Meeting News

NIH Features Early Progress in Understanding Microbiome’s Role in IBD

Last week at the NIH conference marking the culmination of the 10-year Human Microbiome Project, several researchers shared their early findings on the link between the gut microbiota and inflammatory bowel disease, including their role in disease activity, diagnosis and future therapeutics.

Characterizing the microbiome in IBD

On Wednesday, Curtis Huttenhower, PhD, of the T.H. Chan Harvard School of Public Health and Broad Institute, shared some preliminary results from the Inflammatory Bowel Disease Multi’omics Database (IBDMDB), part of the Human Microbiome Project aiming to provide an integrated resource for characterizing the gut microbiota as it relates to IBD diagnosis and therapies.

IBD “is of course ... both a critical health condition in and of itself, and has become a really interesting model for the complex involvement of the gut microbiome specifically in chronic disease,” Huttenhower said during his presentation. “Over about the past 5 to 10 years now, some better studies of the microbiome have helped to very quickly refine our understanding of this involvement from a high-level observation of ecological disruptions, reductions in diversity in the gut community during IBD, down to a much better understanding of specific taxa and their common metabolic and other molecular functions that are disrupted in subsets of IBD.”

IBDMDB researchers followed more than 100 individuals for 1 year, including patients with Crohn’s disease or ulcerative colitis and controls, and analyzed more than 4,000 stool, biopsy and blood samples to develop molecular profiles of host and microbial activity during IBD.

Highlighting some pilot studies within this project, Huttenhower said IBDMDB investigators identified microbially-processed small molecules implicated in IBD inflammation and severity by integrating microbial profiles with metabolomics. Additionally, they were able to pinpoint uniquely expressed microbes and pathways in a subset of patients with active disease.

IBDMDB “data represent a substantial community resource for future multi’omics studies in IBD, and have also served to provide the first integrated molecular profile of immune activity and clinical response during disease progression,” he and colleagues wrote.

Long-term goals of this research include better understanding the mechanisms driving dysbiosis in IBD, “what’s causal vs. responsive in the microbiome during IBD, changes in disease activity, and ... helping to translate some of the emerging ecological understanding of the microbiome’s involvement into activities that would help in the clinic,” Huttenhower said. “This might involve for example, understanding the heterogeneity of the disease, ... helping to predict response to treatment over time, predicting either the onset or remission of flares and disease activity, ... and then identifying either on the host or microbial side, pathways, molecular targets that might be either causal or points of intervention for new treatments.”

Mycobiome, bacteriome interact in Crohn’s

On Thursday, Mahmoud Ghannoum, PhD, of Case Western Reserve University and University Hospital Cleveland Medical Center, discussed his work on understanding how fungal and bacterial communities within the gut microbiome — the mycobiome and the bacteriome — interact to create biofilms, and how these interactions affect microbial dysbiosis in Crohn’s disease.

Mahmoud Ghannoum, PhD
Mahmoud Ghannoum

“It’s not only bacteria, it’s not only fungi, but both of them work together to cause problems,” Ghannoum said during his talk.

Healio Gastroenterology previously reported on Ghannoum’s research published in mBio, which suggested the fungal species Candida tropicalis may play a role in Crohn’s disease by interacting with the bacterial pathogens Escherichia coli and Serratia marcescens. During his presentation, he detailed the findings of this in vitro study, adding that his team more recently confirmed them in an in vivo mouse model, and found that the biofilms created by these organisms alter metabolites. He also mentioned similar findings in a study of oral cancer patients show the effects of these microbial interactions span different diseases.

“There is a need to develop multiple resources, imaging and in vivo models, to address these polymicrobial organisms, define the mechanism underlying the interaction, not only between the organisms, but also between the organisms and the host, and also define how the metabolites interact with this,” he concluded.

Diet’s effects on microbiome in IBD

Also on Thursday, Gary Wu, MD, of the University of Pennsylvania School of Medicine, discussed how the impact of diet on the microbiome and its metabolome shows therapeutic potential in IBD.

Despite the high level of efficacy of a defined formula diet in Crohn’s disease, “we really don’t understand how ... that particular diet actually works,” Wu said. Knowing that diet affects the composition of the gut microbiota and the small molecules that it makes, Wu and colleagues have used the exclusive elemental diet as a therapeutic probe to better understand these mechanisms in hopes of identifying new therapeutic targets in IBD.

Dietary additives

“If we can understand the proof of concept mechanisms, we could define better diets for patients with IBD,” he said.

