution of rectal bleeding by day 12 (P value not shown).
Eight additional weeks of maintenance on curcumin alone resulted in 93% retention at week 16 of clinical response, 80% retention of remissions, and 40% maintenance of clinical biomarker responses.
CurQD, but not placebo, was associated with activation of the aryl-hydrocarbon receptor (AhR) pathway. AhR is a nuclear receptor that has been implicated as a mediator of inflammatory bowel disease.
“Induction of AhR merits further study as [a] potential treatment target in active UC,” the investigators wrote.
Small molecule
“This is a very promising and nicely conducted trial. Previously there are separate trials both determining potential mechanisms of action as well as efficacy of curcumin and Qing Dai separately in this population. This is a nice study that uses the combination in patients with mild to moderate UC,” said Ashwin N. Ananthakrishnan, MBBS, MPH, a gastroenterology physician and researcher at Massachusetts General Hospital in Boston.
“Immunosuppressive treatments are very effective in our patients with IBD but there remains concern (particularly for patients) about the consequences of immunosuppression including risk of treatment associated cancer. Thus, there is a lot of interest in rigorous studies of nonimmunosuppressive treatments that may still be effective in relieving objective inflammation (apart from just symptomatic improvement). This study provides a nice evidence base for that. There remain multiple limitations including small sample size, potential generalizability to other populations, and importantly whether the efficacy is driven by curcumin or Qing Dai,” he said in reply to a request for independent commentary.
Dr. Ananthakrishnan was not involved in the study.
“This is great work! We are also studying Qing Dai/indigo naturalis and have developed a single small molecule that works similarly to this therapy,” Matt Davidson, PhD, of Azora Therapeutics in Encino, Calif., said in an online chat section of the meeting website.
In a separate scientific poster presented at the meeting, Dr. Davidson and Julie Saiki, PhD, also from Azora, reported that their company is developing a novel synthetic small molecule prodrug of indirubin, an AhR agonist derived from indigo that is purported to maximize colonic exposure while minimizing systemic exposure.
In mouse models of colitis, oral administration of the prodrug significantly reduced Disease Activity Index and weight loss similar in magnitude to the active compound indirubin, they reported.
The study was supported by Sheba Medical Center. Mr. Salomon disclosed speaking fees from various companies and has received consulting fees and has an equity position in EvNature, the manufacturer of CurQD. Dr. Ananthakrishnan reported having no disclosures relative to the study. Dr. Davidson is CEO and cofounder of Avora Therapeutics.
AT THE CROHN’S & COLITIS CONGRESS
Adult stem cells can heal intractable perianal Crohn’s fistulae
AURORA, COLO. – Perianal Crohn’s disease with fistula is notoriously difficult to treat and can make patients’ lives miserable, but a new, minimally invasive approach involving local injection of mesenchymal stem cells is both safe and, in a significant proportion of patients, highly effective, according to a colorectal surgeon.
“It’s a really debilitating phenotype, a spectrum of phenotypes,” Amy Lightner, MD, of the Cleveland Clinic said at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
Although some patients have minimal symptoms, others may require multiple setons to aid in drainage and healing, while others may require fistulotomy, endorectal advancement flap, intersphincteric fistula tract (LIFT) procedure, diversion, or proctectomy.
“Why is it so difficult to treat? Well, part of it is that this is an anatomic defect, and this is why 90% of patients will come to the operating room and will see their surgeons on a frequent basis. The other part of that is that we have medical therapies to treat these fistulas but they’re really largely ineffective, because there is that anatomical defect, the hole there that needs to be closed,” Dr. Lightner said.
Up to 20% of patients may require a permanent stoma, and an additional 20% may require temporary fecal diversion.
Mesenchymal stem cells (MSC) are derived from bone marrow, fat stores, or umbilical cord tissues. Unlike embryonic stem cells, which have the ability to metamorphose into a multitude of other cell types, mesenchymal stem cells are differentiated “adult” cells.
They work by secreting anti-inflammatory cytokines and recruiting immune cells to stimulate tissue repair and healing. The cells are delivered in a minimally invasive outpatient setting, and there is no risk of incontinence compared with more invasive procedures such as fistulotomy or advancement flaps.
Effective and safe
MSCs were first used in Spain in 2003 to successfully treat a young women with a complex fistula with five perianal tracts converging into a rectovaginal fistula. The investigators injected a single dose of 9 x 106 MSCs into the site, and the fistula healed within 3 months.
Since then in multiple clinical trials involving more than 400 patients, injection of MSCs has resulted in fistula closure and complete healing by 8-12 weeks in 50%-85% of patients, Dr. Lightner said.
The treatment effect is also durable, she said, pointing to data from the ADMIRE-CD study, in which 51.5% of Crohn’s disease patients with treatment-refractory complex perianal fistula were healed at 24 weeks following injection of adipose-derived stem cells, compared with 35.6% of controls. At 1 year of follow-up, respective rates of healing were 56.3% vs. 38.6%.
Dr. Lightner also cited a case report of a patient whose fistula remained healed 4 years after receiving MSCs for refractory perianal Crohn’s fistulas.
Although MSCs are derived from healthy donors, they do not bear cellular surface antigens that would instigate a destructive host immune response, and to date, there have been no reports from clinical trials of systemic infections or complications. The most frequently reported adverse events have been injection-site pain in about 12%-15% of patients, and perianal abscess in 5%-13%, with similar frequencies in treatment and control groups.
Dr. Lightner and colleagues are currently exploring additional indications for stem cell therapy with MSCs, including other complex fistula phenotypes, intestinal Crohn’s disease, and ulcerative colitis.
Other approaches
In a separate presentation, James D. Lewis, MD, MSCE, of the University of Pennsylvania in Philadelphia talked about what would be needed to achieve a “medical moonshot” with the goal of curing inflammatory bowel disease (IBD), and touched on hematopoietic stem cell transplants as a potential option for patients with chronic, severe, and intractable disease.
One of his patients was a woman in her 60s who was diagnosed with stricturing and penetrating Crohn’s disease in her 30s, with the disease involving the ileum and entire colon. She had previously undergone three small bowel resections and a partial colon resection, and had never experienced remission despite taking steroids, azathioprine, methotrexate, four anti-TNF drugs, ustekinumab (Stelara), and vedolizumab (Entyvio).
Following an autologous hematopoietic stem cell transplant, she had a Simple Endoscopic Score for Crohn’s Disease (SES-CD) of 0. Her course was complicated by demand ischemia and acute kidney injury.
An IBD specialist who was not involved in either study commented in an interview that both MSCs and stem cell transplants show promise for treatment-refractory IBD,
“Both approaches are very promising, but stem cell transplants for IBD haven’t been formally studied yet so the data aren’t as strong, but there is promise for the future,” said Berkeley N. Limketkai, MD, PhD, from the University of California, Los Angeles.
“The challenges, however, are also the morbidity associated with actually undergoing such procedures,” he continued. Short- and long-term morbidities associated with hematopoietic stem cell transplants may include mucositis; hemorrhagic cystitis; prolonged, severe pancytopenia; infection; graft-versus-host disease; graft failure; pulmonary complications, veno-occlusive disease of the liver; and thrombotic microangiopathy.
Dr. Limketkai said that over time as the protocols for stem cell transplants in IBD improve, the benefits for select patients may more clearly outweigh the risks.
Dr. Lightner’s work is supported by the Leona M. and Harry B. Helmsley Charitable Trust and the American Society of Colon and Rectal Surgery. She disclosed consulting fees from Boomerang Medical, Mesoblast Limited, Ossium Health, and Takeda Pharmaceuticals USA. Dr. Lewis’ work is supported by grants from the National Institutes of Health, and from AbbVie, Takeda, Janssen, and Nestlé Health Science. He has also served as a consultant to and data safety monitoring board member for several entities. Dr. Limketkai disclosed consulting for Azora Therapeutics.
AURORA, COLO. – Perianal Crohn’s disease with fistula is notoriously difficult to treat and can make patients’ lives miserable, but a new, minimally invasive approach involving local injection of mesenchymal stem cells is both safe and, in a significant proportion of patients, highly effective, according to a colorectal surgeon.
“It’s a really debilitating phenotype, a spectrum of phenotypes,” Amy Lightner, MD, of the Cleveland Clinic said at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
Although some patients have minimal symptoms, others may require multiple setons to aid in drainage and healing, while others may require fistulotomy, endorectal advancement flap, intersphincteric fistula tract (LIFT) procedure, diversion, or proctectomy.
“Why is it so difficult to treat? Well, part of it is that this is an anatomic defect, and this is why 90% of patients will come to the operating room and will see their surgeons on a frequent basis. The other part of that is that we have medical therapies to treat these fistulas but they’re really largely ineffective, because there is that anatomical defect, the hole there that needs to be closed,” Dr. Lightner said.
Up to 20% of patients may require a permanent stoma, and an additional 20% may require temporary fecal diversion.
Mesenchymal stem cells (MSC) are derived from bone marrow, fat stores, or umbilical cord tissues. Unlike embryonic stem cells, which have the ability to metamorphose into a multitude of other cell types, mesenchymal stem cells are differentiated “adult” cells.
