Human gut bacteria produce ΤΗ17-modulating bile acid metabolites

Bile acids are steroid-like natural products that are secreted into the gastrointestinal (GI) tract of vertebrate animals after eating — where they act as “detergents” that aid in digestion, as well as ligands for host receptors. In the gut, host-derived primary bile acids are metabolized by resident microbes to form a large group of compounds called secondary bile acids. Both primary and secondary bile acids regulate host metabolism and immune responses. [As ligands for receptors, bile acids represent “extracellular signals,” which then elicit various responses in particular cell-types of the host. This is why the attached article is relevant to gene-environment interactions.] 😉

Bile acids modulate the differentiation and function of T cells, including pro-inflammatory TH17 cells and anti-inflammatory regulatory T (Treg) cells, which help to protect the host against extracellular pathogens and to maintain host immune tolerance, respectively. Specifically, secondary bile acids — such as isoallo-lithocholic acid (isoalloLCA) and iso-deoxycholic acid (isoDCA) — modulate the differentiation of Treg cells. Moreover, 3-oxoLCA inhibits TH17 cell differentiation by blocking the function of the nuclear hormone receptor retinoic-acid-receptor-related orphan nuclear receptor-γt (RORγt).

3-OxoLCA is absent from the caecum of germ-free C57BL/6 mice — suggesting that gut bacteria may synthesize 3-oxoLCA. However, it is not known which commensal [i.e., the relationship between individuals of two species in which one species obtains food or other benefits from the other without either harming or benefiting the latter] bacterial species, and which bacterial enzyme(s) produce(s) 3-oxoLCA, and whether this compound (or additional secondary bile acids) that modulate TH17 cell responses) are implicated in the pathogenesis of inflammatory bowel disease (IBD).

In the attached paper, authors used a screen of human stool isolates to identify the gut bacterial species that produces 3-oxoLCA, as well as an abundant gut metabolite, isolithocholic acid (isoLCA); authors go on to demonstrate these metabolites inhibit TH17 cell differentiation. Multi-omics analyses of two IBD registries revealed that 3-oxoLCA and isoLCA, as well as the bacterial genes responsible for their production, are negatively associated with IBD and TH17-cell-related host gene expression. Taken together, these data suggest that bacterial production of the “3-oxoLCA and isoLCA bile acids” may contribute clinically to gut immune homeostasis in humans.
Recall that: The genetic architecture [i.e., total landscape of genetic contributions to a given phenotype] represents the contribution of: [a] genetics [DNA sequence differences], [b] epigenetics [DNA methylation, RNA-interference, histone modification, and/or chromatin remodeling — all processes that do not alter DNA sequence], [c] environmental factors, [d] endogenous influences, and [e] the interindividual microbiome. This topic [attached paper] suggests that a trait such as “individual risk of IBD” might be affected by at least three, if not all five, of these categories…!! 😊

Nature 31 Mar 2022; 603: 907-912

COMMENT: This discussion is a great gene-environmental interaction. Hope all is well. JB

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