Gastroenterology

Researchers are gaining new insight into the relationship between the human cytomegalovirus (HCMV), a common herpes virus found in the gut, and the immune response associated with CD83 antibody in some individuals with Alzheimer’s disease (AD).

Using tissue samples from deceased donors with AD, the study showed CD83-positive (CD83+) microglia in the superior frontal gyrus (SFG) are significantly associated with elevated immunoglobulin gamma 4 (IgG4) and HCMV in the transverse colon (TC), increased anti-HCMV IgG4 in the cerebrospinal fluid (CSF), and both HCMV and IgG4 in the SFG and vagus nerve.

“Our results indicate a complex, cross-tissue interaction between HCMV and the host adaptive immune response associated with CD83+ microglia in persons with AD,” noted the investigators, including Benjamin P. Readhead, MBBS, research associate professor, ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe.

The results suggest antiviral therapy in patients with biomarker evidence of HCMV, IgG4, or CD83+ microglia might ward off dementia.

“We’re preparing to conduct a clinical trial to evaluate whether careful use of existing antivirals might be clinically helpful in preventing or slowing progression of CD83+ associated Alzheimer’s disease,” Readhead said in an interview.

The study was published on December 19, 2024, in Alzheimer’s & Dementia.

 

Vagus Nerve a Potential Pathway?

CMV is a common virus. In the United States, nearly one in three children are already infected with CMV by age 5 years. Over half the adults have been infected with CMV by age 40 years, the Centers for Disease Control and Prevention reported.

It is typically passed through bodily fluids and spread only when the virus is active. It’s not considered a sexually transmitted disease.

Compared with other IgG subclasses, IgG4 is believed to be a less inflammatory, and therefore less damaging, immune response. But this response may be less effective at clearing infections and allow invasion of HCMV into the brain.

Experts speculate HCMV may travel via the vagus nerve from the colon to the brain where it triggers the onset of AD. 

The researchers previously found a CD83+ microglial subtype in the SFG of 47% of brain donors with AD vs 25% of unaffected control individuals. They reported this subtype is associated with increased IgG4 in the TC.

The current analysis extends investigations of the potential etiology and clinicopathologic relevance of CD83+ microglia in the context of AD.

Researchers conducted experiments using donated tissue samples from deceased patients with AD and control individuals. Sources for these samples included the Banner cohort, for whom classifications for the presence of CD83+ microglia were available, as were tissue samples from the SFG, TC, and vagus nerve, and the Religious Orders Study and Rush Memory and Aging Project (ROSMAP), in which participants without known dementia are evaluated annually.

From the Banner cohort, researchers completed immunohistochemistry (IHC) studies on 34 SFG samples (21 AD and 13 control individuals) and included 25 TC samples (13 AD and 12 control individuals) and 8 vagal nerve samples (6 AD and 2 control individuals) in the study. From the ROSMAP cohort, they completed IHC studies on 27 prefrontal cortex samples from individuals with AD.

They carefully selected these samples to ensure matching for critical factors such as postmortem interval, age, and sex, as well as other relevant covariates, said the authors.

The study verified that CD83+ microglia are associated with IgG4 and HCMV in the TC and showed a significant association between CD83+ microglia and IgG4 immunoreactivity in the TC.

Investigators confirmed HCMV positivity in all nine CD83+ TC samples evaluated and in one CD83– TC sample, indicating a strong positive association between HCMV within the TC and CD83+ microglia within the SFG.

HCMV IgG seroprevalence is common, varies by age and comorbidity, and is present in 79% of 85-year-olds, the investigators noted. “Despite this, we note that HCMV presence in the TC was not ubiquitous and was significantly associated with CD83+ microglia and HCMV in the SFG,” they wrote.

This observation, they added, “may help reconcile how a common pathogen might contribute to a disease that most individuals do not develop.”

The experiments also uncovered increased anti-HCMV IgG4 in the CSF and evidence of HCMV and IgG4 in the vagus nerve.

“Overall, the histochemical staining patterns observed in TC, SFG, and vagus nerve of CD83+ subjects are consistent with active HCMV infection,” the investigators wrote. “Taken together, these results indicate a multiorgan presence of IgG4 and HCMV in subjects with CD83+ microglia within the SFG,” they added.

 

Accelerated AD Pathology

The team showed HCMV infection accelerates production of two pathologic features of AD — amyloid beta (Abeta) and tau — and causes neuronal death. “We observed high, positive correlations between the abundance of HCMV, and both Abeta42 and pTau-212,” they wrote.

As HCMV histochemistry is consistent with an active HCMV infection, the findings “may indicate an opportunity for the administration of antiviral therapy in subjects with AD and biomarker evidence of HCMV, IgG4, or CD83+ microglia,” they added.

In addition to planning a clinical trial of existing antivirals, the research team is developing a blood test that can help identify patients with an active HCMV infection who might benefit from such an intervention, said Readhead.

But he emphasized that the research is still in its infancy. “Our study is best understood as a series of interesting scientific findings that warrant further exploration, replication, and validation in additional study populations.”

Although it’s too early for the study to impact practice, “we’re motivated to understand whether these findings have implications for clinical care,” he added.

 

Tipping the Balance

A number of experts have weighed in on the research via the Science Media Center, an independent forum featuring the voices and views on science news from experts in the field.

Andrew Doig, PhD, professor, Division of Neuroscience, University of Manchester in England, said the new work supports the hypothesis that HCMV might be a trigger that tips the balance from a healthy brain to one with dementia. “If so, antiviral drugs against HCMV might be beneficial in reducing the risk of AD.”

Doig noted newly approved drugs for AD are expensive, provide only a small benefit, and have significant risks, such as causing brain hemorrhages. “Antiviral drugs are an attractive alternative that are well worth exploring.”

Richard Oakley, PhD, associate director of research and innovation, Alzheimer’s Society, cautioned the study only established a connection and didn’t directly show the virus leads to AD. “Also, the virus is not found in the brain of everyone with Alzheimer’s disease, the most common form of dementia.”

The significance of the new findings is “far from clear,” commented William McEwan, PhD, group leader at the UK Dementia Research Institute at Cambridge, England. “The study does not address how common this infection is in people without Alzheimer’s and therefore cannot by itself suggest that HCMV infection, or the associated immune response, is a driver of disease.”

The experts agreed follow-up research is needed to confirm these new findings and understand what they mean.

The study received support from the National Institute on Aging, National Institutes of Health, Global Lyme Alliance, National Institute of Neurological Disorders and Stroke, Arizona Alzheimer’s Consortium, The Benter Foundation, and NOMIS Stiftung. Readhead is a coinventor on a patent application for an IgG4-based peripheral biomarker for the detection of CD83+ microglia. Doig is a founder, director, and consultant for PharmaKure, which works on AD drugs and diagnostics, although not on viruses. He has cowritten a review on Viral Involvement in Alzheimer’s Disease. McEwan reported receiving research funding from Takeda Pharmaceuticals and is a founder and consultant to Trimtech Therapeutics.

A version of this article first appeared on Medscape.com.

Researchers are gaining new insight into the relationship between the human cytomegalovirus (HCMV), a common herpes virus found in the gut, and the immune response associated with CD83 antibody in some individuals with Alzheimer’s disease (AD).

Using tissue samples from deceased donors with AD, the study showed CD83-positive (CD83+) microglia in the superior frontal gyrus (SFG) are significantly associated with elevated immunoglobulin gamma 4 (IgG4) and HCMV in the transverse colon (TC), increased anti-HCMV IgG4 in the cerebrospinal fluid (CSF), and both HCMV and IgG4 in the SFG and vagus nerve.

“Our results indicate a complex, cross-tissue interaction between HCMV and the host adaptive immune response associated with CD83+ microglia in persons with AD,” noted the investigators, including Benjamin P. Readhead, MBBS, research associate professor, ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe.

The results suggest antiviral therapy in patients with biomarker evidence of HCMV, IgG4, or CD83+ microglia might ward off dementia.

“We’re preparing to conduct a clinical trial to evaluate whether careful use of existing antivirals might be clinically helpful in preventing or slowing progression of CD83+ associated Alzheimer’s disease,” Readhead said in an interview.

The study was published on December 19, 2024, in Alzheimer’s & Dementia.

 

Vagus Nerve a Potential Pathway?

CMV is a common virus. In the United States, nearly one in three children are already infected with CMV by age 5 years. Over half the adults have been infected with CMV by age 40 years, the Centers for Disease Control and Prevention reported.

It is typically passed through bodily fluids and spread only when the virus is active. It’s not considered a sexually transmitted disease.

Compared with other IgG subclasses, IgG4 is believed to be a less inflammatory, and therefore less damaging, immune response. But this response may be less effective at clearing infections and allow invasion of HCMV into the brain.

Experts speculate HCMV may travel via the vagus nerve from the colon to the brain where it triggers the onset of AD. 

The researchers previously found a CD83+ microglial subtype in the SFG of 47% of brain donors with AD vs 25% of unaffected control individuals. They reported this subtype is associated with increased IgG4 in the TC.

The current analysis extends investigations of the potential etiology and clinicopathologic relevance of CD83+ microglia in the context of AD.

Researchers conducted experiments using donated tissue samples from deceased patients with AD and control individuals. Sources for these samples included the Banner cohort, for whom classifications for the presence of CD83+ microglia were available, as were tissue samples from the SFG, TC, and vagus nerve, and the Religious Orders Study and Rush Memory and Aging Project (ROSMAP), in which participants without known dementia are evaluated annually.

From the Banner cohort, researchers completed immunohistochemistry (IHC) studies on 34 SFG samples (21 AD and 13 control individuals) and included 25 TC samples (13 AD and 12 control individuals) and 8 vagal nerve samples (6 AD and 2 control individuals) in the study. From the ROSMAP cohort, they completed IHC studies on 27 prefrontal cortex samples from individuals with AD.

They carefully selected these samples to ensure matching for critical factors such as postmortem interval, age, and sex, as well as other relevant covariates, said the authors.

The study verified that CD83+ microglia are associated with IgG4 and HCMV in the TC and showed a significant association between CD83+ microglia and IgG4 immunoreactivity in the TC.

Investigators confirmed HCMV positivity in all nine CD83+ TC samples evaluated and in one CD83– TC sample, indicating a strong positive association between HCMV within the TC and CD83+ microglia within the SFG.

HCMV IgG seroprevalence is common, varies by age and comorbidity, and is present in 79% of 85-year-olds, the investigators noted. “Despite this, we note that HCMV presence in the TC was not ubiquitous and was significantly associated with CD83+ microglia and HCMV in the SFG,” they wrote.

This observation, they added, “may help reconcile how a common pathogen might contribute to a disease that most individuals do not develop.”

The experiments also uncovered increased anti-HCMV IgG4 in the CSF and evidence of HCMV and IgG4 in the vagus nerve.

“Overall, the histochemical staining patterns observed in TC, SFG, and vagus nerve of CD83+ subjects are consistent with active HCMV infection,” the investigators wrote. “Taken together, these results indicate a multiorgan presence of IgG4 and HCMV in subjects with CD83+ microglia within the SFG,” they added.

 

Accelerated AD Pathology

The team showed HCMV infection accelerates production of two pathologic features of AD — amyloid beta (Abeta) and tau — and causes neuronal death. “We observed high, positive correlations between the abundance of HCMV, and both Abeta42 and pTau-212,” they wrote.

As HCMV histochemistry is consistent with an active HCMV infection, the findings “may indicate an opportunity for the administration of antiviral therapy in subjects with AD and biomarker evidence of HCMV, IgG4, or CD83+ microglia,” they added.

In addition to planning a clinical trial of existing antivirals, the research team is developing a blood test that can help identify patients with an active HCMV infection who might benefit from such an intervention, said Readhead.

But he emphasized that the research is still in its infancy. “Our study is best understood as a series of interesting scientific findings that warrant further exploration, replication, and validation in additional study populations.”

Although it’s too early for the study to impact practice, “we’re motivated to understand whether these findings have implications for clinical care,” he added.

 

Tipping the Balance

A number of experts have weighed in on the research via the Science Media Center, an independent forum featuring the voices and views on science news from experts in the field.

Andrew Doig, PhD, professor, Division of Neuroscience, University of Manchester in England, said the new work supports the hypothesis that HCMV might be a trigger that tips the balance from a healthy brain to one with dementia. “If so, antiviral drugs against HCMV might be beneficial in reducing the risk of AD.”

Doig noted newly approved drugs for AD are expensive, provide only a small benefit, and have significant risks, such as causing brain hemorrhages. “Antiviral drugs are an attractive alternative that are well worth exploring.”

Richard Oakley, PhD, associate director of research and innovation, Alzheimer’s Society, cautioned the study only established a connection and didn’t directly show the virus leads to AD. “Also, the virus is not found in the brain of everyone with Alzheimer’s disease, the most common form of dementia.”

The significance of the new findings is “far from clear,” commented William McEwan, PhD, group leader at the UK Dementia Research Institute at Cambridge, England. “The study does not address how common this infection is in people without Alzheimer’s and therefore cannot by itself suggest that HCMV infection, or the associated immune response, is a driver of disease.”

The experts agreed follow-up research is needed to confirm these new findings and understand what they mean.

The study received support from the National Institute on Aging, National Institutes of Health, Global Lyme Alliance, National Institute of Neurological Disorders and Stroke, Arizona Alzheimer’s Consortium, The Benter Foundation, and NOMIS Stiftung. Readhead is a coinventor on a patent application for an IgG4-based peripheral biomarker for the detection of CD83+ microglia. Doig is a founder, director, and consultant for PharmaKure, which works on AD drugs and diagnostics, although not on viruses. He has cowritten a review on Viral Involvement in Alzheimer’s Disease. McEwan reported receiving research funding from Takeda Pharmaceuticals and is a founder and consultant to Trimtech Therapeutics.

A version of this article first appeared on Medscape.com.

Researchers are gaining new insight into the relationship between the human cytomegalovirus (HCMV), a common herpes virus found in the gut, and the immune response associated with CD83 antibody in some individuals with Alzheimer’s disease (AD).

Using tissue samples from deceased donors with AD, the study showed CD83-positive (CD83+) microglia in the superior frontal gyrus (SFG) are significantly associated with elevated immunoglobulin gamma 4 (IgG4) and HCMV in the transverse colon (TC), increased anti-HCMV IgG4 in the cerebrospinal fluid (CSF), and both HCMV and IgG4 in the SFG and vagus nerve.

“Our results indicate a complex, cross-tissue interaction between HCMV and the host adaptive immune response associated with CD83+ microglia in persons with AD,” noted the investigators, including Benjamin P. Readhead, MBBS, research associate professor, ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe.

The results suggest antiviral therapy in patients with biomarker evidence of HCMV, IgG4, or CD83+ microglia might ward off dementia.

“We’re preparing to conduct a clinical trial to evaluate whether careful use of existing antivirals might be clinically helpful in preventing or slowing progression of CD83+ associated Alzheimer’s disease,” Readhead said in an interview.

The study was published on December 19, 2024, in Alzheimer’s & Dementia.

 

Vagus Nerve a Potential Pathway?

CMV is a common virus. In the United States, nearly one in three children are already infected with CMV by age 5 years. Over half the adults have been infected with CMV by age 40 years, the Centers for Disease Control and Prevention reported.