They work by secreting anti-inflammatory cytokines and recruiting immune cells to stimulate tissue repair and healing. The cells are delivered in a minimally invasive outpatient setting, and there is no risk of incontinence compared with more invasive procedures such as fistulotomy or advancement flaps.
Effective and safe
MSCs were first used in Spain in 2003 to successfully treat a young women with a complex fistula with five perianal tracts converging into a rectovaginal fistula. The investigators injected a single dose of 9 x 106 MSCs into the site, and the fistula healed within 3 months.
Since then in multiple clinical trials involving more than 400 patients, injection of MSCs has resulted in fistula closure and complete healing by 8-12 weeks in 50%-85% of patients, Dr. Lightner said.
The treatment effect is also durable, she said, pointing to data from the ADMIRE-CD study, in which 51.5% of Crohn’s disease patients with treatment-refractory complex perianal fistula were healed at 24 weeks following injection of adipose-derived stem cells, compared with 35.6% of controls. At 1 year of follow-up, respective rates of healing were 56.3% vs. 38.6%.
Dr. Lightner also cited a case report of a patient whose fistula remained healed 4 years after receiving MSCs for refractory perianal Crohn’s fistulas.
Although MSCs are derived from healthy donors, they do not bear cellular surface antigens that would instigate a destructive host immune response, and to date, there have been no reports from clinical trials of systemic infections or complications. The most frequently reported adverse events have been injection-site pain in about 12%-15% of patients, and perianal abscess in 5%-13%, with similar frequencies in treatment and control groups.
Dr. Lightner and colleagues are currently exploring additional indications for stem cell therapy with MSCs, including other complex fistula phenotypes, intestinal Crohn’s disease, and ulcerative colitis.
Other approaches
In a separate presentation, James D. Lewis, MD, MSCE, of the University of Pennsylvania in Philadelphia talked about what would be needed to achieve a “medical moonshot” with the goal of curing inflammatory bowel disease (IBD), and touched on hematopoietic stem cell transplants as a potential option for patients with chronic, severe, and intractable disease.
One of his patients was a woman in her 60s who was diagnosed with stricturing and penetrating Crohn’s disease in her 30s, with the disease involving the ileum and entire colon. She had previously undergone three small bowel resections and a partial colon resection, and had never experienced remission despite taking steroids, azathioprine, methotrexate, four anti-TNF drugs, ustekinumab (Stelara), and vedolizumab (Entyvio).
Following an autologous hematopoietic stem cell transplant, she had a Simple Endoscopic Score for Crohn’s Disease (SES-CD) of 0. Her course was complicated by demand ischemia and acute kidney injury.
An IBD specialist who was not involved in either study commented in an interview that both MSCs and stem cell transplants show promise for treatment-refractory IBD,
“Both approaches are very promising, but stem cell transplants for IBD haven’t been formally studied yet so the data aren’t as strong, but there is promise for the future,” said Berkeley N. Limketkai, MD, PhD, from the University of California, Los Angeles.
“The challenges, however, are also the morbidity associated with actually undergoing such procedures,” he continued. Short- and long-term morbidities associated with hematopoietic stem cell transplants may include mucositis; hemorrhagic cystitis; prolonged, severe pancytopenia; infection; graft-versus-host disease; graft failure; pulmonary complications, veno-occlusive disease of the liver; and thrombotic microangiopathy.
Dr. Limketkai said that over time as the protocols for stem cell transplants in IBD improve, the benefits for select patients may more clearly outweigh the risks.
Dr. Lightner’s work is supported by the Leona M. and Harry B. Helmsley Charitable Trust and the American Society of Colon and Rectal Surgery. She disclosed consulting fees from Boomerang Medical, Mesoblast Limited, Ossium Health, and Takeda Pharmaceuticals USA. Dr. Lewis’ work is supported by grants from the National Institutes of Health, and from AbbVie, Takeda, Janssen, and Nestlé Health Science. He has also served as a consultant to and data safety monitoring board member for several entities. Dr. Limketkai disclosed consulting for Azora Therapeutics.
AURORA, COLO. – Perianal Crohn’s disease with fistula is notoriously difficult to treat and can make patients’ lives miserable, but a new, minimally invasive approach involving local injection of mesenchymal stem cells is both safe and, in a significant proportion of patients, highly effective, according to a colorectal surgeon.
“It’s a really debilitating phenotype, a spectrum of phenotypes,” Amy Lightner, MD, of the Cleveland Clinic said at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
Although some patients have minimal symptoms, others may require multiple setons to aid in drainage and healing, while others may require fistulotomy, endorectal advancement flap, intersphincteric fistula tract (LIFT) procedure, diversion, or proctectomy.
“Why is it so difficult to treat? Well, part of it is that this is an anatomic defect, and this is why 90% of patients will come to the operating room and will see their surgeons on a frequent basis. The other part of that is that we have medical therapies to treat these fistulas but they’re really largely ineffective, because there is that anatomical defect, the hole there that needs to be closed,” Dr. Lightner said.
Up to 20% of patients may require a permanent stoma, and an additional 20% may require temporary fecal diversion.
Mesenchymal stem cells (MSC) are derived from bone marrow, fat stores, or umbilical cord tissues. Unlike embryonic stem cells, which have the ability to metamorphose into a multitude of other cell types, mesenchymal stem cells are differentiated “adult” cells.
They work by secreting anti-inflammatory cytokines and recruiting immune cells to stimulate tissue repair and healing. The cells are delivered in a minimally invasive outpatient setting, and there is no risk of incontinence compared with more invasive procedures such as fistulotomy or advancement flaps.
Effective and safe
MSCs were first used in Spain in 2003 to successfully treat a young women with a complex fistula with five perianal tracts converging into a rectovaginal fistula. The investigators injected a single dose of 9 x 106 MSCs into the site, and the fistula healed within 3 months.
Since then in multiple clinical trials involving more than 400 patients, injection of MSCs has resulted in fistula closure and complete healing by 8-12 weeks in 50%-85% of patients, Dr. Lightner said.
The treatment effect is also durable, she said, pointing to data from the ADMIRE-CD study, in which 51.5% of Crohn’s disease patients with treatment-refractory complex perianal fistula were healed at 24 weeks following injection of adipose-derived stem cells, compared with 35.6% of controls. At 1 year of follow-up, respective rates of healing were 56.3% vs. 38.6%.
Dr. Lightner also cited a case report of a patient whose fistula remained healed 4 years after receiving MSCs for refractory perianal Crohn’s fistulas.
Although MSCs are derived from healthy donors, they do not bear cellular surface antigens that would instigate a destructive host immune response, and to date, there have been no reports from clinical trials of systemic infections or complications. The most frequently reported adverse events have been injection-site pain in about 12%-15% of patients, and perianal abscess in 5%-13%, with similar frequencies in treatment and control groups.
Dr. Lightner and colleagues are currently exploring additional indications for stem cell therapy with MSCs, including other complex fistula phenotypes, intestinal Crohn’s disease, and ulcerative colitis.
Other approaches
In a separate presentation, James D. Lewis, MD, MSCE, of the University of Pennsylvania in Philadelphia talked about what would be needed to achieve a “medical moonshot” with the goal of curing inflammatory bowel disease (IBD), and touched on hematopoietic stem cell transplants as a potential option for patients with chronic, severe, and intractable disease.
One of his patients was a woman in her 60s who was diagnosed with stricturing and penetrating Crohn’s disease in her 30s, with the disease involving the ileum and entire colon. She had previously undergone three small bowel resections and a partial colon resection, and had never experienced remission despite taking steroids, azathioprine, methotrexate, four anti-TNF drugs, ustekinumab (Stelara), and vedolizumab (Entyvio).
Following an autologous hematopoietic stem cell transplant, she had a Simple Endoscopic Score for Crohn’s Disease (SES-CD) of 0. Her course was complicated by demand ischemia and acute kidney injury.
An IBD specialist who was not involved in either study commented in an interview that both MSCs and stem cell transplants show promise for treatment-refractory IBD,
“Both approaches are very promising, but stem cell transplants for IBD haven’t been formally studied yet so the data aren’t as strong, but there is promise for the future,” said Berkeley N. Limketkai, MD, PhD, from the University of California, Los Angeles.
“The challenges, however, are also the morbidity associated with actually undergoing such procedures,” he continued. Short- and long-term morbidities associated with hematopoietic stem cell transplants may include mucositis; hemorrhagic cystitis; prolonged, severe pancytopenia; infection; graft-versus-host disease; graft failure; pulmonary complications, veno-occlusive disease of the liver; and thrombotic microangiopathy.
Dr. Limketkai said that over time as the protocols for stem cell transplants in IBD improve, the benefits for select patients may more clearly outweigh the risks.