The key question regarding the efficacy of exclusive enteral nutrition in IBD, Wu said, is whether it provides something good for patients that a regular diet lacks, or rather excludes something from a regular diet that is bad for patients with IBD. Mouse studies, for example, have raised the possibility that dietary additives like artificial sweeteners and emulsifiers might change the composition of the microbiome and lead to an inflammatory response, he noted.

Wu shared data from two human intervention studies examining the effect of defined formula diets on both the gut microbiome and its metabolome, including the Pediatric Longitudinal Study of Elemental Diet and Stool Microbiota Composition (PLEASE) and the Food And Resulting Microbial Metabolites (FARMM) study.

The PLEASE study, a prospective cohort study of 90 pediatric patients with Crohn’s treated with either an elemental diet or anti-TNF therapy, revealed that “dysbiosis is not simply one thing,” Wu said. “It’s a compilation of many things: dysbiosis induced by inflammation, use of antibiotics, alterations by diet, and whether or not you just simply have a diagnosis of IBD.”

Further, this study showed that elemental diets have a particular microbiome signature, and specifically he and colleagues observed a decrease in fungus associated with these diets.

The FARMM study, a 2-week intensive, inpatient, controlled feeding experiment as part of the Crohn’s and Colitis Foundation’s Microbiome Initiative, evaluated the gut microbiota in healthy individuals including 10 vegans, 10 omnivores, and 10 omnivores who were randomly assigned to consume a defined formula diet for IBD called Modulan. This study revealed that Modulan essentially “engineered the microbiota into a different configuration,” Wu said.

He and colleagues are also recruiting for the ongoing Holiday study in which they are evaluating the use of antimicrobials for inducing remission in refractory IBD patients.

“We’re cautiously optimistic that we’re going to be seeing some pretty interesting things,” he said.

Additional studies are also exploring the role of diet as a maintenance therapy for patients who respond to the antimicrobial intervention, specifically trying to identify safe whole foods that could potentially be paired with an elemental diet for this purpose, he added. – by Adam Leitenberger

References:

The Inflammatory Bowel Disease Multi’omics Database. Accessed August 18, 2017. ibdmdb.org.

NIH. The Human Microbiome: Emerging themes at the horizon of the 21st century; Aug. 16-18, 2017; Bethesda, MD

Disclosures: Healio Gastroenterology and Liver Disease was unable to confirm the researchers’ relevant financial disclosures at the time of publication.

Last week at the NIH conference marking the culmination of the 10-year Human Microbiome Project, several researchers shared their early findings on the link between the gut microbiota and inflammatory bowel disease, including their role in disease activity, diagnosis and future therapeutics.

Characterizing the microbiome in IBD

On Wednesday, Curtis Huttenhower, PhD, of the T.H. Chan Harvard School of Public Health and Broad Institute, shared some preliminary results from the Inflammatory Bowel Disease Multi’omics Database (IBDMDB), part of the Human Microbiome Project aiming to provide an integrated resource for characterizing the gut microbiota as it relates to IBD diagnosis and therapies.

IBD “is of course ... both a critical health condition in and of itself, and has become a really interesting model for the complex involvement of the gut microbiome specifically in chronic disease,” Huttenhower said during his presentation. “Over about the past 5 to 10 years now, some better studies of the microbiome have helped to very quickly refine our understanding of this involvement from a high-level observation of ecological disruptions, reductions in diversity in the gut community during IBD, down to a much better understanding of specific taxa and their common metabolic and other molecular functions that are disrupted in subsets of IBD.”

IBDMDB researchers followed more than 100 individuals for 1 year, including patients with Crohn’s disease or ulcerative colitis and controls, and analyzed more than 4,000 stool, biopsy and blood samples to develop molecular profiles of host and microbial activity during IBD.

Highlighting some pilot studies within this project, Huttenhower said IBDMDB investigators identified microbially-processed small molecules implicated in IBD inflammation and severity by integrating microbial profiles with metabolomics. Additionally, they were able to pinpoint uniquely expressed microbes and pathways in a subset of patients with active disease.

IBDMDB “data represent a substantial community resource for future multi’omics studies in IBD, and have also served to provide the first integrated molecular profile of immune activity and clinical response during disease progression,” he and colleagues wrote.

Long-term goals of this research include better understanding the mechanisms driving dysbiosis in IBD, “what’s causal vs. responsive in the microbiome during IBD, changes in disease activity, and ... helping to translate some of the emerging ecological understanding of the microbiome’s involvement into activities that would help in the clinic,” Huttenhower said. “This might involve for example, understanding the heterogeneity of the disease, ... helping to predict response to treatment over time, predicting either the onset or remission of flares and disease activity, ... and then identifying either on the host or microbial side, pathways, molecular targets that might be either causal or points of intervention for new treatments.”

