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Close ties between the microbiome and inflammatory bowel disease

Two recent studies have identified changes caused by the community of microbes living in the gut that could contribute to inflammatory bowel disease (IBD), including microbial metabolic byproducts (substances produced by microbes) and the human immune system’s response. One of the drivers of IBD (which includes Crohn’s disease and ulcerative colitis) is thought to be an improper immune response to the gut microbiome, the trillions of microbes living in the gastrointestinal tract. Studies have implicated the microbiome as a key player in IBD, but the many and complex ways in which the microbiome affects the disease are not well understood. One complicating factor is that the disease is not active all the time— people typically experience periodic “flare-ups” of symptoms interspersed with latent periods—and the microbiome during an inactive period may be different from during a flare-up.

To better understand the interactions between the microbiome and its human host during IBD, the NIDDK supported studies through the NIH’s Integrative Human Microbiome Project, which includes a multi- center study to understand how the human gut microbiome changes over time in adults and children with IBD. Researchers recruited 132 adult and pediatric volunteers, both female and male, either with IBD (Crohn’s disease or ulcerative colitis) or without. Changes in the participants’ guts and their microbiomes were tracked and catalogued through analysis of stool and other samples over 1 year, including microbiome composition, microbial metabolites, microbial and human gene activities, and immune response. The researchers found that, in the people with IBD, the composition of the microbiome changed significantly during a disease flare-up and then returned to an individual’s initial, “baseline” composition when the flare subsided. There were corresponding changes in microbial metabolites during a flare-up, such as lower levels of short-chain fatty acids, which play important roles in digestive health and have been shown to protect against digestive diseases. Also, blood samples from patients experiencing flare-ups showed higher levels of antibodies produced in response to microbial infections and inflammation, implicating the immune response as another key player in active IBD. These changes provide clues to the causes of IBD and could point to therapeutic targets or diagnostic markers to help predict flare-ups, which could be treated aggressively before symptoms become severe.

Another NIDDK-supported study delved further into the changes in the microbiome and the microbial metabolites in people with IBD. Researchers analyzed stool samples from 155 men and women with IBD (Crohn’s disease or ulcerative colitis), or with no IBD, to identify differences in their microbiomes. They found that the microbial communities in people with IBD were less diverse than those in healthy people, confirming results from previous studies. Looking at over 8,000 different microbial metabolites, the researchers found higher levels of some metabolites in people with IBD, although a majority were depleted in the disease, reflecting the lower microbial diversity. By comparing these differences in metabolites with the differences in the microbiomes, the researchers were able to link specific metabolites to the types of gut bacteria that produce them, revealing new markers to help with diagnosis of IBD, and importantly, new targets for therapy.

The relationship between IBD and the gut microbiome is complex, but gaining a better understanding of it would present potential new targets for therapy. These studies and others represent pioneering work to more comprehensively characterize the metabolic and immune impacts of host-microbial interactions that contribute to disease development.

Lloyd-Price J, Arze C, Ananthakrishnan AN,…Huttenhower C. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. Nature 569: 655-662, 2019.

Franzosa EA, Sirota-Madi A, Avila-Pacheco J,...Xavier RJ. Gut microbiome structure and metabolic activity in inflammatory bowel disease. Nat Microbiol 4: 293-305, 2019.