Dr. Lightner’s work is supported by the Leona M. and Harry B. Helmsley Charitable Trust and the American Society of Colon and Rectal Surgery. She disclosed consulting fees from Boomerang Medical, Mesoblast Limited, Ossium Health, and Takeda Pharmaceuticals USA. Dr. Lewis’ work is supported by grants from the National Institutes of Health, and from AbbVie, Takeda, Janssen, and Nestlé Health Science. He has also served as a consultant to and data safety monitoring board member for several entities. Dr. Limketkai disclosed consulting for Azora Therapeutics.
AT CROHN’S & COLITIS CONGRESS
Gut enzymes fingered in some 5-ASA treatment failures
AURORA, COLO. – The therapeutic action of 5-aminosalicylic acid (5-ASA), one of the most frequently prescribed drugs for inflammatory bowel disease (IBD), can be defeated by enzymes that reside in the very gut that the drug is designed to treat.
“What we found is two gut microbial acetyltransferase families that were previously unknown to be participating in drug metabolism that directly inactivate the drug 5-ASA. It seems that in turn, having a subset of these microbial acetyltransferases is prospectively linked with treatment failure, and could potentially explain why some of these patients of ours fail on the drug,” Raaj S. Mehta, MD, MPH, a postdoctoral fellow at Massachusetts General Hospital in Boston, said at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
More than half of all patients with IBD treated with 5-ASA either lose their response to the drug or never respond to it at all, including some of his own patients, Dr. Mehta said.
There is an urgent need for a way to predict which patients will be likely to respond to 5-ASA and other drugs to treat IBD, he said.
The same old story
In the early 1990s, investigators at St. Radboud Hospital, Nijmegen, the Netherlands, studied cultured feces from patients with IBD treated with 5-ASA, and found in some patients that the drug was metabolized into N-acetyl-5-ASA. In an earlier, double-blind comparison trial in patients with idiopathic proctitis, the same investigators found N-acetyl-5-ASA to be “no better than placebo.”
“But prior to our work, we didn’t know which specific bacteria or enzymes performed this conversion ... of the drug, and we didn’t know if having these enzymes in your intestines or colon could explain why people are at risk for failing on 5-ASA,” Dr. Mehta said.
New evidence
Dr. Mehta and his colleagues first turned to the Human Microbiome Project 2, a cohort of 132 persons with IBD followed for 1 year each, with the goal of generating molecular profiles of host and microbial activity over time.
The patients provided stool samples about every 2 weeks, as well as blood and biopsy specimens, and reported details on their use of medications.
The investigators generated metagenomic, metatranscriptomic, genomic, and metabolomic profiles from the data, and then narrowed their focus to 45 participants who used 5-ASA and 34 who did not.
They found that “5-ASA has a major impact on the fecal metabolome,” with significant increases in fecal drug levels of both 5-ASA and the inactive metabolites, as well as more than 2,000 other metabolites.
Looking at the gemomics of gut microbiota, the investigators identified gene clusters in two superfamilies of enzymes, thiolases and acyl CoA N-acyltransferases. They identified 12 candidates.
To bolster their findings, they then expressed one gene from each superfamily in Escherichia coli and purified the protein. When they cocultured it with acetylCoA and 5-ASA, there was a greater than 25% conversion of the drug within 1 hour.
They also found that microbial thiolases appear to step outside of their normal roles to inactivate 5-ASA in a manner similar to that of an N-acetyltrasferase not found in persons with IBD.
Clinical relevance
To see whether their findings had clinical implications, the investigators conducted a case-cohort study nested within the Human Microbiome Project 2 cohort. They saw that, after adjusting for age, sex, IBD type, smoking, and N-acetyltransferase (NAT2) phenotype, 4 of the 12 acetyltranfserase candidates were associated with a roughly threefold increase in steroid use, suggesting that 5-ASA treatment had failed the patients.
“So then to take it one step further, we turned to the SPARC IBD cohort,” Dr. Mehta said.
SPARC IBD is an ongoing prospective cohort of patients who provide stool samples and detailed medication and symptom data.
They identified 208 cohort members who were on 5-ASA, were free of steroids at baseline, and who had fecal metabolomic data available. In this group, there were 60 cases of new corticosteroid prescriptions after about 8 months of follow-up.
The authors found that having three or four of the suspect acetyltransferases in gut microbiota was associated with a an overall odds ratio for 5-ASA treatment failure of 3.12 (95% confidence interval, 1.41-6.89).
“Taken together, I think this advances the idea of using the microbiome for personalized medicine in IBD,” Dr. Mehta said.
“Right now it’s an ideal outcome for a patient with [ulcerative colitis] to retain a robust remission on 5-ASA alone,” commented session moderator Michael J. Rosen, MD, MSCI, a pediatric gastroenterologist at Stanford University Medical Center in Palo Alto, Calif., who was not involved in the study.
Asked in an interview whether the findings would be likely to change clinical practice, Dr. Rosen replied that “I think it’s fairly early stage, but I think it’s wonderful that they sort of rediscovered this older data and are modernizing it to understand why [5-ASA] may not work for some patients. It certainly seems like it might be a tractable approach to use the microbiome to personalize therapy and potentially increase the effectiveness of 5-ASA.”
The study was supported by grants from Pfizer, the National Institutes of Health, American College of Gastroenterology, and the Crohn’s & Colitis Foundation. Dr. Mehta disclosed that his team has filed a provisional patent application related to the work. Dr. Rosen reported no relevant conflict of interest.
AURORA, COLO. – The therapeutic action of 5-aminosalicylic acid (5-ASA), one of the most frequently prescribed drugs for inflammatory bowel disease (IBD), can be defeated by enzymes that reside in the very gut that the drug is designed to treat.
“What we found is two gut microbial acetyltransferase families that were previously unknown to be participating in drug metabolism that directly inactivate the drug 5-ASA. It seems that in turn, having a subset of these microbial acetyltransferases is prospectively linked with treatment failure, and could potentially explain why some of these patients of ours fail on the drug,” Raaj S. Mehta, MD, MPH, a postdoctoral fellow at Massachusetts General Hospital in Boston, said at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
More than half of all patients with IBD treated with 5-ASA either lose their response to the drug or never respond to it at all, including some of his own patients, Dr. Mehta said.
There is an urgent need for a way to predict which patients will be likely to respond to 5-ASA and other drugs to treat IBD, he said.
The same old story
In the early 1990s, investigators at St. Radboud Hospital, Nijmegen, the Netherlands, studied cultured feces from patients with IBD treated with 5-ASA, and found in some patients that the drug was metabolized into N-acetyl-5-ASA. In an earlier, double-blind comparison trial in patients with idiopathic proctitis, the same investigators found N-acetyl-5-ASA to be “no better than placebo.”
“But prior to our work, we didn’t know which specific bacteria or enzymes performed this conversion ... of the drug, and we didn’t know if having these enzymes in your intestines or colon could explain why people are at risk for failing on 5-ASA,” Dr. Mehta said.
New evidence
Dr. Mehta and his colleagues first turned to the Human Microbiome Project 2, a cohort of 132 persons with IBD followed for 1 year each, with the goal of generating molecular profiles of host and microbial activity over time.
The patients provided stool samples about every 2 weeks, as well as blood and biopsy specimens, and reported details on their use of medications.
The investigators generated metagenomic, metatranscriptomic, genomic, and metabolomic profiles from the data, and then narrowed their focus to 45 participants who used 5-ASA and 34 who did not.
They found that “5-ASA has a major impact on the fecal metabolome,” with significant increases in fecal drug levels of both 5-ASA and the inactive metabolites, as well as more than 2,000 other metabolites.
Looking at the gemomics of gut microbiota, the investigators identified gene clusters in two superfamilies of enzymes, thiolases and acyl CoA N-acyltransferases. They identified 12 candidates.
To bolster their findings, they then expressed one gene from each superfamily in Escherichia coli and purified the protein. When they cocultured it with acetylCoA and 5-ASA, there was a greater than 25% conversion of the drug within 1 hour.
They also found that microbial thiolases appear to step outside of their normal roles to inactivate 5-ASA in a manner similar to that of an N-acetyltrasferase not found in persons with IBD.
Clinical relevance
To see whether their findings had clinical implications, the investigators conducted a case-cohort study nested within the Human Microbiome Project 2 cohort. They saw that, after adjusting for age, sex, IBD type, smoking, and N-acetyltransferase (NAT2) phenotype, 4 of the 12 acetyltranfserase candidates were associated with a roughly threefold increase in steroid use, suggesting that 5-ASA treatment had failed the patients.
“So then to take it one step further, we turned to the SPARC IBD cohort,” Dr. Mehta said.
SPARC IBD is an ongoing prospective cohort of patients who provide stool samples and detailed medication and symptom data.
They identified 208 cohort members who were on 5-ASA, were free of steroids at baseline, and who had fecal metabolomic data available. In this group, there were 60 cases of new corticosteroid prescriptions after about 8 months of follow-up.
The authors found that having three or four of the suspect acetyltransferases in gut microbiota was associated with a an overall odds ratio for 5-ASA treatment failure of 3.12 (95% confidence interval, 1.41-6.89).
“Taken together, I think this advances the idea of using the microbiome for personalized medicine in IBD,” Dr. Mehta said.
