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Journal Article
Bacterial metabolism of bile acids promotes generation of peripheral regulatory T cells
2020
Overview
Intestinal health relies on the immunosuppressive activity of CD4
+
regulatory T (T
reg
) cells
1
. Expression of the transcription factor Foxp3 defines this lineage, and can be induced extrathymically by dietary or commensal-derived antigens in a process assisted by a
Foxp3
enhancer known as conserved non-coding sequence 1 (CNS1)
2
–
4
. Products of microbial fermentation including butyrate facilitate the generation of peripherally induced T
reg
(pT
reg
) cells
5
–
7
, indicating that metabolites shape the composition of the colonic immune cell population. In addition to dietary components, bacteria modify host-derived molecules, generating a number of biologically active substances. This is epitomized by the bacterial transformation of bile acids, which creates a complex pool of steroids
8
with a range of physiological functions
9
. Here we screened the major species of deconjugated bile acids for their ability to potentiate the differentiation of pT
reg
cells. We found that the secondary bile acid 3β-hydroxydeoxycholic acid (isoDCA) increased Foxp3 induction by acting on dendritic cells (DCs) to diminish their immunostimulatory properties. Ablating one receptor, the farnesoid X receptor, in DCs enhanced the generation of T
reg
cells and imposed a transcriptional profile similar to that induced by isoDCA, suggesting an interaction between this bile acid and nuclear receptor. To investigate isoDCA in vivo, we took a synthetic biology approach and designed minimal microbial consortia containing engineered
Bacteroides
strains. IsoDCA-producing consortia increased the number of colonic RORγt-expressing T
reg
cells in a CNS1-dependent manner, suggesting enhanced extrathymic differentiation.
The secondary bile acid 3β-hydroxy-deoxycholic (isodeoxycholic) acid, produced by gut bacteria, promotes the generation of colonic extrathymic regulatory T cells, whose immunosuppressive activities are known to be essential for intestinal health.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 82/58
/ Ablation
/ Acids
/ Analysis
/ Animals
/ Antigens
/ Bacteria
/ Bile
/ Bile Acids and Salts - chemistry
/ Bile Acids and Salts - metabolism
/ Dendritic Cells - immunology
/ Dendritic Cells - metabolism
/ Female
/ Humanities and Social Sciences
/ Kinases
/ Male
/ Mammals
/ Mice
/ Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism
/ Receptors, Cytoplasmic and Nuclear - metabolism
/ Science
/ T-Lymphocytes, Regulatory - cytology