It is typically passed through bodily fluids and spread only when the virus is active. It’s not considered a sexually transmitted disease.

Compared with other IgG subclasses, IgG4 is believed to be a less inflammatory, and therefore less damaging, immune response. But this response may be less effective at clearing infections and allow invasion of HCMV into the brain.

Experts speculate HCMV may travel via the vagus nerve from the colon to the brain where it triggers the onset of AD. 

The researchers previously found a CD83+ microglial subtype in the SFG of 47% of brain donors with AD vs 25% of unaffected control individuals. They reported this subtype is associated with increased IgG4 in the TC.

The current analysis extends investigations of the potential etiology and clinicopathologic relevance of CD83+ microglia in the context of AD.

Researchers conducted experiments using donated tissue samples from deceased patients with AD and control individuals. Sources for these samples included the Banner cohort, for whom classifications for the presence of CD83+ microglia were available, as were tissue samples from the SFG, TC, and vagus nerve, and the Religious Orders Study and Rush Memory and Aging Project (ROSMAP), in which participants without known dementia are evaluated annually.

From the Banner cohort, researchers completed immunohistochemistry (IHC) studies on 34 SFG samples (21 AD and 13 control individuals) and included 25 TC samples (13 AD and 12 control individuals) and 8 vagal nerve samples (6 AD and 2 control individuals) in the study. From the ROSMAP cohort, they completed IHC studies on 27 prefrontal cortex samples from individuals with AD.

They carefully selected these samples to ensure matching for critical factors such as postmortem interval, age, and sex, as well as other relevant covariates, said the authors.

The study verified that CD83+ microglia are associated with IgG4 and HCMV in the TC and showed a significant association between CD83+ microglia and IgG4 immunoreactivity in the TC.

Investigators confirmed HCMV positivity in all nine CD83+ TC samples evaluated and in one CD83– TC sample, indicating a strong positive association between HCMV within the TC and CD83+ microglia within the SFG.

HCMV IgG seroprevalence is common, varies by age and comorbidity, and is present in 79% of 85-year-olds, the investigators noted. “Despite this, we note that HCMV presence in the TC was not ubiquitous and was significantly associated with CD83+ microglia and HCMV in the SFG,” they wrote.

This observation, they added, “may help reconcile how a common pathogen might contribute to a disease that most individuals do not develop.”

The experiments also uncovered increased anti-HCMV IgG4 in the CSF and evidence of HCMV and IgG4 in the vagus nerve.

“Overall, the histochemical staining patterns observed in TC, SFG, and vagus nerve of CD83+ subjects are consistent with active HCMV infection,” the investigators wrote. “Taken together, these results indicate a multiorgan presence of IgG4 and HCMV in subjects with CD83+ microglia within the SFG,” they added.

 

Accelerated AD Pathology

The team showed HCMV infection accelerates production of two pathologic features of AD — amyloid beta (Abeta) and tau — and causes neuronal death. “We observed high, positive correlations between the abundance of HCMV, and both Abeta42 and pTau-212,” they wrote.

As HCMV histochemistry is consistent with an active HCMV infection, the findings “may indicate an opportunity for the administration of antiviral therapy in subjects with AD and biomarker evidence of HCMV, IgG4, or CD83+ microglia,” they added.

In addition to planning a clinical trial of existing antivirals, the research team is developing a blood test that can help identify patients with an active HCMV infection who might benefit from such an intervention, said Readhead.

But he emphasized that the research is still in its infancy. “Our study is best understood as a series of interesting scientific findings that warrant further exploration, replication, and validation in additional study populations.”

Although it’s too early for the study to impact practice, “we’re motivated to understand whether these findings have implications for clinical care,” he added.

 

Tipping the Balance

A number of experts have weighed in on the research via the Science Media Center, an independent forum featuring the voices and views on science news from experts in the field.

Andrew Doig, PhD, professor, Division of Neuroscience, University of Manchester in England, said the new work supports the hypothesis that HCMV might be a trigger that tips the balance from a healthy brain to one with dementia. “If so, antiviral drugs against HCMV might be beneficial in reducing the risk of AD.”

Doig noted newly approved drugs for AD are expensive, provide only a small benefit, and have significant risks, such as causing brain hemorrhages. “Antiviral drugs are an attractive alternative that are well worth exploring.”

Richard Oakley, PhD, associate director of research and innovation, Alzheimer’s Society, cautioned the study only established a connection and didn’t directly show the virus leads to AD. “Also, the virus is not found in the brain of everyone with Alzheimer’s disease, the most common form of dementia.”

The significance of the new findings is “far from clear,” commented William McEwan, PhD, group leader at the UK Dementia Research Institute at Cambridge, England. “The study does not address how common this infection is in people without Alzheimer’s and therefore cannot by itself suggest that HCMV infection, or the associated immune response, is a driver of disease.”

The experts agreed follow-up research is needed to confirm these new findings and understand what they mean.

The study received support from the National Institute on Aging, National Institutes of Health, Global Lyme Alliance, National Institute of Neurological Disorders and Stroke, Arizona Alzheimer’s Consortium, The Benter Foundation, and NOMIS Stiftung. Readhead is a coinventor on a patent application for an IgG4-based peripheral biomarker for the detection of CD83+ microglia. Doig is a founder, director, and consultant for PharmaKure, which works on AD drugs and diagnostics, although not on viruses. He has cowritten a review on Viral Involvement in Alzheimer’s Disease. McEwan reported receiving research funding from Takeda Pharmaceuticals and is a founder and consultant to Trimtech Therapeutics.

A version of this article first appeared on Medscape.com.

The scientific report that offers evidence-based guidance for the next iteration of the Dietary Guidelines for Americans has been submitted to federal agencies, and the document — which already has generated controversy because of its emphasis on plant-based foods — is now open for public comment.

The advisory committee that developed the report examined the scientific evidence on specific nutrition and public health topics using data analysis, systematic reviews, and food modeling. 

“We saw something over and over again — when you look at a population level, diets for which the predominant composition was plants performed better when it came to health outcomes,” advisory committee member Cheryl Anderson, PhD, MPH, who is a professor and dean of the Herbert Wertheim School of Public Health and Human Longevity Science at the University of California, San Diego, said in an interview. “There’s a pretty consistent body of literature showing benefits of fruits, vegetables, and legumes and reductions in salt, added sugars, and saturated fats.”

Clinicians should read and comment on the report, said Anderson.

“Commenting sends the right signal that they are interested in what’s needed for nutrition education,” she said. “It will also activate a conversation with the people who are writing the guidelines.”

Instructions for submitting comments online through February 10, 2025, and for participating in the oral comment meeting on January 16, 2025, are posted online.

The Department of Agriculture (USDA) and the Department of Health & Human Services will use the report as a key resource, alongside the public comments and agency input, as they jointly develop the Dietary Guidelines for Americans, 2025-2030.

 

Meat Given a Back Seat

Overall, the advisory committee defined a “healthy dietary pattern” as one that is “higher in vegetables, fruits, legumes (ie, beans, peas, lentils), nuts, whole grains, fish/seafood, and vegetable oils higher in unsaturated fat — and lower in red and processed meats, sugar-sweetened foods and beverages, refined grains, and saturated fat.”

The report emphasizes “plain drinking water” as the primary beverage for people to consume and states that sugar-sweetened beverage consumption should be limited.

It recommends limiting total saturated fat intake to less than 10% of daily calories and replacing it with unsaturated fat, particularly polyunsaturated fats.

Notably, the report advocates increasing the consumption of beans, peas, and lentils and decreasing starchy vegetables (such as potatoes), as well as reducing total protein foods by reducing meat, poultry, and eggs. This recommendation and the report’s broad emphasis on plant-based foods have drawn criticism, mainly from the food industry.

Also likely to be controversial are the recommendations to move beans, peas, and lentils from the vegetable group to the protein group and the proposed reorganization of the order of the protein foods group to list beans, peas, and lentils first, followed by nuts, seeds, and soy products; then seafood; and finally meats, poultry, and eggs.

Gastroenterologists and dietitians should support the emphasis on plant-based protein sources, water for hydration, and the importance of personalized nutrition plans, including culturally diverse and ethnic food options, said Stephanie Gold, MD, assistant professor of medicine at the Icahn School of Medicine at Mount Sinai and a gastroenterologist at Mount Sinai Hospital, both in New York City.

“The newly proposed 2025 Dietary Guidelines are approaching a Mediterranean-style diet by focusing on plant-based protein sources while limiting red meat and saturated fats, as well as added sugar. By including these legumes in the protein category (not only as a starchy vegetable), the proposed guideline recognizes both the health benefits and sustainability of plant-based proteins,” Gold said in an interview.

Although the report recognizes “the potential negative impact and the varying definitions of ultra-processed foods, it does not provide concrete recommendations regarding intake, and perhaps, this could be an area of focus going forward,” she added.

Anderson noted that the science around ultra-processed food is “underdeveloped.” However, the definition of a healthy diet “has never suggested that we have foods that are extremely processed in it.”

“Right now, there’s a lot of interest in ultra-processed foods and what they mean for health, but the science is going to need to catch up with that interest,” Anderson said.

 

What’s Next

The release of the scientific report is part of a five-step process to develop the new guidelines that included input from the public during the report’s development. According to the USDA, the advisory committee received approximately 9900 public comments, more than any other previous committee.

Once the new dietary guidelines are complete, Anderson said, “clinicians have an opportunity to really lean into a science-based framework to talk about overall health concerns and reducing the burden of diet-related illnesses with their patients.”

Meanwhile, they can voice their approval or concerns about the scientific report.

Anderson and Gold reported no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

The scientific report that offers evidence-based guidance for the next iteration of the Dietary Guidelines for Americans has been submitted to federal agencies, and the document — which already has generated controversy because of its emphasis on plant-based foods — is now open for public comment.

The advisory committee that developed the report examined the scientific evidence on specific nutrition and public health topics using data analysis, systematic reviews, and food modeling. 

“We saw something over and over again — when you look at a population level, diets for which the predominant composition was plants performed better when it came to health outcomes,” advisory committee member Cheryl Anderson, PhD, MPH, who is a professor and dean of the Herbert Wertheim School of Public Health and Human Longevity Science at the University of California, San Diego, said in an interview. “There’s a pretty consistent body of literature showing benefits of fruits, vegetables, and legumes and reductions in salt, added sugars, and saturated fats.”

Clinicians should read and comment on the report, said Anderson.

“Commenting sends the right signal that they are interested in what’s needed for nutrition education,” she said. “It will also activate a conversation with the people who are writing the guidelines.”

Instructions for submitting comments online through February 10, 2025, and for participating in the oral comment meeting on January 16, 2025, are posted online.

The Department of Agriculture (USDA) and the Department of Health & Human Services will use the report as a key resource, alongside the public comments and agency input, as they jointly develop the Dietary Guidelines for Americans, 2025-2030.

 

Meat Given a Back Seat

Overall, the advisory committee defined a “healthy dietary pattern” as one that is “higher in vegetables, fruits, legumes (ie, beans, peas, lentils), nuts, whole grains, fish/seafood, and vegetable oils higher in unsaturated fat — and lower in red and processed meats, sugar-sweetened foods and beverages, refined grains, and saturated fat.”

The report emphasizes “plain drinking water” as the primary beverage for people to consume and states that sugar-sweetened beverage consumption should be limited.

It recommends limiting total saturated fat intake to less than 10% of daily calories and replacing it with unsaturated fat, particularly polyunsaturated fats.

Notably, the report advocates increasing the consumption of beans, peas, and lentils and decreasing starchy vegetables (such as potatoes), as well as reducing total protein foods by reducing meat, poultry, and eggs. This recommendation and the report’s broad emphasis on plant-based foods have drawn criticism, mainly from the food industry.

Also likely to be controversial are the recommendations to move beans, peas, and lentils from the vegetable group to the protein group and the proposed reorganization of the order of the protein foods group to list beans, peas, and lentils first, followed by nuts, seeds, and soy products; then seafood; and finally meats, poultry, and eggs.

Gastroenterologists and dietitians should support the emphasis on plant-based protein sources, water for hydration, and the importance of personalized nutrition plans, including culturally diverse and ethnic food options, said Stephanie Gold, MD, assistant professor of medicine at the Icahn School of Medicine at Mount Sinai and a gastroenterologist at Mount Sinai Hospital, both in New York City.

“The newly proposed 2025 Dietary Guidelines are approaching a Mediterranean-style diet by focusing on plant-based protein sources while limiting red meat and saturated fats, as well as added sugar. By including these legumes in the protein category (not only as a starchy vegetable), the proposed guideline recognizes both the health benefits and sustainability of plant-based proteins,” Gold said in an interview.

Although the report recognizes “the potential negative impact and the varying definitions of ultra-processed foods, it does not provide concrete recommendations regarding intake, and perhaps, this could be an area of focus going forward,” she added.

Anderson noted that the science around ultra-processed food is “underdeveloped.” However, the definition of a healthy diet “has never suggested that we have foods that are extremely processed in it.”

“Right now, there’s a lot of interest in ultra-processed foods and what they mean for health, but the science is going to need to catch up with that interest,” Anderson said.

 

What’s Next

The release of the scientific report is part of a five-step process to develop the new guidelines that included input from the public during the report’s development. According to the USDA, the advisory committee received approximately 9900 public comments, more than any other previous committee.

Once the new dietary guidelines are complete, Anderson said, “clinicians have an opportunity to really lean into a science-based framework to talk about overall health concerns and reducing the burden of diet-related illnesses with their patients.”

Meanwhile, they can voice their approval or concerns about the scientific report.

Anderson and Gold reported no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

The scientific report that offers evidence-based guidance for the next iteration of the Dietary Guidelines for Americans has been submitted to federal agencies, and the document — which already has generated controversy because of its emphasis on plant-based foods — is now open for public comment.

The advisory committee that developed the report examined the scientific evidence on specific nutrition and public health topics using data analysis, systematic reviews, and food modeling. 

“We saw something over and over again — when you look at a population level, diets for which the predominant composition was plants performed better when it came to health outcomes,” advisory committee member Cheryl Anderson, PhD, MPH, who is a professor and dean of the Herbert Wertheim School of Public Health and Human Longevity Science at the University of California, San Diego, said in an interview. “There’s a pretty consistent body of literature showing benefits of fruits, vegetables, and legumes and reductions in salt, added sugars, and saturated fats.”

Clinicians should read and comment on the report, said Anderson.

“Commenting sends the right signal that they are interested in what’s needed for nutrition education,” she said. “It will also activate a conversation with the people who are writing the guidelines.”

Instructions for submitting comments online through February 10, 2025, and for participating in the oral comment meeting on January 16, 2025, are posted online.

The Department of Agriculture (USDA) and the Department of Health & Human Services will use the report as a key resource, alongside the public comments and agency input, as they jointly develop the Dietary Guidelines for Americans, 2025-2030.

 

Meat Given a Back Seat

Overall, the advisory committee defined a “healthy dietary pattern” as one that is “higher in vegetables, fruits, legumes (ie, beans, peas, lentils), nuts, whole grains, fish/seafood, and vegetable oils higher in unsaturated fat — and lower in red and processed meats, sugar-sweetened foods and beverages, refined grains, and saturated fat.”

