Synthesis and identification of lithocholic acid 3-sulfate as RORγt ligand to inhibit Th17 cell differentiation

Abstract

Primary bile acids (BAs), products of cholesterol metabolism and clearance, are synthesized in the liver and released into the intestine to facilitate the digestion and absorption of lipids. BAs are further converted by gut commensal bacteria into secondary colonic BAs and the metabolism disorder is closely linked to cholestatic liver diseases via regulating immune response. However, the effect and underlying mechanism of these host‐microorganism biliary metabolites on T lymphocyte remain unclear. In the current study, we synthesized a sulfated product of lithocholic acid (LCA), lithocholic acid 3‐sulfate (LCA‐3‐S), and investigated the binding affinity of the BAs metabolites on RORγt, the transcription factor of IL‐17A. Our results demonstrated that the sulfate of LCA, LCA‐3‐S, exhibited better effect than its oxidated metabolite, 3‐oxo‐LCA, binding to RORγt. The results further demonstrated that LCA‐3‐S selectively suppressed Th17 cell differentiation without influence on Th1, Th2, and Treg cells. Collectively, we synthesized the sulfated biliary metabolite LCA‐3‐S and demonstrated that LCA‐3‐S selectively inhibited Th17 cell differentiation by targeting RORγt, indicating that metabolite disorder of BAs resulting in the decrease of LCA‐3‐S probably contributes to the pathogenesis of cholestatic liver diseases.

The role of Th17 cells in inflammatory bowel disease and the research progress

“…studied the binding affinity of bile acid metabolites to the IL-17A transcription factor RORγt by synthesizing the sulfated product of LCA, LCA-3-sulfate (LCA-3-S). LCA-3-S specifically targets RORγt to inhibit Th17 cell differentiation, a process that does not affect Th1, Th2, and Treg cell differentiation ( 68 ).…”

Effect of gut flora mediated‐bile acid metabolism on intestinal immune microenvironment

“…Researchers synthesised LCA 3-sulphate (LCA-3-S), which binds to RORγt and selectively suppress Th17 cell differentiation [130]. UDCA has been used in the clinic for many years and has a good curative effect on PSC [131].…”

Effect of gut flora mediated-bile acid metabolism on intestinal immune microenvironment

“…Researchers have synthesized LCA 3-sulfate (LCA-3-S) that binds to RORγt and selectively suppresses Th17 cell differentiation 127 . UDCA has been used clinically for many years and has a good curative effect on PSC 128 .It also degrade TGF-β and inhibits the differentiation and activation of Treg cells 129 , and UDCA enhances the anti-tumor efficacy of anti-pd-1.…”