美国康奈尔大学Frank C. Schroeder等研究人员合作发现，宿主代谢平衡微生物对胆汁酸信号的调控。2025年1月8日，《自然》杂志在线发表了这项成果。

研究人员通过小鼠组织的无标的代谢组学分析，发现了一类胆汁酸-甲基半胱氨酸（BA-MCY）共轭物，它们在肠道中丰富，并依赖于泛醇胺酶1（VNN1），这是一种在肠道组织中高度表达的酶。宿主依赖的MCY结合反转了BA在肝胆系统中的功能。尽管来自微生物群的游离BA作为法尼醇X受体（FXR）的激动剂，并负向调节BA的生成，BA-MCY则作为FXR的强效拮抗剂，在体内促进BA生物合成基因的表达。

补充稳定同位素标记的BA-MCY以FXR依赖的方式增加了BA的生成，而在高胆固醇血症小鼠模型中补充BA-MCY则减少了肝脏中的脂质积累，这与BA-MCY作为肠道FXR拮抗剂的作用一致。在微生物群缺失的小鼠中，BA-MCY的水平降低，通过移植人类粪便微生物群可以恢复其水平。饮食干预（如菊粉纤维）进一步提高了游离BA和BA-MCY的水平，表明宿主通过微生物群衍生的游离BA调节BA-MCY的生成。研究人员还发现，BA-MCY在人体血清中也存在。

综合来看，这些结果表明，宿主的BA-MCY共轭物平衡了宿主依赖和微生物群依赖的代谢途径，这些途径调节FXR依赖的生理过程。

据介绍，来自肠道微生物群的代谢物（包括BA）广泛调节脊椎动物的生理过程，包括发育、代谢、免疫反应和认知功能。然而，宿主反应在多大程度上，平衡微生物群衍生代谢物的生理效应仍不清楚。

附：英文原文

Title: Host metabolism balances microbial regulation of bile acid signalling

Author: 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.

Issue&Volume: 2025-01-08

Abstract: Metabolites derived from the intestinal microbiota, including bile acids (BA), extensively modulate vertebrate physiology, including development1, metabolism2,3,4, immune responses5,6,7 and cognitive function8. However, to what extent host responses balance the physiological effects of microbiota-derived metabolites remains unclear9,10. 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.

DOI: 10.1038/s41586-024-08379-9

Source: https://www.nature.com/articles/s41586-024-08379-9