The report emphasizes “plain drinking water” as the primary beverage for people to consume and states that sugar-sweetened beverage consumption should be limited.

It recommends limiting total saturated fat intake to less than 10% of daily calories and replacing it with unsaturated fat, particularly polyunsaturated fats.

Notably, the report advocates increasing the consumption of beans, peas, and lentils and decreasing starchy vegetables (such as potatoes), as well as reducing total protein foods by reducing meat, poultry, and eggs. This recommendation and the report’s broad emphasis on plant-based foods have drawn criticism, mainly from the food industry.

Also likely to be controversial are the recommendations to move beans, peas, and lentils from the vegetable group to the protein group and the proposed reorganization of the order of the protein foods group to list beans, peas, and lentils first, followed by nuts, seeds, and soy products; then seafood; and finally meats, poultry, and eggs.

Gastroenterologists and dietitians should support the emphasis on plant-based protein sources, water for hydration, and the importance of personalized nutrition plans, including culturally diverse and ethnic food options, said Stephanie Gold, MD, assistant professor of medicine at the Icahn School of Medicine at Mount Sinai and a gastroenterologist at Mount Sinai Hospital, both in New York City.

“The newly proposed 2025 Dietary Guidelines are approaching a Mediterranean-style diet by focusing on plant-based protein sources while limiting red meat and saturated fats, as well as added sugar. By including these legumes in the protein category (not only as a starchy vegetable), the proposed guideline recognizes both the health benefits and sustainability of plant-based proteins,” Gold said in an interview.

Although the report recognizes “the potential negative impact and the varying definitions of ultra-processed foods, it does not provide concrete recommendations regarding intake, and perhaps, this could be an area of focus going forward,” she added.

Anderson noted that the science around ultra-processed food is “underdeveloped.” However, the definition of a healthy diet “has never suggested that we have foods that are extremely processed in it.”

“Right now, there’s a lot of interest in ultra-processed foods and what they mean for health, but the science is going to need to catch up with that interest,” Anderson said.

 

What’s Next

The release of the scientific report is part of a five-step process to develop the new guidelines that included input from the public during the report’s development. According to the USDA, the advisory committee received approximately 9900 public comments, more than any other previous committee.

Once the new dietary guidelines are complete, Anderson said, “clinicians have an opportunity to really lean into a science-based framework to talk about overall health concerns and reducing the burden of diet-related illnesses with their patients.”

Meanwhile, they can voice their approval or concerns about the scientific report.

Anderson and Gold reported no relevant conflicts of interest.

A version of this article first appeared on Medscape.com.

The World Health Organization Regional Office for Europe (WHO/Europe) and the European Association for the Study of the Liver held a symposium on December 11 to establish the European Alcohol Health Alliance to reduce alcohol-related harms across Europe. 

Europe has the highest levels of alcohol consumption in the world. Alcohol is the continent’s leading cause of death, accounting for almost 800,000 deaths per year, or 1 in 11 deaths in the region. 

This news organization spoke with Frank Murray, MBBCh, a consultant gastroenterologist and hepatologist at Bon Secours Hospital and Beaumont Private Clinic in Dublin, Ireland, who attended the symposium. The intention is to launch the European Alcohol Health Alliance in 2025. 

“We’d like to see evidence-based policies to reduce alcohol harm, which we think would be good for individual citizens and the economy,” said Murray. 

The symposium brought together multiple professional societies to discuss problems related to alcohol use, possible solutions, and their willingness to collaborate. Murray noted that attendees were enthusiastic about forming an alliance. 

Among the alliance’s first priorities, he noted, are changing the pricing and availability of alcohol, implementing restrictions in marketing and advertising, protecting children from alcohol harm, and labeling products with health warnings. 

“It’s interesting that the most dangerous product in the supermarket is sold without any nutrition or content information and without any warnings,” he said. 

 

‘David and Goliath’ 

This news organization also spoke with Barbara Broers, MD, professor of addiction medicine at the University of Geneva in Switzerland, who did not attend the meeting. 

She noted that although methods for reducing alcohol intake are well known, little action is taken to implement them. The alcohol industry is a major reason for this, she said, because it will “do everything to keep its business going.” 

One tactic, according to Broers and Murray, is heavy governmental lobbying. The industry’s resources for lobbying and advocating greatly outweigh any counterforce in what Murray described as a “bit of a David and Goliath” situation. 

“The alcohol industry should not have any role in policy making for alcohol, because it has a conflict of interest that clearly gets in the way of giving public health advice. It wants to maximize profits, while public health requires policies to reduce alcohol consumption,” he noted. 

Among the aims of the European Alcohol Health Alliance is “to rebalance the battle between those advocating for and against alcohol,” he continued.

 

Public Misperceptions

Although alcohol’s harmful effects on the liver are well known, Broers and Murray noted that its other effects are less known. 

A 2024 study found that whereas 90% of Europeans are aware of alcohol’s causal role in liver disease, just 68% are aware of a causal role for heart diseases and 53% for cancer. And only 15% were aware of a causal link with female breast cancer, even though drinking alcohol causes up to 1 in 10 cases of breast cancer.

Adding to a general lack of public awareness, methodologically flawed research may have generated a false impression that moderate drinking is beneficial for health, according to a s ystematic review and meta-analysis of 107 longitudinal studies. 

Broers noted that more work must be done to increase public knowledge about the harmful effects of alcohol, and especially its link to cancer. “We now know that a person’s risk of cancer increases right from the first drink, but I think the people don’t know this,” she said. 

“Local context and culture have a significant impact on the prevalence of alcohol consumption within a population, as well as the pattern of alcohol consumption,” Andrew Smyth, MBBCh, PhD, professor of clinical epidemiology at the University of Galway in Ireland, told this news organization. 

“Each country, region, and area are likely to need culturally appropriate and socially acceptable solutions to overcome their own hurdles,” he added.

 

Normalizing Abstinence

“Alcohol is involved in our social lives in so many ways. Reducing it would be Sisyphus’s work,” said Bernhard Maisch, MD, professor at Philipps University of Marburg, Germany. 

Jelena Šarić Posavec, a former PhD student at the University of Ljubljana in Slovenia, said that, while numerous obstacles make addressing alcohol-related harms difficult in Europe, solutions exist, too. 

Broers noted, for example, that Germany is working to change social perceptions around not drinking. “No alcohol should be the norm and should be considered positive. People should know that they might feel much better if they don’t drink at all.” 

Short-term improvements from abstaining from alcohol may be felt in sleep and energy levels, with long-term health effects ranging from weight to liver health and cancer risk, she noted. The problem, she said, however, lies in how to communicate this message. 

Murray, Broers, Smyth, Maisch, and Posavec reported having no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The World Health Organization Regional Office for Europe (WHO/Europe) and the European Association for the Study of the Liver held a symposium on December 11 to establish the European Alcohol Health Alliance to reduce alcohol-related harms across Europe. 

Europe has the highest levels of alcohol consumption in the world. Alcohol is the continent’s leading cause of death, accounting for almost 800,000 deaths per year, or 1 in 11 deaths in the region. 

This news organization spoke with Frank Murray, MBBCh, a consultant gastroenterologist and hepatologist at Bon Secours Hospital and Beaumont Private Clinic in Dublin, Ireland, who attended the symposium. The intention is to launch the European Alcohol Health Alliance in 2025. 

“We’d like to see evidence-based policies to reduce alcohol harm, which we think would be good for individual citizens and the economy,” said Murray. 

The symposium brought together multiple professional societies to discuss problems related to alcohol use, possible solutions, and their willingness to collaborate. Murray noted that attendees were enthusiastic about forming an alliance. 

Among the alliance’s first priorities, he noted, are changing the pricing and availability of alcohol, implementing restrictions in marketing and advertising, protecting children from alcohol harm, and labeling products with health warnings. 

“It’s interesting that the most dangerous product in the supermarket is sold without any nutrition or content information and without any warnings,” he said. 

 

‘David and Goliath’ 

This news organization also spoke with Barbara Broers, MD, professor of addiction medicine at the University of Geneva in Switzerland, who did not attend the meeting. 

She noted that although methods for reducing alcohol intake are well known, little action is taken to implement them. The alcohol industry is a major reason for this, she said, because it will “do everything to keep its business going.” 

One tactic, according to Broers and Murray, is heavy governmental lobbying. The industry’s resources for lobbying and advocating greatly outweigh any counterforce in what Murray described as a “bit of a David and Goliath” situation. 

“The alcohol industry should not have any role in policy making for alcohol, because it has a conflict of interest that clearly gets in the way of giving public health advice. It wants to maximize profits, while public health requires policies to reduce alcohol consumption,” he noted. 

Among the aims of the European Alcohol Health Alliance is “to rebalance the battle between those advocating for and against alcohol,” he continued.

 

Public Misperceptions

Although alcohol’s harmful effects on the liver are well known, Broers and Murray noted that its other effects are less known. 

A 2024 study found that whereas 90% of Europeans are aware of alcohol’s causal role in liver disease, just 68% are aware of a causal role for heart diseases and 53% for cancer. And only 15% were aware of a causal link with female breast cancer, even though drinking alcohol causes up to 1 in 10 cases of breast cancer.

Adding to a general lack of public awareness, methodologically flawed research may have generated a false impression that moderate drinking is beneficial for health, according to a s ystematic review and meta-analysis of 107 longitudinal studies. 

Broers noted that more work must be done to increase public knowledge about the harmful effects of alcohol, and especially its link to cancer. “We now know that a person’s risk of cancer increases right from the first drink, but I think the people don’t know this,” she said. 

“Local context and culture have a significant impact on the prevalence of alcohol consumption within a population, as well as the pattern of alcohol consumption,” Andrew Smyth, MBBCh, PhD, professor of clinical epidemiology at the University of Galway in Ireland, told this news organization. 

“Each country, region, and area are likely to need culturally appropriate and socially acceptable solutions to overcome their own hurdles,” he added.

 

Normalizing Abstinence

“Alcohol is involved in our social lives in so many ways. Reducing it would be Sisyphus’s work,” said Bernhard Maisch, MD, professor at Philipps University of Marburg, Germany. 

Jelena Šarić Posavec, a former PhD student at the University of Ljubljana in Slovenia, said that, while numerous obstacles make addressing alcohol-related harms difficult in Europe, solutions exist, too. 

Broers noted, for example, that Germany is working to change social perceptions around not drinking. “No alcohol should be the norm and should be considered positive. People should know that they might feel much better if they don’t drink at all.” 

Short-term improvements from abstaining from alcohol may be felt in sleep and energy levels, with long-term health effects ranging from weight to liver health and cancer risk, she noted. The problem, she said, however, lies in how to communicate this message. 

Murray, Broers, Smyth, Maisch, and Posavec reported having no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The World Health Organization Regional Office for Europe (WHO/Europe) and the European Association for the Study of the Liver held a symposium on December 11 to establish the European Alcohol Health Alliance to reduce alcohol-related harms across Europe. 

Europe has the highest levels of alcohol consumption in the world. Alcohol is the continent’s leading cause of death, accounting for almost 800,000 deaths per year, or 1 in 11 deaths in the region. 

This news organization spoke with Frank Murray, MBBCh, a consultant gastroenterologist and hepatologist at Bon Secours Hospital and Beaumont Private Clinic in Dublin, Ireland, who attended the symposium. The intention is to launch the European Alcohol Health Alliance in 2025. 

“We’d like to see evidence-based policies to reduce alcohol harm, which we think would be good for individual citizens and the economy,” said Murray. 

The symposium brought together multiple professional societies to discuss problems related to alcohol use, possible solutions, and their willingness to collaborate. Murray noted that attendees were enthusiastic about forming an alliance. 

Among the alliance’s first priorities, he noted, are changing the pricing and availability of alcohol, implementing restrictions in marketing and advertising, protecting children from alcohol harm, and labeling products with health warnings. 

“It’s interesting that the most dangerous product in the supermarket is sold without any nutrition or content information and without any warnings,” he said. 

 

‘David and Goliath’ 

This news organization also spoke with Barbara Broers, MD, professor of addiction medicine at the University of Geneva in Switzerland, who did not attend the meeting. 

She noted that although methods for reducing alcohol intake are well known, little action is taken to implement them. The alcohol industry is a major reason for this, she said, because it will “do everything to keep its business going.” 

One tactic, according to Broers and Murray, is heavy governmental lobbying. The industry’s resources for lobbying and advocating greatly outweigh any counterforce in what Murray described as a “bit of a David and Goliath” situation. 

“The alcohol industry should not have any role in policy making for alcohol, because it has a conflict of interest that clearly gets in the way of giving public health advice. It wants to maximize profits, while public health requires policies to reduce alcohol consumption,” he noted. 

Among the aims of the European Alcohol Health Alliance is “to rebalance the battle between those advocating for and against alcohol,” he continued.

 

Public Misperceptions

Although alcohol’s harmful effects on the liver are well known, Broers and Murray noted that its other effects are less known. 

A 2024 study found that whereas 90% of Europeans are aware of alcohol’s causal role in liver disease, just 68% are aware of a causal role for heart diseases and 53% for cancer. And only 15% were aware of a causal link with female breast cancer, even though drinking alcohol causes up to 1 in 10 cases of breast cancer.

Adding to a general lack of public awareness, methodologically flawed research may have generated a false impression that moderate drinking is beneficial for health, according to a s ystematic review and meta-analysis of 107 longitudinal studies. 

Broers noted that more work must be done to increase public knowledge about the harmful effects of alcohol, and especially its link to cancer. “We now know that a person’s risk of cancer increases right from the first drink, but I think the people don’t know this,” she said. 

“Local context and culture have a significant impact on the prevalence of alcohol consumption within a population, as well as the pattern of alcohol consumption,” Andrew Smyth, MBBCh, PhD, professor of clinical epidemiology at the University of Galway in Ireland, told this news organization. 

“Each country, region, and area are likely to need culturally appropriate and socially acceptable solutions to overcome their own hurdles,” he added.

 

Normalizing Abstinence

“Alcohol is involved in our social lives in so many ways. Reducing it would be Sisyphus’s work,” said Bernhard Maisch, MD, professor at Philipps University of Marburg, Germany. 

Jelena Šarić Posavec, a former PhD student at the University of Ljubljana in Slovenia, said that, while numerous obstacles make addressing alcohol-related harms difficult in Europe, solutions exist, too. 

Broers noted, for example, that Germany is working to change social perceptions around not drinking. “No alcohol should be the norm and should be considered positive. People should know that they might feel much better if they don’t drink at all.” 

Short-term improvements from abstaining from alcohol may be felt in sleep and energy levels, with long-term health effects ranging from weight to liver health and cancer risk, she noted. The problem, she said, however, lies in how to communicate this message. 

Murray, Broers, Smyth, Maisch, and Posavec reported having no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration (FDA) has approved ustekinumab-stba (Steqeyma) as a biosimilar to the interleukin-12 and -23 inhibitor ustekinumab (Stelara) for the treatment of adults with active Crohn’s disease or ulcerative colitis and for both children aged ≥ 6 years and adults with moderate to severe plaque psoriasis or active psoriatic arthritis.

This is the seventh ustekinumab biosimilar approved by the FDA. The biosimilar, developed by Celltrion, has a license entry date in February 2025 as part of the settlement and license agreement with the manufacturer of the reference biologic, Johnson & Johnson.

