Microbial bile acid metabolites modulate gut RORγ+ regulatory T cell homeostasis

Abstract

The metabolic pathways encoded by the human gut microbiome constantly interact with host gene products through numerous bioactive molecules 1. Primary bile acids (BAs) are synthesized within hepatocytes and released into the duodenum to facilitate absorption of lipids or fat-soluble vitamins 2. Some BAs (~5%) escape into the colon, where gut commensal bacteria convert them into a variety of intestinal BAs 2 that are important hormones regulating host cholesterol metabolism and energy balance via several nuclear receptors and/or G protein-coupled receptors 3,4. These receptors play pivotal roles in shaping host innate immune responses 1,5. However, the impact of this host-microbe biliary network on the adaptive immune system remains poorly characterized. Here we report that both dietary and microbial factors influence the composition of the gut BA pool and modulate an important population of colonic Foxp3 + regulatory T cells (Tregs) expressing the transcriptional factor RORγ. Genetic abolition of BA metabolic pathways in individual gut symbionts significantly decreases this Treg population. Restoration of the intestinal BA pool increases colonic RORγ + Treg levels and ameliorates host susceptibility to inflammatory colitis via BA nuclear receptors. Thus, a pan-genomic biliary network interaction between hosts and their bacterial symbionts can control host immunologic homeostasis via the resulting metabolites.

Bile acids mediate signaling between microbiome and the immune system

“…The effect of isoDCA on dendritic cells in this study is in contrast to recent work of T‐cell‐modulating bile acids, which potentiate Treg generation in a cell‐intrinsic manner 5,6 . This suggests that bile acids have diverse effects on the adaptive immune system and affect multiple cell types, opening the door for further research on how microbial metabolites can influence immune responses.…”

“…The molecular mechanism by which the microbiome interacts with peripherally induced Treg (pTreg) is likely complex and multifactorial; however, part of the effect is mediated via the release of microbial fermentation products, such as butyrate and other short‐chain fatty acids 1–3 . In a string of recent studies, a role for host bile acids has also been shown to induce pTreg generation, with this function dependent on commensal colonization 4–6 . In the recent issue of Nature , Rudensky and colleagues dissect the molecular fermentation pathway where the gut microbiome converts an endogenous bile acid into an immunologically active bile acid with the capacity to induce pTreg in the gut 4 …”

“…Further complexity is added to the system through the effect of diet, which can influence the composition of both bile acids and the microbiota. A recent study in Nature 6 demonstrated that mice fed a nutrient‐poor diet showed reduced presence of bile acids and subsequent reduction in pTreg generation. Mice fed a minimal diet were susceptible to intestinal inflammation, an effect which could be blocked through supplementation with select bile acids.…”

A Standard Lipid Panel Is Insufficient for the Care of a Patient on a High-Fat, Low-Carbohydrate Ketogenic Diet

“…One of these diseases is ulcerative colitis, an inflammatory bowel disease. Ketogenic diets may dampen inflammation within the gastrointestinal tract by inhibiting the activity of the NLRP3 inflammasome (8), promoting intestinal stem cell regeneration and gut healing (9), and stimulating the release of bile acids that facilitate intestinal immune system homeostasis (10,11).…”

Gut Microbial-Derived Metabolomics of Asthma

“…These effects have been attributed to inhibition of the inflammatory unfolded protein response [60]. Additionally, it was recently found that depletion of gut microbial bile acids leads to reduced gut RORγ+ regulatory T cells via a mechanism involving bile acid activity at the vitamin D receptor [61], though it is not clear if this has an effect on distant organs such as the lung.…”