Two Nature papers reveal that bile acids play a key role in regulating intestinal immunity and inflammation

January 13, 2020 / Bio Valley bio on / - -- bile is the juice produced by the liver and gallbladder Bile acids in bile can dissolve fat Can they also play a role in immune response and inflammation? According to two independent studies conducted by Harvard Medical School, the answer seems to be yes These two studies in mice have found that bile acid can promote the differentiation and activity of several types of T cells involved in the regulation of inflammation and related to intestinal inflammatory diseases They also reveal that gut microbes are essential for the transformation of bile acids into immune signaling molecules This provides a potential therapeutic approach for regulating intestinal inflammation, which can lead to 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 play their immunomodulatory role by interacting with immune cells in the gut Once bile acids leave the gallbladder and complete their lipolysis, they pass through the digestive tract, where intestinal bacteria modify them into immune regulatory molecules These modified bile acids then activate two types of immune cells: regulatory T cells (Treg) and effector helper T cells (Th17 in particular), which regulate the immune response by inhibiting or promoting inflammation The relevant research results were recently published in the journal Nature, and the title of the paper is "bill acid metrics control Th17 and Treg cell differentiation" Picture from nature, 2019, DOI: 10.1038/s41586-019-1785-z Under normal circumstances, the levels of pro-inflammatory Th17 cells and anti-inflammatory Treg cells are in balance with each other, so as to maintain a certain degree of resistance to pathogens without causing too much tissue damaging inflammation These cells play a key role in intestinal infection Th17 cells initiate inflammation to suppress intestinal infection, and once the threat is removed, Treg cells suppress inflammation If not limited, Th17 cell activity can also lead to abnormal inflammation, which can promote autoimmune diseases and damage the gut In the experiment, the huh team used undifferentiated mouse T cells (the initial mouse T cells) and exposed them to a variety of bile acid metabolites at one time These experiments show that two different bile acid metabolites have different effects on T cells: one promotes Treg cell differentiation, and the other 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 dropped and rose accordingly In addition, they found the presence of these two bile acid byproducts in human feces, including those of patients with IBD "Our findings identify an important regulatory mechanism for gut immunity: Microbes in the gut modify bile acids and turn them into inflammatory regulators," huh added If confirmed in further studies, these results may help to develop small molecular drugs targeting Treg and Th17 cells to control inflammation and treat autoimmune diseases affecting the gut In the second study, Dennis Kasper, Professor of immunology at the Blavatnik Institute of Harvard Medical School, and his team focused on a subgroup of Treg cells (called colon Treg cells) that inhibit inflammation in the colon due to exposure to intestinal microorganisms In contrast, most other immune cells originate in the thymus The related research results were recently published in the Nature journal, and the title of the paper was "microbial bill acid substances modular GUR γ + regulatory T cell homeostasis" Lower levels of colon Treg cells are associated with the development of autoimmune diseases such as IBD and Crohn's disease Kasper's experiments showed that intestinal microorganisms and diet could modify bile acids in a synergistic way, which in turn affected the level of colon Treg cells in mice They also found that the low level of colon Treg cells induced by the lack of bile acid or bile acid sensing protein made mice susceptible to inflammatory colitis, a disease similar to human IBD In order to test the hypothesis that intestinal bacteria will convert the dietary bile acid produced by food intake into immune signal molecules, Kasper team silenced the bile acid transformation gene in a variety of intestinal bacteria, and then colonized the genetically modified and non genetically modified intestinal bacteria into mice specially bred to make the intestinal tract sterile Mice inoculated with intestinal bacteria lacking bile acid transformation genes had significantly reduced colon Treg cell levels They then fed the mice either a nutritious diet or a minimum food (the minimum food needed to sustain life) Mice with normal gut microbes had lower levels of colon Treg cells and bile acids after ingestion of minimal food than those fed with nutritious food However, intestinal sterile mice also had lower Treg cell levels after ingesting nutritious foods - a finding that suggests that both intestinal microorganisms and dietary bile acids are necessary to regulate immune cell levels To test whether bile acids are directly involved in immune cell regulation, the Kasper team then mixed various bile acid molecules with drinking water from mice with low Treg cell levels and minimal food intake After a few weeks, the levels of anti-inflammatory Treg cells in these mice increased In the final step, the Kasper team gave three groups of mice a compound that induced colitis The first group of mice received the minimum food without added bile acid molecule, the second group of mice received the nutritious food, the third group of mice received the minimum food and drinking water with added bile acid molecule As expected, colitis was only seen in mice that received minimal food without the addition of bile acid molecules This confirms that bile acids play a key role in Treg cell regulation, intestinal inflammation and risk of colitis Kasper, "our results confirm that there are elegant tripartite interactions between gut microbes, bile acids, and the immune system Importantly, our study suggests that it is reasonable to consider the use of certain intestinal bacteria as a means of regulating disease risk " (BIOON Com) reference: 1 Saiyu hang et al Bill acid substances control Th17 and Treg cell differentiation Nature, 2019, DOI: 10.1038/s41586-019-1785-z 2 Xinyang song et al Microbial bill acid substances modular root γ + regulatory T cell homestasis Nature, 2019, doi:10.1038/s41586-019-1865-0 3.Fat-dissolving bile acids may help regulate gut immunity and inflammation https://medicalxpress.com/news/2020-01-fat-dissolving-bile-acids-gut-immunity.html