Ustekinumab-stba will be available in two formulations: A subcutaneous injection in two strengths — a 45 mg/0.5 mL or 90 mg/1 mL solution in a single-dose, prefilled syringe — and an intravenous infusion of a 130 mg/26 mL (5 mg/mL) solution in a single-dose vial.

“The approval of Steqeyma reflects Celltrion’s continued investment in providing treatment options to patients diagnosed with ulcerative colitis, Crohn’s disease, psoriasis, and psoriatic arthritis,” said Thomas Nusbickel, Chief Commercial Officer at Celltrion USA, Jersey City, New Jersey, in a press release.

The FDA has previously approved the company’s adalimumab biosimilar Yuflyma and its infliximab biosimilar Zymfentra.

The full prescribing information for ustekinumab-stba is available here.

A version of this article first appeared on Medscape.com. 

The Food and Drug Administration (FDA) has approved ustekinumab-stba (Steqeyma) as a biosimilar to the interleukin-12 and -23 inhibitor ustekinumab (Stelara) for the treatment of adults with active Crohn’s disease or ulcerative colitis and for both children aged ≥ 6 years and adults with moderate to severe plaque psoriasis or active psoriatic arthritis.

This is the seventh ustekinumab biosimilar approved by the FDA. The biosimilar, developed by Celltrion, has a license entry date in February 2025 as part of the settlement and license agreement with the manufacturer of the reference biologic, Johnson & Johnson.

Ustekinumab-stba will be available in two formulations: A subcutaneous injection in two strengths — a 45 mg/0.5 mL or 90 mg/1 mL solution in a single-dose, prefilled syringe — and an intravenous infusion of a 130 mg/26 mL (5 mg/mL) solution in a single-dose vial.

“The approval of Steqeyma reflects Celltrion’s continued investment in providing treatment options to patients diagnosed with ulcerative colitis, Crohn’s disease, psoriasis, and psoriatic arthritis,” said Thomas Nusbickel, Chief Commercial Officer at Celltrion USA, Jersey City, New Jersey, in a press release.

The FDA has previously approved the company’s adalimumab biosimilar Yuflyma and its infliximab biosimilar Zymfentra.

The full prescribing information for ustekinumab-stba is available here.

A version of this article first appeared on Medscape.com. 

The Food and Drug Administration (FDA) has approved ustekinumab-stba (Steqeyma) as a biosimilar to the interleukin-12 and -23 inhibitor ustekinumab (Stelara) for the treatment of adults with active Crohn’s disease or ulcerative colitis and for both children aged ≥ 6 years and adults with moderate to severe plaque psoriasis or active psoriatic arthritis.

This is the seventh ustekinumab biosimilar approved by the FDA. The biosimilar, developed by Celltrion, has a license entry date in February 2025 as part of the settlement and license agreement with the manufacturer of the reference biologic, Johnson & Johnson.

Ustekinumab-stba will be available in two formulations: A subcutaneous injection in two strengths — a 45 mg/0.5 mL or 90 mg/1 mL solution in a single-dose, prefilled syringe — and an intravenous infusion of a 130 mg/26 mL (5 mg/mL) solution in a single-dose vial.

“The approval of Steqeyma reflects Celltrion’s continued investment in providing treatment options to patients diagnosed with ulcerative colitis, Crohn’s disease, psoriasis, and psoriatic arthritis,” said Thomas Nusbickel, Chief Commercial Officer at Celltrion USA, Jersey City, New Jersey, in a press release.

The FDA has previously approved the company’s adalimumab biosimilar Yuflyma and its infliximab biosimilar Zymfentra.

The full prescribing information for ustekinumab-stba is available here.

A version of this article first appeared on Medscape.com. 

Alpha-gal syndrome (AGS), a tickborne disease commonly called “red meat allergy,” is a serious, potentially life-threatening allergy to the carbohydrate alpha-gal. The alpha-gal carbohydrate is found in most mammals, though it is not in humans, apes, or old-world monkeys. People with AGS can have allergic reactions when they consume mammalian meat, dairy products, or other products derived from mammals. People often live with this disease for years before receiving a correct diagnosis, greatly impacting their quality of life. The number of suspected cases is also rising. 

More than 110,000 suspected AGS cases were identified between 2010 and 2022, according to a Centers for Disease Control and Prevention (CDC) report.¹ However, because the diagnosis requires a positive test and a clinical exam and some people may not get tested, as many as 450,000 people might be affected by AGS in the United States. Additionally, a CDC survey found that nearly half (42%) of US healthcare providers had never heard of AGS.² Among those who had, less than one third (29%) knew how to diagnose the condition. 

Here are 5 things clinicians need to know about AGS.

 

1. People can develop AGS after being bitten by a tick, primarily the lone star tick (Amblyomma americanum), in the United States.

In the United States, AGS is primarily associated with the bite of a lone star tick, but other kinds of ticks have not been ruled out. The majority of suspected AGS cases in the United States were reported in parts of Arkansas, Delaware, Illinois, Indiana, Kansas, Kentucky, Maryland, Mississippi, Missouri, North Carolina, Oklahoma, Tennessee, and Virginia. The lone star tick is widely distributed with established populations in Alabama, Arkansas, Connecticut, Delaware, Florida, Georgia, Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana, Michigan, Minnesota, Mississippi, Missouri, Nebraska, New Hampshire, New Jersey, New York, North Carolina, Ohio, Oklahoma, Pennsylvania, South Carolina, Tennessee, Texas, Virginia, and West Virginia. 

While AGS is associated with tick bites, more research is needed to understand the role ticks play in starting this condition, and why certain people develop AGS. Anyone can develop AGS, but most cases have been reported in adults. 

Know how to recognize the symptoms of AGS and be prepared to test, diagnose, and manage AGS, particularly in states where lone star ticks are found. 

 

2. Tick bites are only one risk factor for developing AGS. 

Many people are bitten by lone star ticks and will never develop AGS. Scientists are exploring the connection between other risk factors and developing AGS. A recent study has shown that people diagnosed with AGS may be more likely to have a family member who was also diagnosed with AGS, have another food allergy, have an allergy to stinging or biting insects, or have A or O blood types.³ 

Research has also shown that environmental risk factors could contribute to developing AGS,⁴ like living in an area with lone star ticks, remembering finding a tick on themselves, recalling multiple tick bites, living near a wooded forest, spending more time outside, or living in areas with deer, such as larger properties, wooded forests, and properties with shrubs and brush. 

Ask your patient questions about other allergies and history of recent tick bites or outdoor exposure to help determine if testing for AGS is appropriate.

 

3. Symptoms of AGS are consistently inconsistent.

There is a spectrum of how sensitive AGS patients are to alpha-gal, and reactions are often different from person to person, which can make it difficult to diagnose. The first allergic reaction to AGS typically occurs between 1-6 months after a tick bite. Symptoms commonly appear 2-6 hours after being in contact with products containing alpha-gal, like red meat (beef, pork, lamb, venison, rabbit, or other meat from mammals), dairy, and some medications. Symptoms can range from mild to severe and include hives or itchy rash; swelling of the lips, throat, tongue, or eyelids; gastrointestinal symptoms such as nausea, vomiting, or diarrhea; heartburn or indigestion; cough, shortness of breath, or difficulty breathing; dizziness or a drop in blood pressure; or anaphylaxis.

Consider AGS if a patient reports waking up in the middle of the night with allergic symptoms after eating alpha-gal containing products for dinner, if allergic reactions are delayed, or if a patient has anaphylaxis of unknown cause, adult-onset allergy, or allergic symptoms and reports a recent tick bite. 

 

4. Diagnosing AGS requires a combination of a blood test and a physical exam.

Diagnosing AGS requires a detailed patient history, physical exam, and a blood test to detect specific immunoglobulin E (IgE) antibodies specific to alpha-gal (alpha-gal sIgE). Tests for alpha-gal sIgE antibodies are available at several large commercial laboratories and some academic institutions. Skin tests to identify reactions to allergens like pork or beef may also be used to inform AGS diagnosis. However, a positive alpha-gal sIgE test or skin test does not mean a person has AGS. Many people, particularly those who live in regions with lone star ticks, have positive alpha-gal specific IgE tests without having AGS. 

Consider the test results along with your patient’s symptoms and risk factors.

 

5. There is no treatment for AGS, but people can take prevention steps and AGS can be managed.

People can protect themselves and their family from AGS by preventing tick bites. Encourage your patients to use an Environmental Protection Agency–registered insect repellent outdoors, wear permethrin-treated clothing, and conduct thorough tick checks after outdoor activities. 

Once a person is no longer exposed to alpha-gal containing products, they should no longer experience symptoms. People with AGS should also proactively prevent tick bites. Tick bites can trigger or reactivate AGS.

For patients who have AGS, help manage their symptoms and identify alpha-gal containing products to avoid.

Dr. Kersh is Chief of the Rickettsial Zoonoses Branch, Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, and disclosed no relevant conflicts of interest.

CDC resources:

About Alpha-gal Syndrome | Alpha-gal Syndrome | CDC 

Clinical Testing and Diagnosis for Alpha-gal Syndrome | Alpha-gal Syndrome | CDC 

Clinical Resources | Alpha-gal Syndrome | CDC 

References 

Thompson JM et al. MMWR Morb Mortal Wkly Rep. 2023;72:815-820. 

Carpenter A et al. MMWR Morb Mortal Wkly Rep. 2023;72:809-814. Taylor ML et al. Ann Allergy, Asthma & Immunol. 2024 Jun;132(6):759.e2-764.e2. Kersh GJ et al. Ann Allergy, Asthma & Immunol. 2023 Apr;130(4):472-478.

Alpha-gal syndrome (AGS), a tickborne disease commonly called “red meat allergy,” is a serious, potentially life-threatening allergy to the carbohydrate alpha-gal. The alpha-gal carbohydrate is found in most mammals, though it is not in humans, apes, or old-world monkeys. People with AGS can have allergic reactions when they consume mammalian meat, dairy products, or other products derived from mammals. People often live with this disease for years before receiving a correct diagnosis, greatly impacting their quality of life. The number of suspected cases is also rising. 

More than 110,000 suspected AGS cases were identified between 2010 and 2022, according to a Centers for Disease Control and Prevention (CDC) report.¹ However, because the diagnosis requires a positive test and a clinical exam and some people may not get tested, as many as 450,000 people might be affected by AGS in the United States. Additionally, a CDC survey found that nearly half (42%) of US healthcare providers had never heard of AGS.² Among those who had, less than one third (29%) knew how to diagnose the condition. 

Here are 5 things clinicians need to know about AGS.

 

1. People can develop AGS after being bitten by a tick, primarily the lone star tick (Amblyomma americanum), in the United States.

In the United States, AGS is primarily associated with the bite of a lone star tick, but other kinds of ticks have not been ruled out. The majority of suspected AGS cases in the United States were reported in parts of Arkansas, Delaware, Illinois, Indiana, Kansas, Kentucky, Maryland, Mississippi, Missouri, North Carolina, Oklahoma, Tennessee, and Virginia. The lone star tick is widely distributed with established populations in Alabama, Arkansas, Connecticut, Delaware, Florida, Georgia, Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana, Michigan, Minnesota, Mississippi, Missouri, Nebraska, New Hampshire, New Jersey, New York, North Carolina, Ohio, Oklahoma, Pennsylvania, South Carolina, Tennessee, Texas, Virginia, and West Virginia. 

While AGS is associated with tick bites, more research is needed to understand the role ticks play in starting this condition, and why certain people develop AGS. Anyone can develop AGS, but most cases have been reported in adults. 

Know how to recognize the symptoms of AGS and be prepared to test, diagnose, and manage AGS, particularly in states where lone star ticks are found. 

 

2. Tick bites are only one risk factor for developing AGS. 

Many people are bitten by lone star ticks and will never develop AGS. Scientists are exploring the connection between other risk factors and developing AGS. A recent study has shown that people diagnosed with AGS may be more likely to have a family member who was also diagnosed with AGS, have another food allergy, have an allergy to stinging or biting insects, or have A or O blood types.³ 

Research has also shown that environmental risk factors could contribute to developing AGS,⁴ like living in an area with lone star ticks, remembering finding a tick on themselves, recalling multiple tick bites, living near a wooded forest, spending more time outside, or living in areas with deer, such as larger properties, wooded forests, and properties with shrubs and brush. 

Ask your patient questions about other allergies and history of recent tick bites or outdoor exposure to help determine if testing for AGS is appropriate.

 

3. Symptoms of AGS are consistently inconsistent.

There is a spectrum of how sensitive AGS patients are to alpha-gal, and reactions are often different from person to person, which can make it difficult to diagnose. The first allergic reaction to AGS typically occurs between 1-6 months after a tick bite. Symptoms commonly appear 2-6 hours after being in contact with products containing alpha-gal, like red meat (beef, pork, lamb, venison, rabbit, or other meat from mammals), dairy, and some medications. Symptoms can range from mild to severe and include hives or itchy rash; swelling of the lips, throat, tongue, or eyelids; gastrointestinal symptoms such as nausea, vomiting, or diarrhea; heartburn or indigestion; cough, shortness of breath, or difficulty breathing; dizziness or a drop in blood pressure; or anaphylaxis.

Consider AGS if a patient reports waking up in the middle of the night with allergic symptoms after eating alpha-gal containing products for dinner, if allergic reactions are delayed, or if a patient has anaphylaxis of unknown cause, adult-onset allergy, or allergic symptoms and reports a recent tick bite. 

 

4. Diagnosing AGS requires a combination of a blood test and a physical exam.

Diagnosing AGS requires a detailed patient history, physical exam, and a blood test to detect specific immunoglobulin E (IgE) antibodies specific to alpha-gal (alpha-gal sIgE). Tests for alpha-gal sIgE antibodies are available at several large commercial laboratories and some academic institutions. Skin tests to identify reactions to allergens like pork or beef may also be used to inform AGS diagnosis. However, a positive alpha-gal sIgE test or skin test does not mean a person has AGS. Many people, particularly those who live in regions with lone star ticks, have positive alpha-gal specific IgE tests without having AGS. 

Consider the test results along with your patient’s symptoms and risk factors.

 

5. There is no treatment for AGS, but people can take prevention steps and AGS can be managed.

People can protect themselves and their family from AGS by preventing tick bites. Encourage your patients to use an Environmental Protection Agency–registered insect repellent outdoors, wear permethrin-treated clothing, and conduct thorough tick checks after outdoor activities. 

Once a person is no longer exposed to alpha-gal containing products, they should no longer experience symptoms. People with AGS should also proactively prevent tick bites. Tick bites can trigger or reactivate AGS.

For patients who have AGS, help manage their symptoms and identify alpha-gal containing products to avoid.

Dr. Kersh is Chief of the Rickettsial Zoonoses Branch, Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, and disclosed no relevant conflicts of interest.

CDC resources:

About Alpha-gal Syndrome | Alpha-gal Syndrome | CDC 

Clinical Testing and Diagnosis for Alpha-gal Syndrome | Alpha-gal Syndrome | CDC 

Clinical Resources | Alpha-gal Syndrome | CDC 

References 

Thompson JM et al. MMWR Morb Mortal Wkly Rep. 2023;72:815-820. 