Mycobiome, bacteriome interact in Crohn’s

On Thursday, Mahmoud Ghannoum, PhD, of Case Western Reserve University and University Hospital Cleveland Medical Center, discussed his work on understanding how fungal and bacterial communities within the gut microbiome — the mycobiome and the bacteriome — interact to create biofilms, and how these interactions affect microbial dysbiosis in Crohn’s disease.

PAGE BREAK
Mahmoud Ghannoum, PhD
Mahmoud Ghannoum

“It’s not only bacteria, it’s not only fungi, but both of them work together to cause problems,” Ghannoum said during his talk.

Healio Gastroenterology previously reported on Ghannoum’s research published in mBio, which suggested the fungal species Candida tropicalis may play a role in Crohn’s disease by interacting with the bacterial pathogens Escherichia coli and Serratia marcescens. During his presentation, he detailed the findings of this in vitro study, adding that his team more recently confirmed them in an in vivo mouse model, and found that the biofilms created by these organisms alter metabolites. He also mentioned similar findings in a study of oral cancer patients show the effects of these microbial interactions span different diseases.

“There is a need to develop multiple resources, imaging and in vivo models, to address these polymicrobial organisms, define the mechanism underlying the interaction, not only between the organisms, but also between the organisms and the host, and also define how the metabolites interact with this,” he concluded.

Diet’s effects on microbiome in IBD

Also on Thursday, Gary Wu, MD, of the University of Pennsylvania School of Medicine, discussed how the impact of diet on the microbiome and its metabolome shows therapeutic potential in IBD.

Despite the high level of efficacy of a defined formula diet in Crohn’s disease, “we really don’t understand how ... that particular diet actually works,” Wu said. Knowing that diet affects the composition of the gut microbiota and the small molecules that it makes, Wu and colleagues have used the exclusive elemental diet as a therapeutic probe to better understand these mechanisms in hopes of identifying new therapeutic targets in IBD.

Dietary additives

“If we can understand the proof of concept mechanisms, we could define better diets for patients with IBD,” he said.

The key question regarding the efficacy of exclusive enteral nutrition in IBD, Wu said, is whether it provides something good for patients that a regular diet lacks, or rather excludes something from a regular diet that is bad for patients with IBD. Mouse studies, for example, have raised the possibility that dietary additives like artificial sweeteners and emulsifiers might change the composition of the microbiome and lead to an inflammatory response, he noted.

PAGE BREAK

Wu shared data from two human intervention studies examining the effect of defined formula diets on both the gut microbiome and its metabolome, including the Pediatric Longitudinal Study of Elemental Diet and Stool Microbiota Composition (PLEASE) and the Food And Resulting Microbial Metabolites (FARMM) study.

The PLEASE study, a prospective cohort study of 90 pediatric patients with Crohn’s treated with either an elemental diet or anti-TNF therapy, revealed that “dysbiosis is not simply one thing,” Wu said. “It’s a compilation of many things: dysbiosis induced by inflammation, use of antibiotics, alterations by diet, and whether or not you just simply have a diagnosis of IBD.”

Further, this study showed that elemental diets have a particular microbiome signature, and specifically he and colleagues observed a decrease in fungus associated with these diets.

The FARMM study, a 2-week intensive, inpatient, controlled feeding experiment as part of the Crohn’s and Colitis Foundation’s Microbiome Initiative, evaluated the gut microbiota in healthy individuals including 10 vegans, 10 omnivores, and 10 omnivores who were randomly assigned to consume a defined formula diet for IBD called Modulan. This study revealed that Modulan essentially “engineered the microbiota into a different configuration,” Wu said.

He and colleagues are also recruiting for the ongoing Holiday study in which they are evaluating the use of antimicrobials for inducing remission in refractory IBD patients.

“We’re cautiously optimistic that we’re going to be seeing some pretty interesting things,” he said.

Additional studies are also exploring the role of diet as a maintenance therapy for patients who respond to the antimicrobial intervention, specifically trying to identify safe whole foods that could potentially be paired with an elemental diet for this purpose, he added. – by Adam Leitenberger

References:

The Inflammatory Bowel Disease Multi’omics Database. Accessed August 18, 2017. ibdmdb.org.

NIH. The Human Microbiome: Emerging themes at the horizon of the 21st century; Aug. 16-18, 2017; Bethesda, MD

Disclosures: Healio Gastroenterology and Liver Disease was unable to confirm the researchers’ relevant financial disclosures at the time of publication.

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