Nov 8, 2018

Bile acid metabolites control Th17 and Treg cell differentiation

BioRxiv : the Preprint Server for Biology
Saiyu HangJun Huh

Abstract

Bile acids are abundantly present in the mammalian gut, where they undergo bacteria-mediated transformation, generating a large pool of bioactive molecules. While they have been shown to affect host metabolism, cancer progression and innate immunity, it is unknown whether bile acids affect the function of adaptive immune cells such as T cells expressing IL-17a (Th17 cells) and regulatory T cells (Tregs) that mediate inflammatory and anti-inflammatory responses, respectively. By screening a small-molecule library primarily composed of bile acid metabolites, we identified two distinct derivatives of lithocholic acid (LCA), 3-oxoLCA and isoalloLCA, as specific regulators of Th17 and Treg cells. While 3-oxoLCA inhibited Th17 cell differentiation by directly binding to its key transcription factor RORγt (retinoid-related orphan receptor γ t), isoalloLCA enhanced differentiation of Tregs through mitochondrial-dependent metabolic changes, leading to an increased expression of Foxp3. IsoalloLCA-dependent Treg enhancement required an intronic Foxp3 enhancer, the conserved noncoding sequence 3 (CNS3), which acts as an epigenetic switch that confers a poised state to the Foxp3 promoter. Lastly, oral administration of 3-oxoLCA and isoalloL...Continue Reading

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Mentioned in this Paper

Metabolic Process, Cellular
Lithocholic Acid
Immune Response
Conserved Sequence
Transformation, Genetic
Bile Acid Measurement
Entire Intestinal Lamina Propria
T-Lymphocyte
Derivatives
Metabolism by Symbiont of Host Protein

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