Search

Bile acids are abundant in the mammalian gut, where they undergo bacteria-mediated transformation to generate a large pool of bioactive molecules. Although bile acids are known to affect host metabolism, cancer progression and innate immunity, it is unknown whether they affect adaptive immune cells such as T helper cells that express IL-17a (T.sub.H17 cells) or regulatory T cells (T.sub.reg cells). Here we screen a library of bile acid metabolites and identify two distinct derivatives of lithocholic acid (LCA), 3-oxoLCA and isoalloLCA, as T cell regulators in mice. 3-OxoLCA inhibited the differentiation of T.sub.H17 cells by directly binding to the key transcription factor retinoid-related orphan receptor-[gamma]t (ROR[gamma]t) and isoalloLCA increased the differentiation of T.sub.reg cells through the production of mitochondrial reactive oxygen species (mitoROS), which led to increased expression of FOXP3. The isoalloLCA-mediated enhancement of T.sub.reg cell differentiation required an intronic Foxp3 enhancer, the conserved noncoding sequence (CNS) 3; this represents a mode of action distinct from that of previously identified metabolites that increase T.sub.reg cell differentiation, which require CNS1. The administration of 3-oxoLCA and isoalloLCA to mice reduced T.sub.H17 cell differentiation and increased T.sub.reg cell differentiation, respectively, in the intestinal lamina propria. Our data suggest mechanisms through which bile acid metabolites control host immune responses, by directly modulating the balance of T.sub.H17 and T.sub.reg cells. Screening of a library of bile acid metabolites revealed two derivatives of lithocholic acid that act as regulators of T helper cells that express IL-17a and regulatory T cells, thus influencing host immune responses., Author(s): Saiyu Hang [sup.1] , Donggi Paik [sup.1] , Lina Yao [sup.2] , Eunha Kim [sup.1] , Jamma Trinath [sup.3] , Jingping Lu [sup.4] , Soyoung Ha [sup.1] , Brandon [...]

The hypoxia-inducible factors (HIFs) coordinate cellular adaptations to low oxygen stress by regulating transcriptional programs in erythropoiesis, angiogenesis and metabolism. These programs promote the growth and progression of many tumours, [...]

An Amendment to this paper has been published and can be accessed via a link at the top of the paper., Author(s): Saiyu Hang [sup.1], Donggi Paik [sup.1], Lina Yao [sup.2], Eunha Kim [sup.1], Jamma Trinath [sup.3], Jingping Lu [sup.4], Soyoung Ha [sup.1], Brandon N. Nelson [sup.5], Samantha P. Kelly [sup.5], [...]