“Right now it’s an ideal outcome for a patient with [ulcerative colitis] to retain a robust remission on 5-ASA alone,” commented session moderator Michael J. Rosen, MD, MSCI, a pediatric gastroenterologist at Stanford University Medical Center in Palo Alto, Calif., who was not involved in the study.
Asked in an interview whether the findings would be likely to change clinical practice, Dr. Rosen replied that “I think it’s fairly early stage, but I think it’s wonderful that they sort of rediscovered this older data and are modernizing it to understand why [5-ASA] may not work for some patients. It certainly seems like it might be a tractable approach to use the microbiome to personalize therapy and potentially increase the effectiveness of 5-ASA.”
The study was supported by grants from Pfizer, the National Institutes of Health, American College of Gastroenterology, and the Crohn’s & Colitis Foundation. Dr. Mehta disclosed that his team has filed a provisional patent application related to the work. Dr. Rosen reported no relevant conflict of interest.
AURORA, COLO. – The therapeutic action of 5-aminosalicylic acid (5-ASA), one of the most frequently prescribed drugs for inflammatory bowel disease (IBD), can be defeated by enzymes that reside in the very gut that the drug is designed to treat.
“What we found is two gut microbial acetyltransferase families that were previously unknown to be participating in drug metabolism that directly inactivate the drug 5-ASA. It seems that in turn, having a subset of these microbial acetyltransferases is prospectively linked with treatment failure, and could potentially explain why some of these patients of ours fail on the drug,” Raaj S. Mehta, MD, MPH, a postdoctoral fellow at Massachusetts General Hospital in Boston, said at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
More than half of all patients with IBD treated with 5-ASA either lose their response to the drug or never respond to it at all, including some of his own patients, Dr. Mehta said.
There is an urgent need for a way to predict which patients will be likely to respond to 5-ASA and other drugs to treat IBD, he said.
The same old story
In the early 1990s, investigators at St. Radboud Hospital, Nijmegen, the Netherlands, studied cultured feces from patients with IBD treated with 5-ASA, and found in some patients that the drug was metabolized into N-acetyl-5-ASA. In an earlier, double-blind comparison trial in patients with idiopathic proctitis, the same investigators found N-acetyl-5-ASA to be “no better than placebo.”
“But prior to our work, we didn’t know which specific bacteria or enzymes performed this conversion ... of the drug, and we didn’t know if having these enzymes in your intestines or colon could explain why people are at risk for failing on 5-ASA,” Dr. Mehta said.
New evidence
Dr. Mehta and his colleagues first turned to the Human Microbiome Project 2, a cohort of 132 persons with IBD followed for 1 year each, with the goal of generating molecular profiles of host and microbial activity over time.
The patients provided stool samples about every 2 weeks, as well as blood and biopsy specimens, and reported details on their use of medications.
The investigators generated metagenomic, metatranscriptomic, genomic, and metabolomic profiles from the data, and then narrowed their focus to 45 participants who used 5-ASA and 34 who did not.
They found that “5-ASA has a major impact on the fecal metabolome,” with significant increases in fecal drug levels of both 5-ASA and the inactive metabolites, as well as more than 2,000 other metabolites.
Looking at the gemomics of gut microbiota, the investigators identified gene clusters in two superfamilies of enzymes, thiolases and acyl CoA N-acyltransferases. They identified 12 candidates.
To bolster their findings, they then expressed one gene from each superfamily in Escherichia coli and purified the protein. When they cocultured it with acetylCoA and 5-ASA, there was a greater than 25% conversion of the drug within 1 hour.
They also found that microbial thiolases appear to step outside of their normal roles to inactivate 5-ASA in a manner similar to that of an N-acetyltrasferase not found in persons with IBD.
Clinical relevance
To see whether their findings had clinical implications, the investigators conducted a case-cohort study nested within the Human Microbiome Project 2 cohort. They saw that, after adjusting for age, sex, IBD type, smoking, and N-acetyltransferase (NAT2) phenotype, 4 of the 12 acetyltranfserase candidates were associated with a roughly threefold increase in steroid use, suggesting that 5-ASA treatment had failed the patients.
“So then to take it one step further, we turned to the SPARC IBD cohort,” Dr. Mehta said.
SPARC IBD is an ongoing prospective cohort of patients who provide stool samples and detailed medication and symptom data.
They identified 208 cohort members who were on 5-ASA, were free of steroids at baseline, and who had fecal metabolomic data available. In this group, there were 60 cases of new corticosteroid prescriptions after about 8 months of follow-up.
The authors found that having three or four of the suspect acetyltransferases in gut microbiota was associated with a an overall odds ratio for 5-ASA treatment failure of 3.12 (95% confidence interval, 1.41-6.89).
“Taken together, I think this advances the idea of using the microbiome for personalized medicine in IBD,” Dr. Mehta said.
“Right now it’s an ideal outcome for a patient with [ulcerative colitis] to retain a robust remission on 5-ASA alone,” commented session moderator Michael J. Rosen, MD, MSCI, a pediatric gastroenterologist at Stanford University Medical Center in Palo Alto, Calif., who was not involved in the study.
Asked in an interview whether the findings would be likely to change clinical practice, Dr. Rosen replied that “I think it’s fairly early stage, but I think it’s wonderful that they sort of rediscovered this older data and are modernizing it to understand why [5-ASA] may not work for some patients. It certainly seems like it might be a tractable approach to use the microbiome to personalize therapy and potentially increase the effectiveness of 5-ASA.”
The study was supported by grants from Pfizer, the National Institutes of Health, American College of Gastroenterology, and the Crohn’s & Colitis Foundation. Dr. Mehta disclosed that his team has filed a provisional patent application related to the work. Dr. Rosen reported no relevant conflict of interest.
AT CROHN’S & COLITIS CONGRESS
Food additives may exacerbate IBD
AURORA, COLO. – Dietary additives lurking in processed foods may contribute to the development or exacerbation of inflammatory bowel disease (IBD), a leading gastroenterologist contends.
At the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association, James D. Lewis, MD, MSCE, AGAF, of the University of Pennsylvania in Philadelphia, highlighted research from both animal and human studies pointing to certain widely used food additives such as carboxymethycellulose (CMC), polysorbate 80, and carrageenan as potential instigators in gastrointestinal inflammation.
he said.
Some additives appear to have deleterious effects on intestinal microbiota, while others may exert their baleful influence through mechanisms such as endoplasmic stress.
“It looks like some people might be a little more sensitive to additives than others, and if you were going to use any of this [research] to try and give some advice, maybe we would say that patients or first-degree relatives of people with IBD may want to avoid foods that contain high levels of additives, and if for no other reason, mothers or people with a family history of IBD might be encouraged to breastfeed to avoid early exposure to additives that are in infant formulas,” he advised.
Processed foods defined
The typical American diet may include a large proportion of processed foods, defined as “foods that have undergone biological, chemical, or physical process to improve texture, taste, or shelf life.”
Processed foods tend to be higher in fats, added sugars, and salts, and lower in fiber and intrinsic vitamins than minimally processed foods.
There is also a category of “ultraprocessed” foods, which contain little or no whole foods but are high in energy density. Many of these super(bad) foods are staples of the American diet, such as chips, hot dogs, chicken nuggets, breakfast cereal, soda, candy, and margarine. These and similar foods contribute from 25% to 50% of daily energy intake in the United States and Canada, Dr. Lewis said.
And North America is not alone, he added, pointing to a 2015 study showing that the consumption of ultraprocessed foods in Sweden increased “dramatically” from 1960 through 2010, and that this increase mirrored an increase in obesity prevalence in that nation.
Emulsifiers and thickeners
Dr. Lewis focused on emulsifiers and thickeners that are commonly added to processed foods and are, according to the Food and Drug Administration, “generally recognized as safe.”
Emulsifiers are “detergent-like molecules that stabilize mixtures of immiscible [nonhomegenous] liquids.”
Thickeners are additives that increase the viscosity of liquids without otherwise substantially changing their other properties.
In addition to the aforementioned products, other common additives include xanthan gum (a polysaccharide used as an emulsifier in salad dressings, baked goods, ice cream, and gluten-free products), maltodextrin (a sugar substitute marketed as “Splenda”), and soy lecithin (a soy derivative used as an emulsifier, stabilizer, and wetting agent).
Evidence of harm
Dr. Lewis noted that in 2013, investigators at the University of Liverpool, England, published a hypothesis suggesting that consumption of emulsifiers in processed foods may promote Crohn’s disease by increasing bacterial translocation. Their hypothesis was based in part on evidence that “very small concentrations of the emulsifier polysorbate 80 enhance bacterial translocation across intestinal epithelia. Undigested emulsifiers may increase bacterial translocation, particularly in the small intestine where the mucus layer is discontinuous. “
The authors also suggested that their hypothesis could be tested in clinical trials comparing enteral feeding with and without emulsifiers.
Other suggestive if not definitive evidence of a potential link between additives and IBD are data showing that IBD is very rare in young children.