Carpenter A et al. MMWR Morb Mortal Wkly Rep. 2023;72:809-814. Taylor ML et al. Ann Allergy, Asthma & Immunol. 2024 Jun;132(6):759.e2-764.e2. Kersh GJ et al. Ann Allergy, Asthma & Immunol. 2023 Apr;130(4):472-478.

Alpha-gal syndrome (AGS), a tickborne disease commonly called “red meat allergy,” is a serious, potentially life-threatening allergy to the carbohydrate alpha-gal. The alpha-gal carbohydrate is found in most mammals, though it is not in humans, apes, or old-world monkeys. People with AGS can have allergic reactions when they consume mammalian meat, dairy products, or other products derived from mammals. People often live with this disease for years before receiving a correct diagnosis, greatly impacting their quality of life. The number of suspected cases is also rising. 

More than 110,000 suspected AGS cases were identified between 2010 and 2022, according to a Centers for Disease Control and Prevention (CDC) report.¹ However, because the diagnosis requires a positive test and a clinical exam and some people may not get tested, as many as 450,000 people might be affected by AGS in the United States. Additionally, a CDC survey found that nearly half (42%) of US healthcare providers had never heard of AGS.² Among those who had, less than one third (29%) knew how to diagnose the condition. 

Here are 5 things clinicians need to know about AGS.

 

1. People can develop AGS after being bitten by a tick, primarily the lone star tick (Amblyomma americanum), in the United States.

In the United States, AGS is primarily associated with the bite of a lone star tick, but other kinds of ticks have not been ruled out. The majority of suspected AGS cases in the United States were reported in parts of Arkansas, Delaware, Illinois, Indiana, Kansas, Kentucky, Maryland, Mississippi, Missouri, North Carolina, Oklahoma, Tennessee, and Virginia. The lone star tick is widely distributed with established populations in Alabama, Arkansas, Connecticut, Delaware, Florida, Georgia, Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana, Michigan, Minnesota, Mississippi, Missouri, Nebraska, New Hampshire, New Jersey, New York, North Carolina, Ohio, Oklahoma, Pennsylvania, South Carolina, Tennessee, Texas, Virginia, and West Virginia. 

While AGS is associated with tick bites, more research is needed to understand the role ticks play in starting this condition, and why certain people develop AGS. Anyone can develop AGS, but most cases have been reported in adults. 

Know how to recognize the symptoms of AGS and be prepared to test, diagnose, and manage AGS, particularly in states where lone star ticks are found. 

 

2. Tick bites are only one risk factor for developing AGS. 

Many people are bitten by lone star ticks and will never develop AGS. Scientists are exploring the connection between other risk factors and developing AGS. A recent study has shown that people diagnosed with AGS may be more likely to have a family member who was also diagnosed with AGS, have another food allergy, have an allergy to stinging or biting insects, or have A or O blood types.³ 

Research has also shown that environmental risk factors could contribute to developing AGS,⁴ like living in an area with lone star ticks, remembering finding a tick on themselves, recalling multiple tick bites, living near a wooded forest, spending more time outside, or living in areas with deer, such as larger properties, wooded forests, and properties with shrubs and brush. 

Ask your patient questions about other allergies and history of recent tick bites or outdoor exposure to help determine if testing for AGS is appropriate.

 

3. Symptoms of AGS are consistently inconsistent.

There is a spectrum of how sensitive AGS patients are to alpha-gal, and reactions are often different from person to person, which can make it difficult to diagnose. The first allergic reaction to AGS typically occurs between 1-6 months after a tick bite. Symptoms commonly appear 2-6 hours after being in contact with products containing alpha-gal, like red meat (beef, pork, lamb, venison, rabbit, or other meat from mammals), dairy, and some medications. Symptoms can range from mild to severe and include hives or itchy rash; swelling of the lips, throat, tongue, or eyelids; gastrointestinal symptoms such as nausea, vomiting, or diarrhea; heartburn or indigestion; cough, shortness of breath, or difficulty breathing; dizziness or a drop in blood pressure; or anaphylaxis.

Consider AGS if a patient reports waking up in the middle of the night with allergic symptoms after eating alpha-gal containing products for dinner, if allergic reactions are delayed, or if a patient has anaphylaxis of unknown cause, adult-onset allergy, or allergic symptoms and reports a recent tick bite. 

 

4. Diagnosing AGS requires a combination of a blood test and a physical exam.

Diagnosing AGS requires a detailed patient history, physical exam, and a blood test to detect specific immunoglobulin E (IgE) antibodies specific to alpha-gal (alpha-gal sIgE). Tests for alpha-gal sIgE antibodies are available at several large commercial laboratories and some academic institutions. Skin tests to identify reactions to allergens like pork or beef may also be used to inform AGS diagnosis. However, a positive alpha-gal sIgE test or skin test does not mean a person has AGS. Many people, particularly those who live in regions with lone star ticks, have positive alpha-gal specific IgE tests without having AGS. 

Consider the test results along with your patient’s symptoms and risk factors.

 

5. There is no treatment for AGS, but people can take prevention steps and AGS can be managed.

People can protect themselves and their family from AGS by preventing tick bites. Encourage your patients to use an Environmental Protection Agency–registered insect repellent outdoors, wear permethrin-treated clothing, and conduct thorough tick checks after outdoor activities. 

Once a person is no longer exposed to alpha-gal containing products, they should no longer experience symptoms. People with AGS should also proactively prevent tick bites. Tick bites can trigger or reactivate AGS.

For patients who have AGS, help manage their symptoms and identify alpha-gal containing products to avoid.

Dr. Kersh is Chief of the Rickettsial Zoonoses Branch, Division of Vector-Borne Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, and disclosed no relevant conflicts of interest.

CDC resources:

About Alpha-gal Syndrome | Alpha-gal Syndrome | CDC 

Clinical Testing and Diagnosis for Alpha-gal Syndrome | Alpha-gal Syndrome | CDC 

Clinical Resources | Alpha-gal Syndrome | CDC 

References 

Thompson JM et al. MMWR Morb Mortal Wkly Rep. 2023;72:815-820. 

Carpenter A et al. MMWR Morb Mortal Wkly Rep. 2023;72:809-814. Taylor ML et al. Ann Allergy, Asthma & Immunol. 2024 Jun;132(6):759.e2-764.e2. Kersh GJ et al. Ann Allergy, Asthma & Immunol. 2023 Apr;130(4):472-478.

Evidence is mounting that new therapies already used to treat gut diseases, type 2 diabetes, and obesity may help people with alcohol use disorder (AUD).

Glucagon-like peptide 1 (GLP-1) receptor agonists, first used to treat diabetes and now widely used for weight loss, and fecal microbiota transplants (FMTs), used to treat diseases such as recurrent Clostridioides difficile infection, are advancing in clinical trials as potential options for treating AUD.

 

AUD Affects 28.9 Million People in the United States

In 2023, 28.9 million people aged 12 years or older in the United States had AUD (10.2% of the people in this age group). The Food and Drug Administration (FDA) has approved three medical therapies: Acamprosate, naltrexone, and disulfiram to help keep people with the disorder from returning to heavy drinking. Acamprosate’s mechanism of action is not clear, but it is thought to modulate and normalize alcohol-related changes in brain activity, thereby reducing withdrawal symptoms. Naltrexone blocks opioid receptors to reduce alcohol cravings. Disulfiram causes a toxic physical reaction when mixed with alcohol.

Some with AUD also benefit from behavioral therapies and support groups such as Alcoholics Anonymous. But for others, nothing has worked, and that’s part of the reason Lorenzo Leggio, MD, PhD, a scientist in the field of alcohol addiction with the National Institutes of Health (NIH), told this news organization that this is the “most exciting moment” for AUD treatment in his more than 2 decades of research in this area.

 

GLP-1 Agonists Showing Consistent Results

GLP-1 receptor agonists work by modulating the brain’s reward pathways, including the areas that regulate cravings and motivation.

“By dampening the reward signals associated with alcohol consumption, GLP-1 agonists may reduce cravings and heavy drinking episodes,” Fares Qeadan, PhD, MS, associate professor of biostatistics in the Department of Public Health Sciences at Loyola University Chicago in Illinois, told this news organization.

“The unique aspect of GLP-1 agonists is their ability to target both metabolic and reward systems in the brain,” he said. While naltrexone or acamprosate blocks the effects of alcohol or reduces withdrawal symptoms, “GLP-1 agonists approach addiction through a broader mechanism, potentially addressing underlying factors that contribute to cravings and compulsive behaviors,” he said.

As part of a study published in October in Addiction, Qeadan’s team found that people with AUD who were prescribed GLP-1 agonists had a 50% lower rate of severe intoxication than those who were not prescribed those medications.

“While this is observational and not yet definitive, it highlights the potential of these drugs to complement existing treatments for AUD,” he said.

Another study, a nationwide cohort study published in JAMA Psychiatry, found that using the GLP-1 receptor agonists semaglutide and liraglutide was linked to a lower risk for AUD-related hospitalizations than traditional AUD medications.

A systematic review, published last month in eClinical Medicine, concluded that, though there is little high-quality evidence demonstrating the effect of GLP-1 receptor agonists on alcohol use, “subgroup analysis from two [randomized, controlled trials] and supporting data from four observational studies suggest that GLP-1 [receptor agonists] may reduce alcohol consumption and improve outcomes in some individuals.”

Studying individual differences in response may have implications for personalized medicine, Qeadan said, as treatments could be tailored to those most likely to benefit, such as people with both metabolic dysfunction and AUD.

“These medications may offer hope for patients who struggle with addiction and have not responded to traditional therapies,” Qeadan said.

 

Exploring FMT as AUD Treatment

FMT is also a new research focus for treating AUD. Jasmohan Bajaj, MD, a gastroenterologist and liver specialist at Virginia Commonwealth University Medical Center, Richmond, is leading the Intestinal Microbiota Transplant in Alcohol-Associated Liver Disease (IMPACT) trial.

AUD has been linked with gut microbial alterations that worsen with cirrhosis. Research has shown that alcohol consumption changes the diversity of bacteria and can lead to bacterial overgrowth and progression of alcohol-associated liver disease.

FMT has been effective in rebalancing gut bacteria by transferring healthy stool from screened donors into patients who have developed an overgrowth of harmful bacteria. In the IMPACT trial, participants, who have not previously received traditional treatment for AUD or for whom treatment has not worked, are randomized either to the oral treatment capsule, which contains freeze-dried stool from a donor with healthy gut bacteria, or placebo.

The trial, sponsored by the NIH, is halfway through its target enrollment of 80.

In a previous smaller, placebo-controlled, phase 1 study, also led by Bajaj and published in Hepatology, 9 of the 10 volunteers who had severe AUD and cirrhosis experienced fewer alcohol cravings and had lower consumption after 15 days. Only three of the placebo participants saw similar improvements. Those who received the microbiota transplant also had fewer AUD-related events over 6 months.

Bajaj said that, if trials show FMT is safe and effective, he envisions the treatment as one tool in a multidisciplinary, integrated clinic that would include a hepatologist and mental health clinicians.

One benefit of the FMT treatment approach is it is given once or twice only, rather than administered regularly.

 

Current Treatments Work, But More are Needed

Leggio, who is clinical director of the National Institute on Drug Abuse Intramural Research Program, said: “We know that alcohol use disorder, and addiction in general, is a brain disease. We also know that the brain does not work in isolation. The brain is constantly interacting with the rest of the body, including with the gut.”

Leggio said it’s important to note that the three FDA-approved medications do work for alcohol addiction. He said they work as well as selective serotonin reuptake inhibitors for depression and beta-blockers for chronic heart failure.

But there are only three, and they don’t work for everyone, he noted. Those are among the reasons developing new treatments is important. New treatments could be used as an alternative or in combination with already approved treatments.

FMT is in “the very early stages” of trials testing its use for AUD, Leggio noted, adding that the studies by Bajaj’s team are among the very few addressing gut dysbiosis in AUD, and all have involved small numbers of patients. “It’s promising. It’s intriguing. It’s exciting. But we are just at the beginning.”

 

Results Consistent Across Species, Labs

GLP-1 agonists are further along in trials but still not ready for prescribing for AUD, Leggio said. The positive results have been consistent across species, different labs, and different research teams around the world.

Researchers have also explored through electronic health record emulation trials whether people already taking GLP-1 agonists for diabetes or obesity drink less alcohol compared with matched cohorts not taking GLP-1s. “They consistently show that the people who are on GLP-1s drink less,” he said.

“[Emulation trials] don’t replace the need for randomized controlled trials, Leggio noted. Leggio’s team is currently working on a randomized, placebo-controlled, double-blinded trial studying GLP-1s in relation to AUD.

 

New Directions 20-Year Highlight

This whole line of research represents “new hope” and has many implications, Leggio said. “I have been in this business for 20-plus years, and I think this is themost exciting moment when we have a very promising target in GLP-1s.”

Regardless of efficacy, he said, the focus on GLP-1 agonists and FMT for AUD has people talking more about addiction and the brain-body connection rather than assuming AUD is a result of poor choices and “bad behavior.”

The momentum of new treatments could also lead to patients and physicians having conversations about existing treatments.

“Hopefully, this momentum will help us destigmatize addiction, and by destigmatizing addiction, there will be an uptick in use of currently approved medications,” Leggio said.

Qeadan, Bajaj, and Leggio reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Evidence is mounting that new therapies already used to treat gut diseases, type 2 diabetes, and obesity may help people with alcohol use disorder (AUD).

Glucagon-like peptide 1 (GLP-1) receptor agonists, first used to treat diabetes and now widely used for weight loss, and fecal microbiota transplants (FMTs), used to treat diseases such as recurrent Clostridioides difficile infection, are advancing in clinical trials as potential options for treating AUD.

 

AUD Affects 28.9 Million People in the United States

In 2023, 28.9 million people aged 12 years or older in the United States had AUD (10.2% of the people in this age group). The Food and Drug Administration (FDA) has approved three medical therapies: Acamprosate, naltrexone, and disulfiram to help keep people with the disorder from returning to heavy drinking. Acamprosate’s mechanism of action is not clear, but it is thought to modulate and normalize alcohol-related changes in brain activity, thereby reducing withdrawal symptoms. Naltrexone blocks opioid receptors to reduce alcohol cravings. Disulfiram causes a toxic physical reaction when mixed with alcohol.

Some with AUD also benefit from behavioral therapies and support groups such as Alcoholics Anonymous. But for others, nothing has worked, and that’s part of the reason Lorenzo Leggio, MD, PhD, a scientist in the field of alcohol addiction with the National Institutes of Health (NIH), told this news organization that this is the “most exciting moment” for AUD treatment in his more than 2 decades of research in this area.

 

GLP-1 Agonists Showing Consistent Results

GLP-1 receptor agonists work by modulating the brain’s reward pathways, including the areas that regulate cravings and motivation.

“By dampening the reward signals associated with alcohol consumption, GLP-1 agonists may reduce cravings and heavy drinking episodes,” Fares Qeadan, PhD, MS, associate professor of biostatistics in the Department of Public Health Sciences at Loyola University Chicago in Illinois, told this news organization.

