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Plant-rich diet protects against foodborne pathogens, mice study shows The second study, published Dec. 25 in Nature and led by Dennis Kasper, focused on a subset of inflammation-taming regulatory T cells, or Tregs, that arise in the colon as a result of exposure to gut microbes. In contrast, most other immune cells originate in the thymus. Low levels of colonic regulatory T cells (colonic Tregs) have been linked to the development of autoimmune conditions such as IBD and Crohn's disease. Kasper's experiments demonstrate that gut microbes and diet work in concert to modify bile acids, which in turn affect the levels of colonic Tregs in mice. They also show that low levels of Treg cells induced by lack of bile acids or deficiency in bile acid sensors makes animals prone to developing inflammatory colitis--a condition that mimics human IBD. To test the hypothesis that gut bacteria convert food-derived bile acids produced in response to food into immune signaling molecules, the researchers silenced bile acid-converting genes in various gut microbes and then put both the modified and nonmodified microbes in mice specially bred to have germ-free guts. Animals whose guts were populated by microbes without bile acid-converting genes had notably lower levels of Treg cells. The researchers then fed animals either nutrient-rich meals or minimal food. Animals with normal microbe populations in their guts that were receiving minimal food had lower levels of colonic Tregs and lower bile acid levels than mice eating rich food. Yet animals with germ-free guts receiving rich food also had low levels of Treg cells--a finding which shows that both gut microbes and food-derived bile acids are required to modulate immune cell levels. To test whether bile acids are directly involved in immune cell regulation, the researchers then mixed various bile acid molecules with the drinking water of animals that had low Treg cell levels and minimal diets. Several weeks later, these animals had an increase in the levels of inflammation-curbing Treg cells. In a final step, the researchers gave three groups of mice a compound that induces colitis. One group was fed a minimal diet, another group received nutrient-rich meals and a third group received minimal food and drank water supplemented with bile acid molecules. As expected, only mice fed minimal diets not supplemented by bile acid molecules developed colitis. The experiment confirmed that bile acids play a critical role in Treg regulation, intestinal inflammation and colitis risk. "Our results demonstrate an elegant three-way interaction between gut microbes, bile acids and the immune system," said Kasper, who is professor of immunology in the Blavatnik Institute at HMS and the William Ellery Channing Professor of Medicine at HMS and Brigham and Women's Hospital. "Importantly, our work suggests it is plausible to think of harnessing certain gut bacteria as a way to modulate disease risk." Source: Harvard Medical School Journal references: Song, X., et al. (2019) Microbial bile acid metabolites modulate gut RORγ+ regulatory T cell homeostasis. Nature . doi.org/10.1038/s41586-019-1865-0 . Hang, S., et al. (2019) Bile acid metabolites control T H 17 and T reg cell differentiation. Nature . doi.org/10.1038/s41586-019-1785-z .



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