“In your early stages of your life, you’re not consuming a lot of ultraprocessed foods. Indeed, the rate of intake of at least fast foods, which you can think of almost as a surrogate for ultraprocessed foods, goes up dramatically when people get to their teens, and this is the same time as we see, really, the big uptick in the incidence of IBD,” Dr. Lewis said.
A link between ultraprocessed food consumption and later development of IBD, primarily Crohn’s disease, is also suggested by data from the Nurses Health Study I and II and Health Professionals Follow-Up study. Among 245,112 participants with about 5.5 million person-years of follow-up, the highest vs. lowest quartile of consumption of ultraprocessed foods was associated with a 70% increase in risk for developing Crohn’s (hazard ratio 1.70, P = .0008).
Animal studies
Evidence for a possible mechanism whereby emulsifiers and thickeners cause intestinal changes comes from a study published in Nature in 2015 showing that adding CMC and PS80 to the drinking water of mice resulted in major shifts in the gut microbiota in both wild-type and interleukin 10 knockout mice, a model for IBD.
When the additives were put into the water the mice had a thinning of the mucus layer, allowing bacteria in closer proximity to the epithelium.
“When you put these into the drinking water of IL-10 knockout mice that are already predisposed to developing colitis, they were far more likely to go on to develop colitis over the course of 3 months,” Dr. Lewis said.
From mouse to man
Dr. Lewis briefly summarized results of the FRESH study that he and colleagues recently published in Gastronterology. In this trial, 16 healthy adult volunteers who agreed to stay and eat all meals at the research center were randomized to receive either an emulsifier-free diet or the identical diet enriched with 15 g of CMC daily for 11 days.
“I will comment that that’s a lot of carboxymethycellulose,” Dr. Lewis said.
The volunteers fed the CMC-enriched diet had a slight increase in abdominal discomfort after eating and a reduction in species diversity in the gut microbiota. In addition, these participants had reductions in levels of short-chain fatty acids and free amino acids, both of which are signs of a health gut environment.
“Furthermore, we identified 2 subjects consuming CMC who exhibited increased microbiota encroachment into the normally sterile inner mucus layer, a central feature of gut inflammation, as well as stark alterations in microbiota composition,” the investigators wrote.
Dr. Lewis cited a separate small study by investigators at the University of Illinois at Chicago and the University of Chicago. These investigators randomized patients with UC in remission to take supplements containing carrageenan – a seaweed-derived food additive that has been shown to cause inflammation in both in vitro and animal models – or placebo . The amount of carrageenan in the capsules was less than that found in an average daily Western diet, the authors noted.
The participants were followed with telephone calls every 2 weeks or until relapse, which was defined as an increase of 2 or more points on the Simple Clinical Colitis Activity Index (SCCAI) and intensification of treatment for UC.
Of the 12 patients who completed the study, 3 in the carrageenan group experienced relapses, compared with none of the patients in the placebo group (P = .046). The relapse occurred at 5, 32, and 42 weeks of follow-up.
Exceptions to the rule
“It’s not clear that all additives are harmful,” Dr. Lewis said, pointing to a placebo-controlled study suggesting a beneficial effect of soy lecithin in patients with UC. The additive is composed of at least 30% of phosphatidycholine, a component of intestinal mucus.
He also noted that there is an ongoing randomized, placebo-controlled trial comparing a low-additive diet to a habitual diet in 154 patients with mildly active, stable Crohn’s disease.
Session moderator Michael J. Rosen, MD, MSCI, a pediatric gastroenterologist at Stanford University Medical Center in Palo Alto, Calif., told this news organization that dietary components do appear to have an influence on the disease course in patients with IBD.
“I do think there are patients with IBD who are maybe genetically predisposed to being sensitive to certain components of diet,” he said in an interview seeking objective commentary.
“Particularly in pediatrics there are lines of evidence of diets maybe having some efficacy in treatment. It needs further study, but one commonality about those diets is that they tend to eliminate processed foods and focus on whole foods,” he said.
Dr. Lewis’ work is supported by grants from the National Institutes of Health, and from AbbVie, Takeda, Janssen, and Nestlé Health Science. He has served as a consultant to and data safety monitoring board member for several entitities. Dr. Rosen reported no conflicts of interest to disclose.
AURORA, COLO. – Dietary additives lurking in processed foods may contribute to the development or exacerbation of inflammatory bowel disease (IBD), a leading gastroenterologist contends.
At the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association, James D. Lewis, MD, MSCE, AGAF, of the University of Pennsylvania in Philadelphia, highlighted research from both animal and human studies pointing to certain widely used food additives such as carboxymethycellulose (CMC), polysorbate 80, and carrageenan as potential instigators in gastrointestinal inflammation.
he said.
Some additives appear to have deleterious effects on intestinal microbiota, while others may exert their baleful influence through mechanisms such as endoplasmic stress.
“It looks like some people might be a little more sensitive to additives than others, and if you were going to use any of this [research] to try and give some advice, maybe we would say that patients or first-degree relatives of people with IBD may want to avoid foods that contain high levels of additives, and if for no other reason, mothers or people with a family history of IBD might be encouraged to breastfeed to avoid early exposure to additives that are in infant formulas,” he advised.
Processed foods defined
The typical American diet may include a large proportion of processed foods, defined as “foods that have undergone biological, chemical, or physical process to improve texture, taste, or shelf life.”
Processed foods tend to be higher in fats, added sugars, and salts, and lower in fiber and intrinsic vitamins than minimally processed foods.
There is also a category of “ultraprocessed” foods, which contain little or no whole foods but are high in energy density. Many of these super(bad) foods are staples of the American diet, such as chips, hot dogs, chicken nuggets, breakfast cereal, soda, candy, and margarine. These and similar foods contribute from 25% to 50% of daily energy intake in the United States and Canada, Dr. Lewis said.
And North America is not alone, he added, pointing to a 2015 study showing that the consumption of ultraprocessed foods in Sweden increased “dramatically” from 1960 through 2010, and that this increase mirrored an increase in obesity prevalence in that nation.
Emulsifiers and thickeners
Dr. Lewis focused on emulsifiers and thickeners that are commonly added to processed foods and are, according to the Food and Drug Administration, “generally recognized as safe.”
Emulsifiers are “detergent-like molecules that stabilize mixtures of immiscible [nonhomegenous] liquids.”
Thickeners are additives that increase the viscosity of liquids without otherwise substantially changing their other properties.
In addition to the aforementioned products, other common additives include xanthan gum (a polysaccharide used as an emulsifier in salad dressings, baked goods, ice cream, and gluten-free products), maltodextrin (a sugar substitute marketed as “Splenda”), and soy lecithin (a soy derivative used as an emulsifier, stabilizer, and wetting agent).
Evidence of harm
Dr. Lewis noted that in 2013, investigators at the University of Liverpool, England, published a hypothesis suggesting that consumption of emulsifiers in processed foods may promote Crohn’s disease by increasing bacterial translocation. Their hypothesis was based in part on evidence that “very small concentrations of the emulsifier polysorbate 80 enhance bacterial translocation across intestinal epithelia. Undigested emulsifiers may increase bacterial translocation, particularly in the small intestine where the mucus layer is discontinuous. “
The authors also suggested that their hypothesis could be tested in clinical trials comparing enteral feeding with and without emulsifiers.
Other suggestive if not definitive evidence of a potential link between additives and IBD are data showing that IBD is very rare in young children.
“In your early stages of your life, you’re not consuming a lot of ultraprocessed foods. Indeed, the rate of intake of at least fast foods, which you can think of almost as a surrogate for ultraprocessed foods, goes up dramatically when people get to their teens, and this is the same time as we see, really, the big uptick in the incidence of IBD,” Dr. Lewis said.
A link between ultraprocessed food consumption and later development of IBD, primarily Crohn’s disease, is also suggested by data from the Nurses Health Study I and II and Health Professionals Follow-Up study. Among 245,112 participants with about 5.5 million person-years of follow-up, the highest vs. lowest quartile of consumption of ultraprocessed foods was associated with a 70% increase in risk for developing Crohn’s (hazard ratio 1.70, P = .0008).
Animal studies
Evidence for a possible mechanism whereby emulsifiers and thickeners cause intestinal changes comes from a study published in Nature in 2015 showing that adding CMC and PS80 to the drinking water of mice resulted in major shifts in the gut microbiota in both wild-type and interleukin 10 knockout mice, a model for IBD.
When the additives were put into the water the mice had a thinning of the mucus layer, allowing bacteria in closer proximity to the epithelium.
“When you put these into the drinking water of IL-10 knockout mice that are already predisposed to developing colitis, they were far more likely to go on to develop colitis over the course of 3 months,” Dr. Lewis said.
From mouse to man
Dr. Lewis briefly summarized results of the FRESH study that he and colleagues recently published in Gastronterology. In this trial, 16 healthy adult volunteers who agreed to stay and eat all meals at the research center were randomized to receive either an emulsifier-free diet or the identical diet enriched with 15 g of CMC daily for 11 days.
“I will comment that that’s a lot of carboxymethycellulose,” Dr. Lewis said.
