The fat-dissolving bile acids churned out by the liver and gallbladder play a role in immunity and inflammation, according to two separate Harvard Medical School studies published in Nature.
The two studies, both conducted in mice, show that bile acids promote the differentiation and activity of several types of T cells involved in regulating inflammation and linked to intestinal inflammatory conditions.
They also reveal that gut microbes are critical for converting bile acids into immune-signaling molecules.
The work suggests possible therapeutic pathways for modulating intestinal inflammation, a process that underlies the development of autoimmune conditions such as inflammatory bowel disease.
The first study, led by immunologist Jun Huh reveals bile acids exert their immune-modulating effect by interacting with immune cells in the gut.
Once bile acids leave the gallbladder and complete their fat-dissolving duties, they make their way down the digestive tract where they are modified into immune-regulatory molecules by gut bacteria.
The modified bile acids then activate two class of immune cells: regulatory T cells (Tregs) and effector helper T cells, specifically Th17, each responsible for modulating immune response by either curbing or promoting inflammation.
Under normal conditions, the levels of proinflammatory Th17 cells and anti-inflammatory Treg cells balance each other, maintaining a degree of protection against pathogens without causing too much tissue-damaging inflammation.
These cells play a key role in the context of intestinal infection.
Th17 cells ignite inflammation to quell the infection, while Tregs curb inflammation once the threat has subsided. Unrestrained, the activity of Th17 can also lead to aberrant inflammation that promotes autoimmune disease and damages the intestine.
In their experiments, the researchers used undifferentiated, or naïve, mouse T cells, and exposed them to various bile acid metabolites one at a time.
The experiments showed that two separate bile acid molecules exerted different effects on T cells—one molecule promoted Treg differentiation, while another molecule inhibited Th17 cell differentiation.
The second study, 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.
“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.”
For more information
Bile acid metabolites control TH17 and Treg cell differentiation
Microbial bile acid metabolites modulate gut ROR?+ regulatory T cell homeostasis
Havard Medical School
This post is also available in: Italian