Bile Acid Metabolized by Gut Bacterium Regulates Colonic T_Reg Cells
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Bile acid metabolites from the gut microbiome regulate a population of colonic T-regulatory cells, revealing a biliary pan-genomic regulatory pathway
Important immune system cells in the intestines of mice produce metabolites (from the metabolization of bile acid) which are essential for gut immune health. Benoist et al. researched a “poorly characterized” pathway between the gut microbiome and the immune system. The presence of bile acid receptors in host cells along with the population behavior of T regulatory cells in the colon reveals that a pan-genomic interaction is occurring between the host and the gut microbiome.
T regulatory cells are a crucial part of the immune system partially due to their responsibility to suppress the immune response. Bacterium in the stomach are not made up of the same cells and genetics as the host. Ensuring that the immune response is controlled is therefore especially essential in the gut, where host cells are symbiont with a huge population of non-self entities. The researchers ask what role bile acid has on the homeostasis in groups of T-regulatory cells throughout the intestines. FOXP3 is a gene expressed (the protein is present) in T regulatory cells that acts as a master function regulator, so the researchers located clusters of them throughout the different areas of the gut. Bile acids are produced in the small intestine, but 5% leaks into the colon which is where the most interesting results are found in this study.
To understand the mechanics and effects of bile acid metabolites on t regulatory cell homeostasis, the researchers study both mice with varying diets ranging from rich to poor and mice with varying bile acid profiles (different amounts and combinations). Bile acid is also known to function as a vitamin and lipid absorber. Aspects of T-reg cells were also considered by blocking specific receptors to understand the pathway. It was hypothesized that gut bacterium would facilitate the induction of the T-regulatory cells mentioned above. Diet only had an effect on T-regulatory cell homeostasis in the colon – not even lymphoid organs responsible for immune cell development were effected. As expected, minimal diet mice had much lower BA content in their feces and a much lower ROR gamma positive T_reg cell population. Mice without the gut microbes (also referred to as germ-free (GF) mice), even when given a rich diet, also had minimal BA metabolites in the feces and a lower cell population. This result shows that mice produce BA’s according to their diet, and the metabolism of these BA’s by bacterium may regulate the population of T_reg cells.
Colitis was used to explore the role of these cells in the gut immune response. ROR gamma positive T regulatory cells effect homeostasis in the colon and also reduce the effects of colitis*** (8,11,22,23). Colitis free mice fed all three diets has no colonic inflammation, which would indicate an immune response and therefore shows that without colitis induced there is no response. After colitis was initiated, the minimal diet mice had a reduced population and indicated a minimal diet may cause severe colitis. Supplementation with BA’s in minimal diet mice did reduce the effects of colitis and increased the T-reg population, but after the onset of colitis supplementation did not help, showing that the homeostasis of this cell group is key to host colitis response. The researchers were then able to display the importance of intestinal BA’s on this cell pool by finding BAR’s (bile acid receptors) to regulate the cell pool of colonic T-cells. The vitamin D receptor (VDR) was explored by studying mice deficient in that gene, meaning the mice cells do not have this BAR. Colitis in deficient mice was significantly more severe, indicating VDR’s intrinsic role of T_reg cell’s inflammation control.
By verifying the importance of diet and microbes in the gut on T_reg cell population, then studying the effects of BA supplementation and colitis immune response, and finally revealing that host VDR’s are key to the induction/homeostasis of these T_reg cells, a major connection between host and microbes was shown. Presence of a bile acid metabolite receptor in host cells indicates a genomic relationship between T_reg cells and both the gut bacterium and host-produced bile. This is a huge immunological discovery that places new importance on the effect of bile acid and bacterium on host inflammation.
In fact, disease progression of human inflammatory bowel diseases and colon/rectal cancers are thought to be mediated by the dysregulation of BA’s***. Improper human colonic T_reg cell regulation is therefore possibly indicates that genetic variation of the VDR in humans impacts disease susceptibility. From this paper, more studies have been conducted to better understand this pathway and its importance. One such paper explores the numerous functions of the FOXP3+ T_reg cell population, finding more of its immune functions and discovering many tissue specific functions like tissue repair ***. The implications of both Benoist et al.’s work and all work done since then in the subject is huge to our understanding of the fascinating symbiosis in our gut. Further, it is a fascinating addition to an increasingly complex understanding of pan-genomics as a whole that inspires more questions than answers: Is there a master regulator of T_reg cell population for all intestinal parts? Is it possible for the bacterium in the gut to improperly metabolize bile acid? Since bile acid metabolites sustain the T-reg cells in the colon, would an increased VDR expression combat a reduction or deficiency in these metabolites? The possibility of treating disease through BA supplementation as well as potential immunological advancements in regards to inflammation control is fascinating. Exciting new therapy and new discoveries can be derived from this work, especially in the area of gastrointestinal health.
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