“The unique aspect of GLP-1 agonists is their ability to target both metabolic and reward systems in the brain,” he said. While naltrexone or acamprosate blocks the effects of alcohol or reduces withdrawal symptoms, “GLP-1 agonists approach addiction through a broader mechanism, potentially addressing underlying factors that contribute to cravings and compulsive behaviors,” he said.

As part of a study published in October in Addiction, Qeadan’s team found that people with AUD who were prescribed GLP-1 agonists had a 50% lower rate of severe intoxication than those who were not prescribed those medications.

“While this is observational and not yet definitive, it highlights the potential of these drugs to complement existing treatments for AUD,” he said.

Another study, a nationwide cohort study published in JAMA Psychiatry, found that using the GLP-1 receptor agonists semaglutide and liraglutide was linked to a lower risk for AUD-related hospitalizations than traditional AUD medications.

A systematic review, published last month in eClinical Medicine, concluded that, though there is little high-quality evidence demonstrating the effect of GLP-1 receptor agonists on alcohol use, “subgroup analysis from two [randomized, controlled trials] and supporting data from four observational studies suggest that GLP-1 [receptor agonists] may reduce alcohol consumption and improve outcomes in some individuals.”

Studying individual differences in response may have implications for personalized medicine, Qeadan said, as treatments could be tailored to those most likely to benefit, such as people with both metabolic dysfunction and AUD.

“These medications may offer hope for patients who struggle with addiction and have not responded to traditional therapies,” Qeadan said.

 

Exploring FMT as AUD Treatment

FMT is also a new research focus for treating AUD. Jasmohan Bajaj, MD, a gastroenterologist and liver specialist at Virginia Commonwealth University Medical Center, Richmond, is leading the Intestinal Microbiota Transplant in Alcohol-Associated Liver Disease (IMPACT) trial.

AUD has been linked with gut microbial alterations that worsen with cirrhosis. Research has shown that alcohol consumption changes the diversity of bacteria and can lead to bacterial overgrowth and progression of alcohol-associated liver disease.

FMT has been effective in rebalancing gut bacteria by transferring healthy stool from screened donors into patients who have developed an overgrowth of harmful bacteria. In the IMPACT trial, participants, who have not previously received traditional treatment for AUD or for whom treatment has not worked, are randomized either to the oral treatment capsule, which contains freeze-dried stool from a donor with healthy gut bacteria, or placebo.

The trial, sponsored by the NIH, is halfway through its target enrollment of 80.

In a previous smaller, placebo-controlled, phase 1 study, also led by Bajaj and published in Hepatology, 9 of the 10 volunteers who had severe AUD and cirrhosis experienced fewer alcohol cravings and had lower consumption after 15 days. Only three of the placebo participants saw similar improvements. Those who received the microbiota transplant also had fewer AUD-related events over 6 months.

Bajaj said that, if trials show FMT is safe and effective, he envisions the treatment as one tool in a multidisciplinary, integrated clinic that would include a hepatologist and mental health clinicians.

One benefit of the FMT treatment approach is it is given once or twice only, rather than administered regularly.

 

Current Treatments Work, But More are Needed

Leggio, who is clinical director of the National Institute on Drug Abuse Intramural Research Program, said: “We know that alcohol use disorder, and addiction in general, is a brain disease. We also know that the brain does not work in isolation. The brain is constantly interacting with the rest of the body, including with the gut.”

Leggio said it’s important to note that the three FDA-approved medications do work for alcohol addiction. He said they work as well as selective serotonin reuptake inhibitors for depression and beta-blockers for chronic heart failure.

But there are only three, and they don’t work for everyone, he noted. Those are among the reasons developing new treatments is important. New treatments could be used as an alternative or in combination with already approved treatments.

FMT is in “the very early stages” of trials testing its use for AUD, Leggio noted, adding that the studies by Bajaj’s team are among the very few addressing gut dysbiosis in AUD, and all have involved small numbers of patients. “It’s promising. It’s intriguing. It’s exciting. But we are just at the beginning.”

 

Results Consistent Across Species, Labs

GLP-1 agonists are further along in trials but still not ready for prescribing for AUD, Leggio said. The positive results have been consistent across species, different labs, and different research teams around the world.

Researchers have also explored through electronic health record emulation trials whether people already taking GLP-1 agonists for diabetes or obesity drink less alcohol compared with matched cohorts not taking GLP-1s. “They consistently show that the people who are on GLP-1s drink less,” he said.

“[Emulation trials] don’t replace the need for randomized controlled trials, Leggio noted. Leggio’s team is currently working on a randomized, placebo-controlled, double-blinded trial studying GLP-1s in relation to AUD.

 

New Directions 20-Year Highlight

This whole line of research represents “new hope” and has many implications, Leggio said. “I have been in this business for 20-plus years, and I think this is themost exciting moment when we have a very promising target in GLP-1s.”

Regardless of efficacy, he said, the focus on GLP-1 agonists and FMT for AUD has people talking more about addiction and the brain-body connection rather than assuming AUD is a result of poor choices and “bad behavior.”

The momentum of new treatments could also lead to patients and physicians having conversations about existing treatments.

“Hopefully, this momentum will help us destigmatize addiction, and by destigmatizing addiction, there will be an uptick in use of currently approved medications,” Leggio said.

Qeadan, Bajaj, and Leggio reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Evidence is mounting that new therapies already used to treat gut diseases, type 2 diabetes, and obesity may help people with alcohol use disorder (AUD).

Glucagon-like peptide 1 (GLP-1) receptor agonists, first used to treat diabetes and now widely used for weight loss, and fecal microbiota transplants (FMTs), used to treat diseases such as recurrent Clostridioides difficile infection, are advancing in clinical trials as potential options for treating AUD.

 

AUD Affects 28.9 Million People in the United States

In 2023, 28.9 million people aged 12 years or older in the United States had AUD (10.2% of the people in this age group). The Food and Drug Administration (FDA) has approved three medical therapies: Acamprosate, naltrexone, and disulfiram to help keep people with the disorder from returning to heavy drinking. Acamprosate’s mechanism of action is not clear, but it is thought to modulate and normalize alcohol-related changes in brain activity, thereby reducing withdrawal symptoms. Naltrexone blocks opioid receptors to reduce alcohol cravings. Disulfiram causes a toxic physical reaction when mixed with alcohol.

Some with AUD also benefit from behavioral therapies and support groups such as Alcoholics Anonymous. But for others, nothing has worked, and that’s part of the reason Lorenzo Leggio, MD, PhD, a scientist in the field of alcohol addiction with the National Institutes of Health (NIH), told this news organization that this is the “most exciting moment” for AUD treatment in his more than 2 decades of research in this area.

 

GLP-1 Agonists Showing Consistent Results

GLP-1 receptor agonists work by modulating the brain’s reward pathways, including the areas that regulate cravings and motivation.

“By dampening the reward signals associated with alcohol consumption, GLP-1 agonists may reduce cravings and heavy drinking episodes,” Fares Qeadan, PhD, MS, associate professor of biostatistics in the Department of Public Health Sciences at Loyola University Chicago in Illinois, told this news organization.

“The unique aspect of GLP-1 agonists is their ability to target both metabolic and reward systems in the brain,” he said. While naltrexone or acamprosate blocks the effects of alcohol or reduces withdrawal symptoms, “GLP-1 agonists approach addiction through a broader mechanism, potentially addressing underlying factors that contribute to cravings and compulsive behaviors,” he said.

As part of a study published in October in Addiction, Qeadan’s team found that people with AUD who were prescribed GLP-1 agonists had a 50% lower rate of severe intoxication than those who were not prescribed those medications.

“While this is observational and not yet definitive, it highlights the potential of these drugs to complement existing treatments for AUD,” he said.

Another study, a nationwide cohort study published in JAMA Psychiatry, found that using the GLP-1 receptor agonists semaglutide and liraglutide was linked to a lower risk for AUD-related hospitalizations than traditional AUD medications.

A systematic review, published last month in eClinical Medicine, concluded that, though there is little high-quality evidence demonstrating the effect of GLP-1 receptor agonists on alcohol use, “subgroup analysis from two [randomized, controlled trials] and supporting data from four observational studies suggest that GLP-1 [receptor agonists] may reduce alcohol consumption and improve outcomes in some individuals.”

Studying individual differences in response may have implications for personalized medicine, Qeadan said, as treatments could be tailored to those most likely to benefit, such as people with both metabolic dysfunction and AUD.

“These medications may offer hope for patients who struggle with addiction and have not responded to traditional therapies,” Qeadan said.

 

Exploring FMT as AUD Treatment

FMT is also a new research focus for treating AUD. Jasmohan Bajaj, MD, a gastroenterologist and liver specialist at Virginia Commonwealth University Medical Center, Richmond, is leading the Intestinal Microbiota Transplant in Alcohol-Associated Liver Disease (IMPACT) trial.

AUD has been linked with gut microbial alterations that worsen with cirrhosis. Research has shown that alcohol consumption changes the diversity of bacteria and can lead to bacterial overgrowth and progression of alcohol-associated liver disease.

FMT has been effective in rebalancing gut bacteria by transferring healthy stool from screened donors into patients who have developed an overgrowth of harmful bacteria. In the IMPACT trial, participants, who have not previously received traditional treatment for AUD or for whom treatment has not worked, are randomized either to the oral treatment capsule, which contains freeze-dried stool from a donor with healthy gut bacteria, or placebo.

The trial, sponsored by the NIH, is halfway through its target enrollment of 80.

In a previous smaller, placebo-controlled, phase 1 study, also led by Bajaj and published in Hepatology, 9 of the 10 volunteers who had severe AUD and cirrhosis experienced fewer alcohol cravings and had lower consumption after 15 days. Only three of the placebo participants saw similar improvements. Those who received the microbiota transplant also had fewer AUD-related events over 6 months.

Bajaj said that, if trials show FMT is safe and effective, he envisions the treatment as one tool in a multidisciplinary, integrated clinic that would include a hepatologist and mental health clinicians.

One benefit of the FMT treatment approach is it is given once or twice only, rather than administered regularly.

 

Current Treatments Work, But More are Needed

Leggio, who is clinical director of the National Institute on Drug Abuse Intramural Research Program, said: “We know that alcohol use disorder, and addiction in general, is a brain disease. We also know that the brain does not work in isolation. The brain is constantly interacting with the rest of the body, including with the gut.”

Leggio said it’s important to note that the three FDA-approved medications do work for alcohol addiction. He said they work as well as selective serotonin reuptake inhibitors for depression and beta-blockers for chronic heart failure.

But there are only three, and they don’t work for everyone, he noted. Those are among the reasons developing new treatments is important. New treatments could be used as an alternative or in combination with already approved treatments.

FMT is in “the very early stages” of trials testing its use for AUD, Leggio noted, adding that the studies by Bajaj’s team are among the very few addressing gut dysbiosis in AUD, and all have involved small numbers of patients. “It’s promising. It’s intriguing. It’s exciting. But we are just at the beginning.”

 

Results Consistent Across Species, Labs

GLP-1 agonists are further along in trials but still not ready for prescribing for AUD, Leggio said. The positive results have been consistent across species, different labs, and different research teams around the world.

Researchers have also explored through electronic health record emulation trials whether people already taking GLP-1 agonists for diabetes or obesity drink less alcohol compared with matched cohorts not taking GLP-1s. “They consistently show that the people who are on GLP-1s drink less,” he said.

“[Emulation trials] don’t replace the need for randomized controlled trials, Leggio noted. Leggio’s team is currently working on a randomized, placebo-controlled, double-blinded trial studying GLP-1s in relation to AUD.

 

New Directions 20-Year Highlight

This whole line of research represents “new hope” and has many implications, Leggio said. “I have been in this business for 20-plus years, and I think this is themost exciting moment when we have a very promising target in GLP-1s.”

Regardless of efficacy, he said, the focus on GLP-1 agonists and FMT for AUD has people talking more about addiction and the brain-body connection rather than assuming AUD is a result of poor choices and “bad behavior.”

The momentum of new treatments could also lead to patients and physicians having conversations about existing treatments.

“Hopefully, this momentum will help us destigmatize addiction, and by destigmatizing addiction, there will be an uptick in use of currently approved medications,” Leggio said.

Qeadan, Bajaj, and Leggio reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

There was a recent flurry of excitement when UK researchers from the Wellcome Sanger Institute, a nonprofit genomics and genetics research organization in Cambridge, England, announced their creation of the most detailed cell map of the human gastrointestinal (GI) tract up to this point. Using spatial and single-cell data from 1.6 million cells (from 271 donors), the scientists’ work, published in Nature, yields valuable information about the gut’s health and disease states.

“We now have a nice idea of what cell types we can find in the gut,” said co-author Rasa Elmentaite, PhD, co-founder and head of Genomics and Data Science at Ensocell.

No small question: How, exactly, does one go about mapping the human gut?

The story behind the construction of the Gut Cell Atlas, an arm of the larger Human Cell Atlas project — which recently published more than 40 studies in Nature in November 2024 — is one of global collaboration and scientific precision across continents.

Most of all, Elmentaite said, it has taken the scientists involved down paths they never anticipated.

 

How It Began

Over the past 5-7 years, there have been many individual publications across institutes where research labs have created snippets of what the cells in the gut look like, said Elmentaite, referring to the GI tract, which in this case encompasses the mouth, throat, esophagus, stomach, small intestine, large intestine, rectum, and anus.

Labs studying gut cells often focus on one specific region, for example, the small intestine or the large intestine, if they’re working on Crohn’s disease research. “It makes sense. The GI tract is really regionalized,” she said.

In 2019 and 2021, Elmentaite and her colleagues published papers that mapped some cells in the human gut, and their work garnered attention from other scientists around the world. That’s how they decided to take on the challenge of creating a more comprehensive map of the cells in both the healthy gut and in GI tracts where disease is present.

“We realized there are so many other labs interested in understanding the intestinal tract holistically,” she said. “We thought it would be really interesting to look at the cells in the context of the whole GI system.”

 

Not a Bad ‘Lockdown Project’

During the pandemic, while the rest of society was playing with sourdough starter, Elmentaite’s lab decided to pool their datasets with data from other labs to see what happened. They had more than 20 datasets at the time and wanted to generate more to fill gaps where there was less information available (eg, data on the cells in the stomach).

“It required getting samples from surgeons, going into the lab and processing those samples into single cells, and then processing that data bioinformatically,” said Elmentaite.

She explained that generating more datasets was not a job for one person and “required convincing a lot of scientists that it was worthwhile,” including a cancer biologist and a mucosal immunologist. They also brought in more technical bioinformatics expertise and recruited an IT team — several people who only worked on processing data and clearing it, “so it was aligned very specifically, and processed very uniformly, across the study,” Elmentaite said.

In the end, with researchers coming together on many Zoom calls from Australia, Germany, Norway, Spain, and numerous locations across the United Kingdom, they were able to integrate 25 single-cell RNA sequencing datasets that encompassed the entire healthy GI tract in development and in adults, leading to a healthy gut reference atlas that includes about 1.1 million cells and 136 cell subgroups.

 

How to Build a Two-Dimensional (2D) Map of the Gut

Here’s where the weeds get taller: Raw sequencing reads — bits of different RNA that the researchers sequenced from individual biological samples — needed to be mapped back to genes so that the researchers could understand what kinds of genes were expressed in the samples.

