Bile Acid Metabolites Control Th17 and Treg Cell Differentiation
Access StatusFull text of the requested work is not available in DASH at this time ("restricted access"). For more information on restricted deposits, see our FAQ.
Devlin, A. Sloan
MetadataShow full item record
CitationHang, S., Paik, D., Yao, L. et al. 2019. Bile Acid Metabolites Control Th17 and Treg Cell Differentiation. Nature Medicine 576: 143–148.
AbstractBile 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 isoalloLCA to mice led to reduced Th17 and increased Treg cell differentiation in the intestinal lamina propria. Altogether, our data suggest novel mechanisms by which bile acid metabolites control host immune responses by directly modulating the Th17 and Treg balance.
Citable link to this pagehttps://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37372880
- HMS Scholarly Articles