The volunteers fed the CMC-enriched diet had a slight increase in abdominal discomfort after eating and a reduction in species diversity in the gut microbiota. In addition, these participants had reductions in levels of short-chain fatty acids and free amino acids, both of which are signs of a health gut environment.
“Furthermore, we identified 2 subjects consuming CMC who exhibited increased microbiota encroachment into the normally sterile inner mucus layer, a central feature of gut inflammation, as well as stark alterations in microbiota composition,” the investigators wrote.
Dr. Lewis cited a separate small study by investigators at the University of Illinois at Chicago and the University of Chicago. These investigators randomized patients with UC in remission to take supplements containing carrageenan – a seaweed-derived food additive that has been shown to cause inflammation in both in vitro and animal models – or placebo . The amount of carrageenan in the capsules was less than that found in an average daily Western diet, the authors noted.
The participants were followed with telephone calls every 2 weeks or until relapse, which was defined as an increase of 2 or more points on the Simple Clinical Colitis Activity Index (SCCAI) and intensification of treatment for UC.
Of the 12 patients who completed the study, 3 in the carrageenan group experienced relapses, compared with none of the patients in the placebo group (P = .046). The relapse occurred at 5, 32, and 42 weeks of follow-up.
Exceptions to the rule
“It’s not clear that all additives are harmful,” Dr. Lewis said, pointing to a placebo-controlled study suggesting a beneficial effect of soy lecithin in patients with UC. The additive is composed of at least 30% of phosphatidycholine, a component of intestinal mucus.
He also noted that there is an ongoing randomized, placebo-controlled trial comparing a low-additive diet to a habitual diet in 154 patients with mildly active, stable Crohn’s disease.
Session moderator Michael J. Rosen, MD, MSCI, a pediatric gastroenterologist at Stanford University Medical Center in Palo Alto, Calif., told this news organization that dietary components do appear to have an influence on the disease course in patients with IBD.
“I do think there are patients with IBD who are maybe genetically predisposed to being sensitive to certain components of diet,” he said in an interview seeking objective commentary.
“Particularly in pediatrics there are lines of evidence of diets maybe having some efficacy in treatment. It needs further study, but one commonality about those diets is that they tend to eliminate processed foods and focus on whole foods,” he said.
Dr. Lewis’ work is supported by grants from the National Institutes of Health, and from AbbVie, Takeda, Janssen, and Nestlé Health Science. He has served as a consultant to and data safety monitoring board member for several entitities. Dr. Rosen reported no conflicts of interest to disclose.
AURORA, COLO. – Dietary additives lurking in processed foods may contribute to the development or exacerbation of inflammatory bowel disease (IBD), a leading gastroenterologist contends.
At the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association, James D. Lewis, MD, MSCE, AGAF, of the University of Pennsylvania in Philadelphia, highlighted research from both animal and human studies pointing to certain widely used food additives such as carboxymethycellulose (CMC), polysorbate 80, and carrageenan as potential instigators in gastrointestinal inflammation.
he said.
Some additives appear to have deleterious effects on intestinal microbiota, while others may exert their baleful influence through mechanisms such as endoplasmic stress.
“It looks like some people might be a little more sensitive to additives than others, and if you were going to use any of this [research] to try and give some advice, maybe we would say that patients or first-degree relatives of people with IBD may want to avoid foods that contain high levels of additives, and if for no other reason, mothers or people with a family history of IBD might be encouraged to breastfeed to avoid early exposure to additives that are in infant formulas,” he advised.
Processed foods defined
The typical American diet may include a large proportion of processed foods, defined as “foods that have undergone biological, chemical, or physical process to improve texture, taste, or shelf life.”
Processed foods tend to be higher in fats, added sugars, and salts, and lower in fiber and intrinsic vitamins than minimally processed foods.
There is also a category of “ultraprocessed” foods, which contain little or no whole foods but are high in energy density. Many of these super(bad) foods are staples of the American diet, such as chips, hot dogs, chicken nuggets, breakfast cereal, soda, candy, and margarine. These and similar foods contribute from 25% to 50% of daily energy intake in the United States and Canada, Dr. Lewis said.
And North America is not alone, he added, pointing to a 2015 study showing that the consumption of ultraprocessed foods in Sweden increased “dramatically” from 1960 through 2010, and that this increase mirrored an increase in obesity prevalence in that nation.
Emulsifiers and thickeners
Dr. Lewis focused on emulsifiers and thickeners that are commonly added to processed foods and are, according to the Food and Drug Administration, “generally recognized as safe.”
Emulsifiers are “detergent-like molecules that stabilize mixtures of immiscible [nonhomegenous] liquids.”
Thickeners are additives that increase the viscosity of liquids without otherwise substantially changing their other properties.
In addition to the aforementioned products, other common additives include xanthan gum (a polysaccharide used as an emulsifier in salad dressings, baked goods, ice cream, and gluten-free products), maltodextrin (a sugar substitute marketed as “Splenda”), and soy lecithin (a soy derivative used as an emulsifier, stabilizer, and wetting agent).
Evidence of harm
Dr. Lewis noted that in 2013, investigators at the University of Liverpool, England, published a hypothesis suggesting that consumption of emulsifiers in processed foods may promote Crohn’s disease by increasing bacterial translocation. Their hypothesis was based in part on evidence that “very small concentrations of the emulsifier polysorbate 80 enhance bacterial translocation across intestinal epithelia. Undigested emulsifiers may increase bacterial translocation, particularly in the small intestine where the mucus layer is discontinuous. “
The authors also suggested that their hypothesis could be tested in clinical trials comparing enteral feeding with and without emulsifiers.
Other suggestive if not definitive evidence of a potential link between additives and IBD are data showing that IBD is very rare in young children.
“In your early stages of your life, you’re not consuming a lot of ultraprocessed foods. Indeed, the rate of intake of at least fast foods, which you can think of almost as a surrogate for ultraprocessed foods, goes up dramatically when people get to their teens, and this is the same time as we see, really, the big uptick in the incidence of IBD,” Dr. Lewis said.
A link between ultraprocessed food consumption and later development of IBD, primarily Crohn’s disease, is also suggested by data from the Nurses Health Study I and II and Health Professionals Follow-Up study. Among 245,112 participants with about 5.5 million person-years of follow-up, the highest vs. lowest quartile of consumption of ultraprocessed foods was associated with a 70% increase in risk for developing Crohn’s (hazard ratio 1.70, P = .0008).
Animal studies
Evidence for a possible mechanism whereby emulsifiers and thickeners cause intestinal changes comes from a study published in Nature in 2015 showing that adding CMC and PS80 to the drinking water of mice resulted in major shifts in the gut microbiota in both wild-type and interleukin 10 knockout mice, a model for IBD.
When the additives were put into the water the mice had a thinning of the mucus layer, allowing bacteria in closer proximity to the epithelium.
“When you put these into the drinking water of IL-10 knockout mice that are already predisposed to developing colitis, they were far more likely to go on to develop colitis over the course of 3 months,” Dr. Lewis said.
From mouse to man
Dr. Lewis briefly summarized results of the FRESH study that he and colleagues recently published in Gastronterology. In this trial, 16 healthy adult volunteers who agreed to stay and eat all meals at the research center were randomized to receive either an emulsifier-free diet or the identical diet enriched with 15 g of CMC daily for 11 days.
“I will comment that that’s a lot of carboxymethycellulose,” Dr. Lewis said.
The volunteers fed the CMC-enriched diet had a slight increase in abdominal discomfort after eating and a reduction in species diversity in the gut microbiota. In addition, these participants had reductions in levels of short-chain fatty acids and free amino acids, both of which are signs of a health gut environment.
“Furthermore, we identified 2 subjects consuming CMC who exhibited increased microbiota encroachment into the normally sterile inner mucus layer, a central feature of gut inflammation, as well as stark alterations in microbiota composition,” the investigators wrote.
Dr. Lewis cited a separate small study by investigators at the University of Illinois at Chicago and the University of Chicago. These investigators randomized patients with UC in remission to take supplements containing carrageenan – a seaweed-derived food additive that has been shown to cause inflammation in both in vitro and animal models – or placebo . The amount of carrageenan in the capsules was less than that found in an average daily Western diet, the authors noted.
The participants were followed with telephone calls every 2 weeks or until relapse, which was defined as an increase of 2 or more points on the Simple Clinical Colitis Activity Index (SCCAI) and intensification of treatment for UC.
Of the 12 patients who completed the study, 3 in the carrageenan group experienced relapses, compared with none of the patients in the placebo group (P = .046). The relapse occurred at 5, 32, and 42 weeks of follow-up.
Exceptions to the rule
“It’s not clear that all additives are harmful,” Dr. Lewis said, pointing to a placebo-controlled study suggesting a beneficial effect of soy lecithin in patients with UC. The additive is composed of at least 30% of phosphatidycholine, a component of intestinal mucus.
He also noted that there is an ongoing randomized, placebo-controlled trial comparing a low-additive diet to a habitual diet in 154 patients with mildly active, stable Crohn’s disease.
