Mayo Clinic researchers have found new evidence linking the millions of bacteria residing in our digestive systems, known as the microbiome, to a network of factors that drive irritable bowel syndrome (IBS). The findings, published in the Sept. 10, 2020 issue of Cell, raise the possibility of targeting the newly discovered microbial pathways to improve debilitating symptoms associated with IBS, including bloating, cramps, diarrhea and constipation.

Irritable bowel syndrome (IBS) is a globally prevalent disorder affecting up to 20% of the U.S. population, predominantly females, and costing nearly $30 billion annually in health care expenses. Like many other diseases, the gut microbiome has been suggested to play a role in IBS, based on studies which show the microbiome in patients with IBS may be different. 

Characterized by abdominal pain and changes in stool form or frequency, IBS symptoms are known to be triggered by diet, host genes and environment, which are also known to modulate the human gut microbiome. But until now, a lack of an integrated systems approach has made it difficult to understand where the microbiome fits in the overall picture. This is also why there has been little success in treating IBS patients with probiotics.

“By integrating multiple layers of data from patients and gut microbiota, we identified purine metabolism as a novel  metabolic pathway in IBS with contribution from both host and gut microbiota,” says author Purna Kashyap, M.B.B.S., the Bernard and Edith Waterman co-director of the Center for Individualized Medicine Microbiome Program at Mayo Clinic.

“The study significantly advances our understanding of how the microbiome plays a role in IBS while at the same time identifying several microbial pathways that can be targeted to lessen abdominal pain or symptoms associated with specific IBS subsets, like diarrhea or constipation.” - Dr. Kashyap

“The fact that this pathway was not previously discovered in animal studies highlights the importance of doing multi-omics studies in humans — including investigating the microbial metagenome, metabolome, host transcriptome, methylome, patient symptoms, diet and gastrointestinal physiology — to identify potential disease mechanisms that may depend on human-specific responses,” Dr. Kashyap says.

Using multiple data layers, individualized approach

For the study, Dr. Kashyap and his team integrated multiple layers of patient data over a six-month period, including symptoms, diet, gastrointestinal function and changes in gene expression in the gastrointestinal (GI) tract. They collected patient stool samples to measure gut bacteria and compounds produced by them, and conducted large intestine exams to obtain colonic biopsies longitudinally — repeated observations of the same variables.

“Then we integrated all of this data into a meaningful format to understand the biological relationships in this highly dynamic ecosystem,” Kashyap says.

Dr. Kashyap explains, one way to approach large data sets is to say, “A is always found when B is present but not when C is present. So A and B must be related.”

However, when his team analyzes large data sets, many of these correlations may not be biologically meaningful. So, his team tried a different approach.

For instance, if a microbe A and compound B were correlated, they went on to check if that microbe A can truly produce or consume the compound B.  Then, to ensure these compounds were biologically relevant, they looked at gene expression and functional changes in the colon. As a result, they focused on a small number of compounds where they found a relevant biological function. These can now be targeted to treat IBS.

In one major finding, the researchers were able to determine how molecules produced by bacteria affect GI function, and how changes in production of specific molecules by bacteria can drive worsening symptoms. 

“Our study highlights the importance of longitudinal sampling and integrating complementary multi-omics data to identify functional mechanisms that can serve as therapeutic targets in a comprehensive treatment strategy for chronic GI diseases,” Dr. Kashyap

Interestingly, these were not the same for every patient, suggesting that an individualized approach is needed.

“Some examples include bacterial production of the compound tryptamine, which increases secretion of water in the intestines, causing diarrhea,” Dr. Kashyap explains. “Also, a lack of bacterial conversion of primary to secondary bile acids; primary bile acids can irritate the colon and cause diarrhea as well."

The researchers also found that short chain fatty acids, which normally increase movement of stool across the intestines, were decreased in patients with constipation.

Applying multi-omics view of microbiome’s impact

Dr. Kashyap says a majority of previous studies faced hurdles in linking the microbiome to IBS because data was investigated with a single snapshot — just one point in time.

“But neither IBS nor the microbiome are static,” Dr. Kashyap explains. “Patients’ symptoms can wax and wane and the microbiota composition and function can change over time. Longitudinal sampling allows us to get over the heterogeneity introduced by these changes.”

That’s why Dr. Kashyap and his team designed the study to get a multi-omics view with repeated observations of the gut microbiome in the context of IBS.

“The study significantly advances our understanding of how the microbiome plays a role in IBS while at the same time identifying several microbial pathways that can be targeted to lessen abdominal pain or symptoms associated with specific IBS subsets, like diarrhea or constipation,” he says. 

The team now intends to follow up on their findings to target some of the pathways they have identified with a goal of developing the next-generation of probiotics that target specific mechanisms responsible for patient symptoms.  But the impact of this study is not limited to IBS.

“Our study highlights the importance of longitudinal sampling and integrating complementary multi-omics data to identify functional mechanisms that can serve as therapeutic targets in a comprehensive treatment strategy for chronic GI diseases,” Dr. Kashyap says.

The research was also led by co-author Dan Knights, Ph.D., associate professor with the Biotechnology Institute, Department of Computer Science and Engineering at the University of Minnesota, Minneapolis, Minn.

This work was supported by NIH DK114007 (P.C.K.), the Center for Individualized Medicine, Mayo Clinic, Rochester, MN (P.C.K.), and Minnesota Partnership for Biotechnology and Medical Genomics (P.C.K. and D.K.). Additional funding was provided by the STRATiGRAD PhD training program of Imperial College London and Societe des Produits Nestle (Y.Y.).

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