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
Department of Chemistry and Chemical Biology, Boyce Thompson Institute, Cornell University, Ithaca, NY, USA.
College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Pocheon-si, Republic of Korea.
Nature. 2025 Feb;638(8049):216-224. doi: 10.1038/s41586-024-08379-9. Epub 2025 Jan 8.
Metabolites derived from the intestinal microbiota, including bile acids (BA), extensively modulate vertebrate physiology, including development, metabolism, immune responses and cognitive function. However, to what extent host responses balance the physiological effects of microbiota-derived metabolites remains unclear. 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.
源自肠道微生物群的代谢产物，包括胆汁酸（BA），广泛调节脊椎动物的生理功能，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产物的生理作用仍不清楚。在这里，我们通过对小鼠组织进行非靶向代谢组学分析，鉴定出一类BA-甲基半胱胺（BA-MCY）共轭物，它们在肠道中含量丰富，且依赖于泛酰巯基乙胺酶1（VNN1），一种在肠道组织中高表达的泛酰巯基乙胺酶。这种宿主依赖性的MCY共轭作用逆转了胆汁酸在肝胆系统中的功能。微生物群衍生的游离胆汁酸作为法尼醇X受体（FXR）的激动剂，负向调节胆汁酸的产生，而BA-MCY则作为FXR的有效拮抗剂，促进体内胆汁酸生物合成基因的表达。补充稳定同位素标记的BA-MCY以FXR依赖性方式增加胆汁酸的产生，在高胆固醇血症小鼠模型中补充BA-MCY可减少肝脏中的脂质积累，这与BA-MCY作为肠道FXR拮抗剂的作用一致。在微生物群缺乏的小鼠中，BA-MCY的水平降低，通过移植人类粪便微生物群可使其恢复。用菊粉纤维进行饮食干预可进一步提高游离胆汁酸和BA-MCY的水平，表明宿主产生BA-MCY受微生物群衍生的游离胆汁酸水平的调节。我们进一步表明，多种BA-MCY也存在于人类血清中。总之，我们的结果表明，宿主的BA-MCY共轭作用平衡了调节FXR依赖性生理功能的宿主依赖性和微生物群依赖性代谢途径。
