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How Gut Microbes Work to Tame Intestinal Inflammation

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Bile acids, well known for their role in dissolving fats and vitamins, are also important players in gut immunity and inflammation because they regulate the activity of key immune cells linked to a range of inflammatory bowel conditions, such as ulcerative colitis and Crohn’s disease, according to new research.

Bile acids made by the liver have long been known for their critical role in helping to absorb the food we ingest.

But, according to a series of new studies from Harvard Medical School, these fat- and vitamin-dissolving substances are also important players in gut immunity and inflammation because they regulate the activity of key immune cells linked to a range of inflammatory bowel conditions, such as ulcerative colitis and Crohn’s disease.

An initial report in 2020 mapped out the effects of bile acids on mouse gut immunity, but left some key questions unanswered: First, just how do bile acids get gut immune cells to perform their immune-regulatory work? Second, which bacteria and bacterial enzymes produce these bile acids? Third, do these bile acids play a role in human intestinal inflammation?

Now, two studies led by the same team of investigators — one published March 16 in Nature and one published in Cell Host & Microbe in 2021 — answer these questions and add further clarity to the initial observations. The research, conducted at the intersection of chemical biology, microbiology, and immunology, was co-led by Sloan Devlin, assistant professor of biological chemistry and molecular pharmacology, and Jun Huh, associate professor of immunology at HMS.

The studies identify three bile acid metabolites and corresponding bacterial genes that produce molecules that affect the activity of inflammation-regulating immune cells. The work also demonstrates that the presence and activity of these bacteria and the immune molecules they produce are notably reduced in patients with inflammatory bowel disease (IBD).

“We carry trillions of bacteria in and on our bodies, and a growing body of research indicates that gut bacteria can affect host immune responses,” Huh said. “Our findings provide a novel mechanistic insight into how these bacteria work to mediate immune regulation in the gut.”

The findings, based on experiments in mice and human stool samples, reveal the identity of three critical microbial players in this cascade and the bacterial genes that regulate bile acid modification. Furthermore, they show that intestinal samples from patients with conditions such as ulcerative colitis or Crohn’s disease have markedly lower levels of both the anti-inflammatory molecules and the bacterial genes responsible for their production.

The findings bring scientists a step closer to developing small-molecule treatments and live bacterial therapeutics that regulate intestinal inflammation.

“All three molecules and the bacterial genes that we discovered that produce these molecules are reduced in patients with IBD,” Devlin said. “Restoring the presence of either the compounds or the bacteria that make them offers a possible therapeutic avenue to treat a range of inflammatory diseases marked by these deficiencies and affecting millions of people worldwide.”

Originally posted on Science Daily. Materials provided by Harvard Medical School. Originally written by Ekaterina Pesheva. Note: Content may be edited for style and length.

1. Paik, D., Yao, L., Zhang, Y. et al. Human gut bacteria produce ΤΗ17-modulating bile acid metabolites. Nature, 2022 DOI: 10.1038/s41586-022-04480-z
2. Wei Li, Saiyu Hang, Yuan Fang, Sena Bae, Yancong Zhang, Minghao Zhang, Gang Wang, Megan D. McCurry, Munhyung Bae, Donggi Paik, Eric A. Franzosa, Fraydoon Rastinejad, Curtis Huttenhower, Lina Yao, A. Sloan Devlin, Jun R. Huh. A bacterial bile acid metabolite modulates Treg activity through the nuclear hormone receptor NR4A1. Cell Host & Microbe, 2021; 29 (9): 1366 DOI: 10.1016/j.chom.2021.07.013


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