“There is a lot of curation there that needs to happen because the versions of transcriptome [a complete set of RNA molecules in a single cell or tissue], and what the genome looks like, is evolving constantly. So we have to map it back to the same transcriptomic reference,” Elmentaite said.

Once they knew all the different genes active in a cell, the researchers were able, using bioinformatics, to pull all of the datasets together and visualize them in a 2D space — essentially, a representation of a map.

“The cells that are transcriptionally more similar to each other, they will cluster together. And the ones that are more distinct transcriptionally will be farther away from each other,” Elmentaite said.

For decades, GI tract researchers had individually studied which types of genes are activated in an epithelial cell vs a T cell vs a B cell, she said, and “then suddenly you’re seeing it on your screen all at once. It’s amazing to see.”

 

In Brutal Detail

One of the biggest challenges in interpreting the data involved many people who made sure that there were no technical differences between the samples, Elmentaite said.

For example, samples processed in different labs may have sequencing differences between them. Or the kind of enzymes used to process the tissue might have been different from lab to lab. Sometimes they’d even record down to the detail what time of the day a sample was collected, if that information was available.

“Computationally, we considered all of these variables and tried to regress as much of that as possible. And then, if we saw clusters that resembled gene expression that we know is consistent with some of the cell types, then we knew that we’d regressed all the batch effects,” said Elmentaite.

 

Before ‘Eureka’ Comes a Few ‘Aha’ Moments

There were many “aha moments,” but also some puzzling ones, she said. One of the biggest surprises was seeing that the identity of a cell believed to be set from development can actually change if a person has a lot of irritation and inflammation, as occurs in inflammatory bowel disease. Epithelial cell metaplasia was one of the surprises.

“Metaplasia describes an activation or differentiation of one differentiated cell type into another differentiated cell type. And we knew that that exists in some of the upper GI diseases, but we didn’t realize that the same sort of mechanism exists in the small intestine,” Elmentaite said.

Epithelial cells are among the most abundant cells in the body. The researchers knew from established research that these cells act a bit like first responders and provide healing to the gut. “We could see that they were producing a lot of mucous that helps to potentially flush down the microbes that are triggering inflammation. But the ‘aha moment’ for us was that actually there’s a dual function in these cells,” she said.

They could see in the transcriptional profile a significant production of chemokines (a family of proteins that play a role in the body’s immune responses) and major histocompatibility complex class II molecules (cell surface proteins involved in the body’s immune response), and the epithelial cells seemed to attract neutrophils and monocytes and to interact with certain T cells — adding to the cycle of chronic inflammation.

“I think for a lot of us, this was a surprise because we think of epithelial cells as more like a barrier, just a passive player in, for example, inflammatory bowel disease,” said Elmentaite.

In addition to reporting their findings on epithelial cell metaplasia, the researchers processed 12 GI disease datasets, including celiac disease, Crohn’s disease, GI-related cancers, and ulcerative colitis.

 

A Gut Cell Atlas for the People (Well, Scientific People)

“The Gut Cell Atlas is usable for everyone, and everyone has a chance to contribute,” said Elmentaite. But 1.6 million cells is only a start and more data are needed, she said, and efforts are being spearheaded at the broader Human Cell Atlas project to collect it. There are also efforts to get all researchers using the same cell annotation, research-wide standards that will make the atlas truly usable for everyone.

Keith Summa, MD, PhD, assistant professor of medicine in the Division of Gastroenterology and Hepatology at Feinberg School of Medicine, Northwestern University, Chicago, focuses much of his work on inflammatory bowel disease as well as disorders of the gut-brain interaction. He conducts basic and translational research using experimental models of intestinal inflammation.

At Northwestern University, they have a tissue biorepository. It includes colon and intestine tissue samples from healthy individuals as well as individuals with different disease states. “One potential area where I could see this being a useful tool for us is that we could utilize the Gut Cell Atlas in the analysis of our tissue samples to see if we find commonalities between what’s described in the atlas and then what we’re observing,” said Summa, who was not involved in the UK-based project.

He said Northwestern University’s biorepository has details about what medications people were on and the extent and severity of their disease.

“We may be able to utilize the Gut Cell Atlas to help us look at specific factors in terms of how people are responding to different treatments, how different cell types are affected by different treatments, or how they are active or not active in different severities of disease. It may help us provide more precision to our understanding of these different conditions,” said Summa.

He also noted how GI specialists use “Crohn’s disease” as a single diagnosis, “but that encompasses a pretty wide spectrum of phenotypes and behaviors,” he said. “I think looking at such a cell-specific level may help to better identify some of the different pathways that are active and the different phenotypes or behaviors of this disease.” 

 

Next Step: Visualize It in a Three-Dimensional (3D) Space

The next stage for Elmentaite and her colleagues is to evolve the 2D map into a 3D map so they can visualize which cells are where and how they are organized in space.

“The next step, which I think is super exciting, is understanding how these cells depend on each other,” she said. “Really functionally understanding if some of them are essential and others are not. And doing AI modeling to understand what we can learn from this vast amount of data that we’re generating. And of course, that includes how we use this knowledge to create precision therapies.”

 

A version of this article appeared on Medscape.com.

There was a recent flurry of excitement when UK researchers from the Wellcome Sanger Institute, a nonprofit genomics and genetics research organization in Cambridge, England, announced their creation of the most detailed cell map of the human gastrointestinal (GI) tract up to this point. Using spatial and single-cell data from 1.6 million cells (from 271 donors), the scientists’ work, published in Nature, yields valuable information about the gut’s health and disease states.

“We now have a nice idea of what cell types we can find in the gut,” said co-author Rasa Elmentaite, PhD, co-founder and head of Genomics and Data Science at Ensocell.

No small question: How, exactly, does one go about mapping the human gut?

The story behind the construction of the Gut Cell Atlas, an arm of the larger Human Cell Atlas project — which recently published more than 40 studies in Nature in November 2024 — is one of global collaboration and scientific precision across continents.

Most of all, Elmentaite said, it has taken the scientists involved down paths they never anticipated.

 

How It Began

Over the past 5-7 years, there have been many individual publications across institutes where research labs have created snippets of what the cells in the gut look like, said Elmentaite, referring to the GI tract, which in this case encompasses the mouth, throat, esophagus, stomach, small intestine, large intestine, rectum, and anus.

Labs studying gut cells often focus on one specific region, for example, the small intestine or the large intestine, if they’re working on Crohn’s disease research. “It makes sense. The GI tract is really regionalized,” she said.

In 2019 and 2021, Elmentaite and her colleagues published papers that mapped some cells in the human gut, and their work garnered attention from other scientists around the world. That’s how they decided to take on the challenge of creating a more comprehensive map of the cells in both the healthy gut and in GI tracts where disease is present.

“We realized there are so many other labs interested in understanding the intestinal tract holistically,” she said. “We thought it would be really interesting to look at the cells in the context of the whole GI system.”

 

Not a Bad ‘Lockdown Project’

During the pandemic, while the rest of society was playing with sourdough starter, Elmentaite’s lab decided to pool their datasets with data from other labs to see what happened. They had more than 20 datasets at the time and wanted to generate more to fill gaps where there was less information available (eg, data on the cells in the stomach).

“It required getting samples from surgeons, going into the lab and processing those samples into single cells, and then processing that data bioinformatically,” said Elmentaite.

She explained that generating more datasets was not a job for one person and “required convincing a lot of scientists that it was worthwhile,” including a cancer biologist and a mucosal immunologist. They also brought in more technical bioinformatics expertise and recruited an IT team — several people who only worked on processing data and clearing it, “so it was aligned very specifically, and processed very uniformly, across the study,” Elmentaite said.

In the end, with researchers coming together on many Zoom calls from Australia, Germany, Norway, Spain, and numerous locations across the United Kingdom, they were able to integrate 25 single-cell RNA sequencing datasets that encompassed the entire healthy GI tract in development and in adults, leading to a healthy gut reference atlas that includes about 1.1 million cells and 136 cell subgroups.

 

How to Build a Two-Dimensional (2D) Map of the Gut

Here’s where the weeds get taller: Raw sequencing reads — bits of different RNA that the researchers sequenced from individual biological samples — needed to be mapped back to genes so that the researchers could understand what kinds of genes were expressed in the samples.

“There is a lot of curation there that needs to happen because the versions of transcriptome [a complete set of RNA molecules in a single cell or tissue], and what the genome looks like, is evolving constantly. So we have to map it back to the same transcriptomic reference,” Elmentaite said.

Once they knew all the different genes active in a cell, the researchers were able, using bioinformatics, to pull all of the datasets together and visualize them in a 2D space — essentially, a representation of a map.

“The cells that are transcriptionally more similar to each other, they will cluster together. And the ones that are more distinct transcriptionally will be farther away from each other,” Elmentaite said.

For decades, GI tract researchers had individually studied which types of genes are activated in an epithelial cell vs a T cell vs a B cell, she said, and “then suddenly you’re seeing it on your screen all at once. It’s amazing to see.”

 

In Brutal Detail

One of the biggest challenges in interpreting the data involved many people who made sure that there were no technical differences between the samples, Elmentaite said.

For example, samples processed in different labs may have sequencing differences between them. Or the kind of enzymes used to process the tissue might have been different from lab to lab. Sometimes they’d even record down to the detail what time of the day a sample was collected, if that information was available.

“Computationally, we considered all of these variables and tried to regress as much of that as possible. And then, if we saw clusters that resembled gene expression that we know is consistent with some of the cell types, then we knew that we’d regressed all the batch effects,” said Elmentaite.

 

Before ‘Eureka’ Comes a Few ‘Aha’ Moments

There were many “aha moments,” but also some puzzling ones, she said. One of the biggest surprises was seeing that the identity of a cell believed to be set from development can actually change if a person has a lot of irritation and inflammation, as occurs in inflammatory bowel disease. Epithelial cell metaplasia was one of the surprises.

“Metaplasia describes an activation or differentiation of one differentiated cell type into another differentiated cell type. And we knew that that exists in some of the upper GI diseases, but we didn’t realize that the same sort of mechanism exists in the small intestine,” Elmentaite said.

Epithelial cells are among the most abundant cells in the body. The researchers knew from established research that these cells act a bit like first responders and provide healing to the gut. “We could see that they were producing a lot of mucous that helps to potentially flush down the microbes that are triggering inflammation. But the ‘aha moment’ for us was that actually there’s a dual function in these cells,” she said.

They could see in the transcriptional profile a significant production of chemokines (a family of proteins that play a role in the body’s immune responses) and major histocompatibility complex class II molecules (cell surface proteins involved in the body’s immune response), and the epithelial cells seemed to attract neutrophils and monocytes and to interact with certain T cells — adding to the cycle of chronic inflammation.

“I think for a lot of us, this was a surprise because we think of epithelial cells as more like a barrier, just a passive player in, for example, inflammatory bowel disease,” said Elmentaite.

In addition to reporting their findings on epithelial cell metaplasia, the researchers processed 12 GI disease datasets, including celiac disease, Crohn’s disease, GI-related cancers, and ulcerative colitis.

 

A Gut Cell Atlas for the People (Well, Scientific People)

“The Gut Cell Atlas is usable for everyone, and everyone has a chance to contribute,” said Elmentaite. But 1.6 million cells is only a start and more data are needed, she said, and efforts are being spearheaded at the broader Human Cell Atlas project to collect it. There are also efforts to get all researchers using the same cell annotation, research-wide standards that will make the atlas truly usable for everyone.

Keith Summa, MD, PhD, assistant professor of medicine in the Division of Gastroenterology and Hepatology at Feinberg School of Medicine, Northwestern University, Chicago, focuses much of his work on inflammatory bowel disease as well as disorders of the gut-brain interaction. He conducts basic and translational research using experimental models of intestinal inflammation.

At Northwestern University, they have a tissue biorepository. It includes colon and intestine tissue samples from healthy individuals as well as individuals with different disease states. “One potential area where I could see this being a useful tool for us is that we could utilize the Gut Cell Atlas in the analysis of our tissue samples to see if we find commonalities between what’s described in the atlas and then what we’re observing,” said Summa, who was not involved in the UK-based project.

He said Northwestern University’s biorepository has details about what medications people were on and the extent and severity of their disease.

“We may be able to utilize the Gut Cell Atlas to help us look at specific factors in terms of how people are responding to different treatments, how different cell types are affected by different treatments, or how they are active or not active in different severities of disease. It may help us provide more precision to our understanding of these different conditions,” said Summa.

He also noted how GI specialists use “Crohn’s disease” as a single diagnosis, “but that encompasses a pretty wide spectrum of phenotypes and behaviors,” he said. “I think looking at such a cell-specific level may help to better identify some of the different pathways that are active and the different phenotypes or behaviors of this disease.” 

 

Next Step: Visualize It in a Three-Dimensional (3D) Space

The next stage for Elmentaite and her colleagues is to evolve the 2D map into a 3D map so they can visualize which cells are where and how they are organized in space.

“The next step, which I think is super exciting, is understanding how these cells depend on each other,” she said. “Really functionally understanding if some of them are essential and others are not. And doing AI modeling to understand what we can learn from this vast amount of data that we’re generating. And of course, that includes how we use this knowledge to create precision therapies.”

 

A version of this article appeared on Medscape.com.

There was a recent flurry of excitement when UK researchers from the Wellcome Sanger Institute, a nonprofit genomics and genetics research organization in Cambridge, England, announced their creation of the most detailed cell map of the human gastrointestinal (GI) tract up to this point. Using spatial and single-cell data from 1.6 million cells (from 271 donors), the scientists’ work, published in Nature, yields valuable information about the gut’s health and disease states.

“We now have a nice idea of what cell types we can find in the gut,” said co-author Rasa Elmentaite, PhD, co-founder and head of Genomics and Data Science at Ensocell.

No small question: How, exactly, does one go about mapping the human gut?

The story behind the construction of the Gut Cell Atlas, an arm of the larger Human Cell Atlas project — which recently published more than 40 studies in Nature in November 2024 — is one of global collaboration and scientific precision across continents.

Most of all, Elmentaite said, it has taken the scientists involved down paths they never anticipated.

 

How It Began

Over the past 5-7 years, there have been many individual publications across institutes where research labs have created snippets of what the cells in the gut look like, said Elmentaite, referring to the GI tract, which in this case encompasses the mouth, throat, esophagus, stomach, small intestine, large intestine, rectum, and anus.

Labs studying gut cells often focus on one specific region, for example, the small intestine or the large intestine, if they’re working on Crohn’s disease research. “It makes sense. The GI tract is really regionalized,” she said.

In 2019 and 2021, Elmentaite and her colleagues published papers that mapped some cells in the human gut, and their work garnered attention from other scientists around the world. That’s how they decided to take on the challenge of creating a more comprehensive map of the cells in both the healthy gut and in GI tracts where disease is present.

“We realized there are so many other labs interested in understanding the intestinal tract holistically,” she said. “We thought it would be really interesting to look at the cells in the context of the whole GI system.”

 

Not a Bad ‘Lockdown Project’

During the pandemic, while the rest of society was playing with sourdough starter, Elmentaite’s lab decided to pool their datasets with data from other labs to see what happened. They had more than 20 datasets at the time and wanted to generate more to fill gaps where there was less information available (eg, data on the cells in the stomach).

“It required getting samples from surgeons, going into the lab and processing those samples into single cells, and then processing that data bioinformatically,” said Elmentaite.