Session moderator Michael J. Rosen, MD, MSCI, a pediatric gastroenterologist at Stanford University Medical Center in Palo Alto, Calif., told this news organization that dietary components do appear to have an influence on the disease course in patients with IBD.
“I do think there are patients with IBD who are maybe genetically predisposed to being sensitive to certain components of diet,” he said in an interview seeking objective commentary.
“Particularly in pediatrics there are lines of evidence of diets maybe having some efficacy in treatment. It needs further study, but one commonality about those diets is that they tend to eliminate processed foods and focus on whole foods,” he said.
Dr. Lewis’ work is supported by grants from the National Institutes of Health, and from AbbVie, Takeda, Janssen, and Nestlé Health Science. He has served as a consultant to and data safety monitoring board member for several entitities. Dr. Rosen reported no conflicts of interest to disclose.
AT THE CROHN’S & COLITIS CONGRESS
Proof lacking for dual-targeted therapy benefit in IBD
AURORA, COLO. – Only sparse evidence supports the use of dual-targeted therapy for patients with severe, refractory inflammatory bowel disease (IBD) -- and additional evidence will be hard to come by, according to a leading IBD researcher.
Dual-targeted therapy consists of either sequential or concomitant treatment with drugs from different classes of agents with distinct, specific mechanisms of action such as the use of a drug targeted against tumor necrosis factor (anti-TNFs) with an interleukin-12/23 inhibitor.
There have been only a handful of randomized clinical trials exploring such combinations, however. In addition, there are barriers to new trials, including the costs and risks of randomized trials, the need for cooperation rather than competition between pharmaceutical companies, and identifying patients who might optimally benefit from dual-targeted therapy, Laura Targownik, MD, said in a presentation at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
“In Canada we have absolutely no chance of getting coverage for this, and I imagine in hearing about the fights you have with insurers here in the [United] States, that you’re anticipating similar problems. So what do we do with this information? I think if we’re going to get answers on this question, it’s probably going to come from real-world evidence, from all of our experiences,” said Dr. Targownik of the Zane Cohen Centre for Digestive Diseases at Mount Sinai Hospital in Toronto.
Who might benefit?
Dual-targeted therapy has the potential to benefit patients with severe disease who may need intensive therapy upfront to prevent complications such as fistulas, strictures, or chronic abdominal pain. It may also benefit those who may require only short-term acute disease control; patients with meaningful yet incomplete responses to single-agent therapy who might have better outcomes with the addition of a second agent; and, patients with a unique phenotype that might be responsive to dual-targeted agents, Dr. Targownik said.
Another reason to consider dual-targeted therapy in IBD comes from applying data from recent clinical trials of upadacitinib (Rinvoq, Abbvie) for ulcerative colitis (UC) and risankizumab-rzaa (Skyrizi, Abbvie) for Crohn’s disease to hypothetical cohorts.
For example, of 1,000 persons with moderate to severe UC treated with upadacitinib, 736 would have a clinical response at the end of the induction, and at the end of the maintenance phase 191 would have endoscopic remissions, and 382 would remain in clinical remission.
Similarly, of 1,000 persons with moderate to severe Crohn’s disease treated with risankizumab, 434 would have a clinical response at the end of induction, and at the end of the maintenance phase, 172 would have endoscopic remissions, and 234 would remain in clinical remission.
“So, the vast majority of our patients are not achieving the targets that we want to hit,” she said.
Evidence from research clinical trials
Data from one of the few trials that have explored dual targeted therapy in IBD were presented at United European Gastroenterology Week in 2022.
The randomized double-blind phase 2a VEGA study looked at induction therapy with either a combination of the IL-23 inhibitor guselkumab (Tremfya, Janssen) and the anti-TNF monoclonal antibody golimumab (Simponi Aria, Janssen) followed by maintenance guselkumab, or each agent alone as induction monotherapy and maintenance.
The study population included 214 patients with moderate to severe UC with a modified Mayo Disease Activity Index scores of 6 or greater and endoscopy scores of 2 or 3 who had not received either anti-TNF or anti IL-23 agents.
At 12 weeks of follow-up, 36.6% of patients who started on combination therapy had clinical remissions, compared with 22.2% of patients on golimumab monotherapy and 22.1% of those on guselkumab alone, a clinically significant difference, Dr. Targownik said.
The combination also resulted in better endoscopic improvement over baseline (49.3% vs. 25% and 29.6%, respectively), although the study was not powered for this outcome.
At 38 weeks, 22.2% of patients who started on golimumab alone were in clinical remission, compared with 31% of those assigned to guselkumab monotherapy and 43.7% of those who started on the combination.
Endoscopic normalization at 38 weeks was seen in 6.9%, 15.5%, and 25.4% of patients, respectively.
“Even in the patients who went back on guselkumab monotherapy that were induced with dual therapy, there were statistically higher rates of clinical remission and endoscopic normalization at the end of the study,” Dr. Targownik said, although she noted that it’s unknown whether the benefit of the combination would be sustained over longer follow-up.
In the open-label EXPLORER Crohn’s disease trial, among 55 patients with high risk Crohn’s disease, within 24 months of diagnosis investigators looked at the triple combination therapy of the anti-integrin agent vedolizumab (Entyvio, Takeda), the anti-TNF agent adalimumab (Humira, Abbvie) and methotrexate. An interim analysis at week 26 of the 34-week trial showed clinical remissions in 54.5% of patients and endoscopic remissions in 34.5%, “which I would argue for an open-label study are not terribly high results,” she said.
Real-world experience
Dr. Targownik pointed to a systematic review and meta-analysis of the safety and effectiveness of combining biologic agents and small molecules in patients with IBD as evidence for how combinations work in the real world.
The analysis included data from 1 clinical trial and 12 observational studies on a total of 266 patients treated with one of seven different combinations. It showed estimates of clinical efficacy ranging from about 40% to 80%, albeit with wide and overlapping confidence intervals, making it difficult to come to any conclusions about the relatively superiority of one combination over another, Dr. Targownik said.
The authors of the meta-analysis did note, however, that the incidence of serious adverse events was relatively low, ranging from 9.6% for the combination of vedolizumab and anti-TNF, to just 1% for the JAK inhibitor tofacitinib (Xeljanz, Pfizer) plus vedolizumab.
Registry data may help
The use of registry data will shed more light on the potential benefits and drawbacks of dual-targeted therapy.
“If we can identify...the patient phenotypes that we want to evaluate dual therapy in, and try to catalog their experiences in a regimented way with defined outcomes and periods of follow-up, we may be able to get more meaningful information,” Dr. Targownik said.
Dr. Targownik disclosed fees, grant support, and/or scientific advisory board participation with multiple companies.
This article was updated 1/25/23.
AURORA, COLO. – Only sparse evidence supports the use of dual-targeted therapy for patients with severe, refractory inflammatory bowel disease (IBD) -- and additional evidence will be hard to come by, according to a leading IBD researcher.
Dual-targeted therapy consists of either sequential or concomitant treatment with drugs from different classes of agents with distinct, specific mechanisms of action such as the use of a drug targeted against tumor necrosis factor (anti-TNFs) with an interleukin-12/23 inhibitor.
There have been only a handful of randomized clinical trials exploring such combinations, however. In addition, there are barriers to new trials, including the costs and risks of randomized trials, the need for cooperation rather than competition between pharmaceutical companies, and identifying patients who might optimally benefit from dual-targeted therapy, Laura Targownik, MD, said in a presentation at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
“In Canada we have absolutely no chance of getting coverage for this, and I imagine in hearing about the fights you have with insurers here in the [United] States, that you’re anticipating similar problems. So what do we do with this information? I think if we’re going to get answers on this question, it’s probably going to come from real-world evidence, from all of our experiences,” said Dr. Targownik of the Zane Cohen Centre for Digestive Diseases at Mount Sinai Hospital in Toronto.
Who might benefit?
Dual-targeted therapy has the potential to benefit patients with severe disease who may need intensive therapy upfront to prevent complications such as fistulas, strictures, or chronic abdominal pain. It may also benefit those who may require only short-term acute disease control; patients with meaningful yet incomplete responses to single-agent therapy who might have better outcomes with the addition of a second agent; and, patients with a unique phenotype that might be responsive to dual-targeted agents, Dr. Targownik said.
Another reason to consider dual-targeted therapy in IBD comes from applying data from recent clinical trials of upadacitinib (Rinvoq, Abbvie) for ulcerative colitis (UC) and risankizumab-rzaa (Skyrizi, Abbvie) for Crohn’s disease to hypothetical cohorts.
For example, of 1,000 persons with moderate to severe UC treated with upadacitinib, 736 would have a clinical response at the end of the induction, and at the end of the maintenance phase 191 would have endoscopic remissions, and 382 would remain in clinical remission.
Similarly, of 1,000 persons with moderate to severe Crohn’s disease treated with risankizumab, 434 would have a clinical response at the end of induction, and at the end of the maintenance phase, 172 would have endoscopic remissions, and 234 would remain in clinical remission.
“So, the vast majority of our patients are not achieving the targets that we want to hit,” she said.
