Host metabolism balances microbial regulation of bile acid signalling

• 成果类型: Article
• 署名作者: Won, Tae Hyung; Arifuzzaman, Mohammad; Parkhurst, Christopher N.; Miranda, Isabella C.; Zhang, Bingsen; Hu, Elin; Kashyap, Sanchita; Letourneau, Jeffrey; Jin, Wen-Bing; Fu, Yousi; Guzior, Douglas V.; Quinn, Robert A.; Guo, Chun-Jun; David, Lawrence A.; Artis, David; Schroeder, Frank C.
• 署名单位: Cornell University; Boyce Thompson Institute for Plant Research; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Duke University; Michigan State University; Michigan State University; Cornell University; Weill Cornell Medicine; Duke University; Cornell University; Weill Cornell Medicine; Pochon Cha University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1639
• DOI: 10.1038/s41586-024-08379-9
• 发表日期: 2025-02-01
• 页码: 216-+
• 关键词: farnesoid-x-receptor; nuclear receptor; n-acyltransferase; fxr; coa; purification; ligands; liver

摘要

Metabolites derived from the intestinal microbiota, including bile acids (BA), extensively modulate vertebrate physiology, including development(1), metabolism(2, 3-4), immune responses(5, 6-7) and cognitive function(8). However, to what extent host responses balance the physiological effects of microbiota-derived metabolites remains unclear(9,10). Here, using untargeted metabolomics of mouse tissues, we identified a family of BA-methylcysteamine (BA-MCY) conjugates that are abundant in the intestine and dependent on vanin 1 (VNN1), a pantetheinase highly expressed in intestinal tissues. This host-dependent MCY conjugation inverts BA function in the hepatobiliary system. Whereas microbiota-derived free BAs function as agonists of the farnesoid X receptor (FXR) and negatively regulate BA production, BA-MCYs act as potent antagonists of FXR and promote expression of BA biosynthesis genes in vivo. Supplementation with stable-isotope-labelled BA-MCY increased BA production in an FXR-dependent manner, and BA-MCY supplementation in a mouse model of hypercholesteraemia decreased lipid accumulation in the liver, consistent with BA-MCYs acting as intestinal FXR antagonists. The levels of BA-MCY were reduced in microbiota-deficient mice and restored by transplantation of human faecal microbiota. Dietary intervention with inulin fibre further increased levels of both free BAs and BA-MCY levels, indicating that BA-MCY production by the host is regulated by levels of microbiota-derived free BAs. We further show that diverse BA-MCYs are also present in human serum. Together, our results indicate that BA-MCY conjugation by the host balances host-dependent and microbiota-dependent metabolic pathways that regulate FXR-dependent physiology.