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Bile Acids Play a Key Role in Regulating Intestinal Immunity and Intestinal Inflammation

Bile is the juice produced by the liver and gallbladder. Bile acids in bile are able to dissolve fats. Can they also play a role in immune responses and inflammation? According to two independent studies conducted by Harvard Medical School, the answer seems to be yes.


These two studies in mice found that bile acids can promote the differentiation and activity of several types of T cells that are involved in regulating inflammation and are associated with intestinal inflammatory diseases. They also reveal that gut microbes are essential for converting bile acids into immune signaling molecules. This provides a potential therapeutic approach for regulating intestinal inflammation, which can cause autoimmune diseases such as inflammatory bowel disease (IBD).


In the first study, Jun Huh, an immunologist at Harvard Medical School and his team, revealed that bile acids exert their immunomodulatory effects by interacting with immune cells in the gut. Once bile acids leave the gallbladder and complete their fat-dissolving effects, they pass through the digestive tract, where gut bacteria modify them into immunomodulatory molecules. These modified bile acids then activate two types of immune cells: regulatory T cells (Treg) and effector helper T cells (especially Th17), each of which regulates the immune response by suppressing or promoting inflammation. The relevant research results were recently published in the journal Nature.


Under normal circumstances, the levels of pro-inflammatory Th17 cells and anti-inflammatory Treg cells are balanced with each other, thereby maintaining a certain degree of resistance to pathogens without causing excessive inflammation that damages the tissue. These cells play a key role in intestinal infections. Th17 cells trigger inflammation to suppress intestinal infections, and once the threat is eliminated, Treg cells suppress inflammation. If not restricted, the activity of Th17 cells can also lead to abnormal inflammation, which promotes autoimmune diseases and damages the intestine.


In the experiment, Huh’s team used undifferentiated mouse T cells (the original mouse T cells) and exposed them to multiple bile acid metabolites at one time. These experiments show that two different bile acid metabolites have different effects on T cells-one metabolite promotes Treg cell differentiation and the other metabolite inhibits Th17 cell differentiation. When the Huh team applied each of these two bile acid metabolites to mice, they observed that their Th17 and Treg cells decreased and rose accordingly. They also found that these two bile acid by-products are also present in human feces, including those from patients with IBD.


Huh added, „Our findings identify an important regulatory mechanism for gut immunity: microorganisms in the gut can modify bile acids and turn them into regulators of inflammation.“


If confirmed in further research, these results may help people develop small-molecule drugs that target Treg and Th17 cells to control inflammation and treat autoimmune diseases that affect the gut.


In the second study, Dennis Kasper, a professor of immunology at the Harvard Medical School’s Bravanik Institute, and his research team focused on a subset of Treg cells (called Colonic Treg cells). In contrast, most other immune cells originate from the thymus. The relevant research results were recently published in the journal Nature and the title of the paper was „Microbial bile acid metabolites modulate gut RORγ + regulatory T cell homeostasis“.


Lower levels of colonic Treg cells are associated with the development of autoimmune diseases such as IBD and Crohn’s disease.


Kasper’s experiments show that gut microbes and diet can work together to modify bile acids, which in turn affects colonic Treg cells in mice. They also found that low levels of colonic Treg cells induced by a lack of bile acids or bile acid-sensing proteins made mice susceptible to inflammatory colitis, a disease similar to human IBD.


To test the intestinal bacteria’s hypothesis that food-borne bile acids produced by ingestion of food into immune signaling molecules, Kasper’s team silenced the bile acid-converting genes in various intestinal bacteria, and then genetically modified The genetically modified intestinal bacteria are colonized into mice that have been specially developed to make the intestines sterile. Mice that received colonization of intestinal bacteria lacking bile acid conversion genes in the intestine had significantly reduced levels of colonic Treg cells. They then fed the mice with nutrient-rich or minimal food.


Mice carrying normal intestinal microorganisms had lower levels of colonic Treg cells and bile acids after ingesting minimal foods compared to ingesting nutrient-rich foods. However, mice with sterile intestines also had lower levels of Treg cells after ingesting nutritious foods-a finding that suggests that both gut microbes and food-borne bile acids are necessary to regulate immune cell levels.


To test whether bile acids are directly involved in immune cell regulation, Kasper’s team then mixed various bile acid molecules with drinking water from mice with lower Treg cell levels and minimal food intake. A few weeks later, these mice had increased levels of Treg cells that inhibit inflammation.


In the final step, Kasper’s team gave three groups of mice a compound that induced colitis. The first group of mice received minimal foods without added bile acid molecules, the second group of mice took nutrient-rich foods, and the third group of mice took minimal foods and drank drinking water supplemented with bile acid molecules . As expected, only those mice that ate minimal foods without added bile acid molecules developed colitis. This confirms that bile acids play a key role in Treg cell regulation, intestinal inflammation, and the risk of colitis.


Kasper, „Our results confirm an elegant tripartite interaction between gut microbes, bile acids, and the immune system. Importantly, our research suggests that consideration of the use of certain gut bacteria as a way to regulate disease risk is reasonable.“

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