Evidence from research clinical trials
Data from one of the few trials that have explored dual targeted therapy in IBD were presented at United European Gastroenterology Week in 2022.
The randomized double-blind phase 2a VEGA study looked at induction therapy with either a combination of the IL-23 inhibitor guselkumab (Tremfya, Janssen) and the anti-TNF monoclonal antibody golimumab (Simponi Aria, Janssen) followed by maintenance guselkumab, or each agent alone as induction monotherapy and maintenance.
The study population included 214 patients with moderate to severe UC with a modified Mayo Disease Activity Index scores of 6 or greater and endoscopy scores of 2 or 3 who had not received either anti-TNF or anti IL-23 agents.
At 12 weeks of follow-up, 36.6% of patients who started on combination therapy had clinical remissions, compared with 22.2% of patients on golimumab monotherapy and 22.1% of those on guselkumab alone, a clinically significant difference, Dr. Targownik said.
The combination also resulted in better endoscopic improvement over baseline (49.3% vs. 25% and 29.6%, respectively), although the study was not powered for this outcome.
At 38 weeks, 22.2% of patients who started on golimumab alone were in clinical remission, compared with 31% of those assigned to guselkumab monotherapy and 43.7% of those who started on the combination.
Endoscopic normalization at 38 weeks was seen in 6.9%, 15.5%, and 25.4% of patients, respectively.
“Even in the patients who went back on guselkumab monotherapy that were induced with dual therapy, there were statistically higher rates of clinical remission and endoscopic normalization at the end of the study,” Dr. Targownik said, although she noted that it’s unknown whether the benefit of the combination would be sustained over longer follow-up.
In the open-label EXPLORER Crohn’s disease trial, among 55 patients with high risk Crohn’s disease, within 24 months of diagnosis investigators looked at the triple combination therapy of the anti-integrin agent vedolizumab (Entyvio, Takeda), the anti-TNF agent adalimumab (Humira, Abbvie) and methotrexate. An interim analysis at week 26 of the 34-week trial showed clinical remissions in 54.5% of patients and endoscopic remissions in 34.5%, “which I would argue for an open-label study are not terribly high results,” she said.
Real-world experience
Dr. Targownik pointed to a systematic review and meta-analysis of the safety and effectiveness of combining biologic agents and small molecules in patients with IBD as evidence for how combinations work in the real world.
The analysis included data from 1 clinical trial and 12 observational studies on a total of 266 patients treated with one of seven different combinations. It showed estimates of clinical efficacy ranging from about 40% to 80%, albeit with wide and overlapping confidence intervals, making it difficult to come to any conclusions about the relatively superiority of one combination over another, Dr. Targownik said.
The authors of the meta-analysis did note, however, that the incidence of serious adverse events was relatively low, ranging from 9.6% for the combination of vedolizumab and anti-TNF, to just 1% for the JAK inhibitor tofacitinib (Xeljanz, Pfizer) plus vedolizumab.
Registry data may help
The use of registry data will shed more light on the potential benefits and drawbacks of dual-targeted therapy.
“If we can identify...the patient phenotypes that we want to evaluate dual therapy in, and try to catalog their experiences in a regimented way with defined outcomes and periods of follow-up, we may be able to get more meaningful information,” Dr. Targownik said.
Dr. Targownik disclosed fees, grant support, and/or scientific advisory board participation with multiple companies.
This article was updated 1/25/23.
AURORA, COLO. – Only sparse evidence supports the use of dual-targeted therapy for patients with severe, refractory inflammatory bowel disease (IBD) -- and additional evidence will be hard to come by, according to a leading IBD researcher.
Dual-targeted therapy consists of either sequential or concomitant treatment with drugs from different classes of agents with distinct, specific mechanisms of action such as the use of a drug targeted against tumor necrosis factor (anti-TNFs) with an interleukin-12/23 inhibitor.
There have been only a handful of randomized clinical trials exploring such combinations, however. In addition, there are barriers to new trials, including the costs and risks of randomized trials, the need for cooperation rather than competition between pharmaceutical companies, and identifying patients who might optimally benefit from dual-targeted therapy, Laura Targownik, MD, said in a presentation at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
“In Canada we have absolutely no chance of getting coverage for this, and I imagine in hearing about the fights you have with insurers here in the [United] States, that you’re anticipating similar problems. So what do we do with this information? I think if we’re going to get answers on this question, it’s probably going to come from real-world evidence, from all of our experiences,” said Dr. Targownik of the Zane Cohen Centre for Digestive Diseases at Mount Sinai Hospital in Toronto.
Who might benefit?
Dual-targeted therapy has the potential to benefit patients with severe disease who may need intensive therapy upfront to prevent complications such as fistulas, strictures, or chronic abdominal pain. It may also benefit those who may require only short-term acute disease control; patients with meaningful yet incomplete responses to single-agent therapy who might have better outcomes with the addition of a second agent; and, patients with a unique phenotype that might be responsive to dual-targeted agents, Dr. Targownik said.
Another reason to consider dual-targeted therapy in IBD comes from applying data from recent clinical trials of upadacitinib (Rinvoq, Abbvie) for ulcerative colitis (UC) and risankizumab-rzaa (Skyrizi, Abbvie) for Crohn’s disease to hypothetical cohorts.
For example, of 1,000 persons with moderate to severe UC treated with upadacitinib, 736 would have a clinical response at the end of the induction, and at the end of the maintenance phase 191 would have endoscopic remissions, and 382 would remain in clinical remission.
Similarly, of 1,000 persons with moderate to severe Crohn’s disease treated with risankizumab, 434 would have a clinical response at the end of induction, and at the end of the maintenance phase, 172 would have endoscopic remissions, and 234 would remain in clinical remission.
“So, the vast majority of our patients are not achieving the targets that we want to hit,” she said.
Evidence from research clinical trials
Data from one of the few trials that have explored dual targeted therapy in IBD were presented at United European Gastroenterology Week in 2022.
The randomized double-blind phase 2a VEGA study looked at induction therapy with either a combination of the IL-23 inhibitor guselkumab (Tremfya, Janssen) and the anti-TNF monoclonal antibody golimumab (Simponi Aria, Janssen) followed by maintenance guselkumab, or each agent alone as induction monotherapy and maintenance.
The study population included 214 patients with moderate to severe UC with a modified Mayo Disease Activity Index scores of 6 or greater and endoscopy scores of 2 or 3 who had not received either anti-TNF or anti IL-23 agents.
At 12 weeks of follow-up, 36.6% of patients who started on combination therapy had clinical remissions, compared with 22.2% of patients on golimumab monotherapy and 22.1% of those on guselkumab alone, a clinically significant difference, Dr. Targownik said.
The combination also resulted in better endoscopic improvement over baseline (49.3% vs. 25% and 29.6%, respectively), although the study was not powered for this outcome.
At 38 weeks, 22.2% of patients who started on golimumab alone were in clinical remission, compared with 31% of those assigned to guselkumab monotherapy and 43.7% of those who started on the combination.
Endoscopic normalization at 38 weeks was seen in 6.9%, 15.5%, and 25.4% of patients, respectively.
“Even in the patients who went back on guselkumab monotherapy that were induced with dual therapy, there were statistically higher rates of clinical remission and endoscopic normalization at the end of the study,” Dr. Targownik said, although she noted that it’s unknown whether the benefit of the combination would be sustained over longer follow-up.
In the open-label EXPLORER Crohn’s disease trial, among 55 patients with high risk Crohn’s disease, within 24 months of diagnosis investigators looked at the triple combination therapy of the anti-integrin agent vedolizumab (Entyvio, Takeda), the anti-TNF agent adalimumab (Humira, Abbvie) and methotrexate. An interim analysis at week 26 of the 34-week trial showed clinical remissions in 54.5% of patients and endoscopic remissions in 34.5%, “which I would argue for an open-label study are not terribly high results,” she said.
Real-world experience
Dr. Targownik pointed to a systematic review and meta-analysis of the safety and effectiveness of combining biologic agents and small molecules in patients with IBD as evidence for how combinations work in the real world.
The analysis included data from 1 clinical trial and 12 observational studies on a total of 266 patients treated with one of seven different combinations. It showed estimates of clinical efficacy ranging from about 40% to 80%, albeit with wide and overlapping confidence intervals, making it difficult to come to any conclusions about the relatively superiority of one combination over another, Dr. Targownik said.
The authors of the meta-analysis did note, however, that the incidence of serious adverse events was relatively low, ranging from 9.6% for the combination of vedolizumab and anti-TNF, to just 1% for the JAK inhibitor tofacitinib (Xeljanz, Pfizer) plus vedolizumab.
Registry data may help
The use of registry data will shed more light on the potential benefits and drawbacks of dual-targeted therapy.
“If we can identify...the patient phenotypes that we want to evaluate dual therapy in, and try to catalog their experiences in a regimented way with defined outcomes and periods of follow-up, we may be able to get more meaningful information,” Dr. Targownik said.
Dr. Targownik disclosed fees, grant support, and/or scientific advisory board participation with multiple companies.
This article was updated 1/25/23.
AT THE CROHN’S & COLITIS CONGRESS