She explained that generating more datasets was not a job for one person and “required convincing a lot of scientists that it was worthwhile,” including a cancer biologist and a mucosal immunologist. They also brought in more technical bioinformatics expertise and recruited an IT team — several people who only worked on processing data and clearing it, “so it was aligned very specifically, and processed very uniformly, across the study,” Elmentaite said.

In the end, with researchers coming together on many Zoom calls from Australia, Germany, Norway, Spain, and numerous locations across the United Kingdom, they were able to integrate 25 single-cell RNA sequencing datasets that encompassed the entire healthy GI tract in development and in adults, leading to a healthy gut reference atlas that includes about 1.1 million cells and 136 cell subgroups.

 

How to Build a Two-Dimensional (2D) Map of the Gut

Here’s where the weeds get taller: Raw sequencing reads — bits of different RNA that the researchers sequenced from individual biological samples — needed to be mapped back to genes so that the researchers could understand what kinds of genes were expressed in the samples.

“There is a lot of curation there that needs to happen because the versions of transcriptome [a complete set of RNA molecules in a single cell or tissue], and what the genome looks like, is evolving constantly. So we have to map it back to the same transcriptomic reference,” Elmentaite said.

Once they knew all the different genes active in a cell, the researchers were able, using bioinformatics, to pull all of the datasets together and visualize them in a 2D space — essentially, a representation of a map.

“The cells that are transcriptionally more similar to each other, they will cluster together. And the ones that are more distinct transcriptionally will be farther away from each other,” Elmentaite said.

For decades, GI tract researchers had individually studied which types of genes are activated in an epithelial cell vs a T cell vs a B cell, she said, and “then suddenly you’re seeing it on your screen all at once. It’s amazing to see.”

 

In Brutal Detail

One of the biggest challenges in interpreting the data involved many people who made sure that there were no technical differences between the samples, Elmentaite said.

For example, samples processed in different labs may have sequencing differences between them. Or the kind of enzymes used to process the tissue might have been different from lab to lab. Sometimes they’d even record down to the detail what time of the day a sample was collected, if that information was available.

“Computationally, we considered all of these variables and tried to regress as much of that as possible. And then, if we saw clusters that resembled gene expression that we know is consistent with some of the cell types, then we knew that we’d regressed all the batch effects,” said Elmentaite.

 

Before ‘Eureka’ Comes a Few ‘Aha’ Moments

There were many “aha moments,” but also some puzzling ones, she said. One of the biggest surprises was seeing that the identity of a cell believed to be set from development can actually change if a person has a lot of irritation and inflammation, as occurs in inflammatory bowel disease. Epithelial cell metaplasia was one of the surprises.

“Metaplasia describes an activation or differentiation of one differentiated cell type into another differentiated cell type. And we knew that that exists in some of the upper GI diseases, but we didn’t realize that the same sort of mechanism exists in the small intestine,” Elmentaite said.

Epithelial cells are among the most abundant cells in the body. The researchers knew from established research that these cells act a bit like first responders and provide healing to the gut. “We could see that they were producing a lot of mucous that helps to potentially flush down the microbes that are triggering inflammation. But the ‘aha moment’ for us was that actually there’s a dual function in these cells,” she said.

They could see in the transcriptional profile a significant production of chemokines (a family of proteins that play a role in the body’s immune responses) and major histocompatibility complex class II molecules (cell surface proteins involved in the body’s immune response), and the epithelial cells seemed to attract neutrophils and monocytes and to interact with certain T cells — adding to the cycle of chronic inflammation.

“I think for a lot of us, this was a surprise because we think of epithelial cells as more like a barrier, just a passive player in, for example, inflammatory bowel disease,” said Elmentaite.

In addition to reporting their findings on epithelial cell metaplasia, the researchers processed 12 GI disease datasets, including celiac disease, Crohn’s disease, GI-related cancers, and ulcerative colitis.

 

A Gut Cell Atlas for the People (Well, Scientific People)

“The Gut Cell Atlas is usable for everyone, and everyone has a chance to contribute,” said Elmentaite. But 1.6 million cells is only a start and more data are needed, she said, and efforts are being spearheaded at the broader Human Cell Atlas project to collect it. There are also efforts to get all researchers using the same cell annotation, research-wide standards that will make the atlas truly usable for everyone.

Keith Summa, MD, PhD, assistant professor of medicine in the Division of Gastroenterology and Hepatology at Feinberg School of Medicine, Northwestern University, Chicago, focuses much of his work on inflammatory bowel disease as well as disorders of the gut-brain interaction. He conducts basic and translational research using experimental models of intestinal inflammation.

At Northwestern University, they have a tissue biorepository. It includes colon and intestine tissue samples from healthy individuals as well as individuals with different disease states. “One potential area where I could see this being a useful tool for us is that we could utilize the Gut Cell Atlas in the analysis of our tissue samples to see if we find commonalities between what’s described in the atlas and then what we’re observing,” said Summa, who was not involved in the UK-based project.

He said Northwestern University’s biorepository has details about what medications people were on and the extent and severity of their disease.

“We may be able to utilize the Gut Cell Atlas to help us look at specific factors in terms of how people are responding to different treatments, how different cell types are affected by different treatments, or how they are active or not active in different severities of disease. It may help us provide more precision to our understanding of these different conditions,” said Summa.

He also noted how GI specialists use “Crohn’s disease” as a single diagnosis, “but that encompasses a pretty wide spectrum of phenotypes and behaviors,” he said. “I think looking at such a cell-specific level may help to better identify some of the different pathways that are active and the different phenotypes or behaviors of this disease.” 

 

Next Step: Visualize It in a Three-Dimensional (3D) Space

The next stage for Elmentaite and her colleagues is to evolve the 2D map into a 3D map so they can visualize which cells are where and how they are organized in space.

“The next step, which I think is super exciting, is understanding how these cells depend on each other,” she said. “Really functionally understanding if some of them are essential and others are not. And doing AI modeling to understand what we can learn from this vast amount of data that we’re generating. And of course, that includes how we use this knowledge to create precision therapies.”

 

A version of this article appeared on Medscape.com.

TOPLINE:

In patients with stage II or III colorectal cancer (CRC), frequent follow-up testing with CT scans and serum carcinoembryonic antigen (CEA) screening provides no significant overall or cancer-specific survival benefits at 10 years, according to findings from a secondary analysis.

METHODOLOGY:

• After curative surgery for CRC, intensive patient follow-up is common in clinical practice. However, there’s limited evidence to suggest that more frequent testing provides a long-term survival benefit.
• In the COLOFOL trial, patients with stage II or III CRC who had undergone curative resection were randomly assigned to either high-frequency follow-up (CT scans and CEA screening at 6, 12, 18, 24, and 36 months) or low-frequency follow-up (testing at 12 and 36 months) after surgery.
• This secondary analysis of the COLOFOL trial included 2456 patients (median age, 65 years), 1227 of whom received high-frequency follow-up and 1229 of whom received low-frequency follow-up.
• The main outcome of the secondary analysis was 10-year overall mortality and CRC–specific mortality rates.
• The analysis included both intention-to-treat and per-protocol approaches, with outcomes measured through December 2020.

TAKEAWAY:

• In the intention-to-treat analysis, the 10-year overall mortality rates were similar between the high- and low-frequency follow-up groups — 27.1% and 28.4%, respectively (risk difference, 1.3%; P = .46).
• A per-protocol analysis confirmed these findings: The 10-year overall mortality risk was 26.4% in the high-frequency group and 27.8% in the low-frequency group.
• The 10-year CRC–specific mortality rate was also similar between the high-frequency and low-frequency groups — 15.6% and 16.0%, respectively — (risk difference, 0.4%; P = .72). The same pattern was seen in the per-protocol analysis, which found a 10-year CRC–specific mortality risk of 15.6% in the high-frequency group and 15.9% in the low-frequency group.
• Subgroup analyses by cancer stage and location (rectal and colon) also revealed no significant differences in mortality outcomes between the two follow-up groups.

IN PRACTICE:

“This secondary analysis of the COLOFOL randomized clinical trial found that, among patients with stage II or III colorectal cancer, more frequent follow-up testing with CT scan and CEA screening, compared with less frequent follow-up, did not result in a significant rate reduction in 10-year overall mortality or colorectal cancer-specific mortality,” the authors concluded. “The results of this trial should be considered as the evidence base for updating clinical guidelines.”

SOURCE:

The study, led by Henrik Toft Sørensen, MD, PhD, DMSc, DSc, Aarhus University Hospital and Aarhus University, Aarhus, Denmark, was published online in JAMA Network Open.

LIMITATIONS:

The staff turnover at recruitment centers potentially affected protocol adherence. The inability to blind patients and physicians to the follow-up frequency was another limitation. The low-frequency follow-up protocol was less intensive than that recommended in the current guidelines by the National Comprehensive Cancer Network and the American Society of Clinical Oncology, potentially limiting comparisons to current standard practices.

DISCLOSURES:

The initial trial received unrestricted grants from multiple organizations including the Nordic Cancer Union, A.P. Møller Foundation, Beckett Foundation, Danish Cancer Society, and Swedish Cancer Foundation project. The authors reported no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

In patients with stage II or III colorectal cancer (CRC), frequent follow-up testing with CT scans and serum carcinoembryonic antigen (CEA) screening provides no significant overall or cancer-specific survival benefits at 10 years, according to findings from a secondary analysis.

METHODOLOGY:

• After curative surgery for CRC, intensive patient follow-up is common in clinical practice. However, there’s limited evidence to suggest that more frequent testing provides a long-term survival benefit.
• In the COLOFOL trial, patients with stage II or III CRC who had undergone curative resection were randomly assigned to either high-frequency follow-up (CT scans and CEA screening at 6, 12, 18, 24, and 36 months) or low-frequency follow-up (testing at 12 and 36 months) after surgery.
• This secondary analysis of the COLOFOL trial included 2456 patients (median age, 65 years), 1227 of whom received high-frequency follow-up and 1229 of whom received low-frequency follow-up.
• The main outcome of the secondary analysis was 10-year overall mortality and CRC–specific mortality rates.
• The analysis included both intention-to-treat and per-protocol approaches, with outcomes measured through December 2020.

TAKEAWAY:

• In the intention-to-treat analysis, the 10-year overall mortality rates were similar between the high- and low-frequency follow-up groups — 27.1% and 28.4%, respectively (risk difference, 1.3%; P = .46).
• A per-protocol analysis confirmed these findings: The 10-year overall mortality risk was 26.4% in the high-frequency group and 27.8% in the low-frequency group.
• The 10-year CRC–specific mortality rate was also similar between the high-frequency and low-frequency groups — 15.6% and 16.0%, respectively — (risk difference, 0.4%; P = .72). The same pattern was seen in the per-protocol analysis, which found a 10-year CRC–specific mortality risk of 15.6% in the high-frequency group and 15.9% in the low-frequency group.
• Subgroup analyses by cancer stage and location (rectal and colon) also revealed no significant differences in mortality outcomes between the two follow-up groups.

IN PRACTICE:

“This secondary analysis of the COLOFOL randomized clinical trial found that, among patients with stage II or III colorectal cancer, more frequent follow-up testing with CT scan and CEA screening, compared with less frequent follow-up, did not result in a significant rate reduction in 10-year overall mortality or colorectal cancer-specific mortality,” the authors concluded. “The results of this trial should be considered as the evidence base for updating clinical guidelines.”

SOURCE:

The study, led by Henrik Toft Sørensen, MD, PhD, DMSc, DSc, Aarhus University Hospital and Aarhus University, Aarhus, Denmark, was published online in JAMA Network Open.

LIMITATIONS:

The staff turnover at recruitment centers potentially affected protocol adherence. The inability to blind patients and physicians to the follow-up frequency was another limitation. The low-frequency follow-up protocol was less intensive than that recommended in the current guidelines by the National Comprehensive Cancer Network and the American Society of Clinical Oncology, potentially limiting comparisons to current standard practices.

DISCLOSURES:

The initial trial received unrestricted grants from multiple organizations including the Nordic Cancer Union, A.P. Møller Foundation, Beckett Foundation, Danish Cancer Society, and Swedish Cancer Foundation project. The authors reported no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

In patients with stage II or III colorectal cancer (CRC), frequent follow-up testing with CT scans and serum carcinoembryonic antigen (CEA) screening provides no significant overall or cancer-specific survival benefits at 10 years, according to findings from a secondary analysis.

METHODOLOGY:

• After curative surgery for CRC, intensive patient follow-up is common in clinical practice. However, there’s limited evidence to suggest that more frequent testing provides a long-term survival benefit.
• In the COLOFOL trial, patients with stage II or III CRC who had undergone curative resection were randomly assigned to either high-frequency follow-up (CT scans and CEA screening at 6, 12, 18, 24, and 36 months) or low-frequency follow-up (testing at 12 and 36 months) after surgery.
• This secondary analysis of the COLOFOL trial included 2456 patients (median age, 65 years), 1227 of whom received high-frequency follow-up and 1229 of whom received low-frequency follow-up.
• The main outcome of the secondary analysis was 10-year overall mortality and CRC–specific mortality rates.
• The analysis included both intention-to-treat and per-protocol approaches, with outcomes measured through December 2020.

TAKEAWAY:

• In the intention-to-treat analysis, the 10-year overall mortality rates were similar between the high- and low-frequency follow-up groups — 27.1% and 28.4%, respectively (risk difference, 1.3%; P = .46).
• A per-protocol analysis confirmed these findings: The 10-year overall mortality risk was 26.4% in the high-frequency group and 27.8% in the low-frequency group.
• The 10-year CRC–specific mortality rate was also similar between the high-frequency and low-frequency groups — 15.6% and 16.0%, respectively — (risk difference, 0.4%; P = .72). The same pattern was seen in the per-protocol analysis, which found a 10-year CRC–specific mortality risk of 15.6% in the high-frequency group and 15.9% in the low-frequency group.
• Subgroup analyses by cancer stage and location (rectal and colon) also revealed no significant differences in mortality outcomes between the two follow-up groups.

IN PRACTICE:

“This secondary analysis of the COLOFOL randomized clinical trial found that, among patients with stage II or III colorectal cancer, more frequent follow-up testing with CT scan and CEA screening, compared with less frequent follow-up, did not result in a significant rate reduction in 10-year overall mortality or colorectal cancer-specific mortality,” the authors concluded. “The results of this trial should be considered as the evidence base for updating clinical guidelines.”

SOURCE:

The study, led by Henrik Toft Sørensen, MD, PhD, DMSc, DSc, Aarhus University Hospital and Aarhus University, Aarhus, Denmark, was published online in JAMA Network Open.

LIMITATIONS:

The staff turnover at recruitment centers potentially affected protocol adherence. The inability to blind patients and physicians to the follow-up frequency was another limitation. The low-frequency follow-up protocol was less intensive than that recommended in the current guidelines by the National Comprehensive Cancer Network and the American Society of Clinical Oncology, potentially limiting comparisons to current standard practices.

DISCLOSURES:

The initial trial received unrestricted grants from multiple organizations including the Nordic Cancer Union, A.P. Møller Foundation, Beckett Foundation, Danish Cancer Society, and Swedish Cancer Foundation project. The authors reported no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.