Chen Jiayi, Yang Hao, Qin Yingjie, Zhou Xinbo, Ma Qingquan
College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China.
Research (Wash D C). 2024 Dec 13;7:0515. doi: 10.34133/research.0515. eCollection 2024.
Metabolic syndrome (MS) is a progressive metabolic disease characterized by obesity and multiple metabolic disorders. Tryptophan (Trp) is an essential amino acid, and its metabolism is linked to numerous physiological functions and diseases. However, the mechanisms by which Trp affects MS are not fully understood. In this study, experiments involving a high-fat diet (HFD) and fecal microbiota transplantation (FMT) were conducted to investigate the role of Trp in regulating metabolic disorders. In a mouse model, Trp supplementation inhibited intestinal farnesoid X receptor (FXR) signaling and promoted hepatic bile acid (BA) synthesis and excretion, accompanied by elevated levels of conjugated BAs and the ratio of non-12-OH to 12-OH BAs in hepatic and fecal BA profiles. As Trp alters the gut microbiota and the abundance of bile salt hydrolase (BSH)-enriched microbes, we collected fresh feces from Trp-supplemented mice and performed FMT and sterile fecal filtrate (SFF) inoculations in HFD-treated mice. FMT and SFF not only displayed lipid-lowering properties but also inhibited intestinal FXR signaling and increased hepatic BA synthesis. This suggests that the gut microbiota play a beneficial role in improving BA metabolism through Trp. Furthermore, fexaramine (a gut-specific FXR agonist) reversed the therapeutic effects of Trp, suggesting that Trp acts through the FXR signaling pathway. Finally, validation in a finishing pig model revealed that Trp improved lipid metabolism, enlarged the hepatic BA pool, and altered numerous glycerophospholipid molecules in the hepatic lipid profile. Our studies suggest that Trp inhibits intestinal FXR signaling mediated by the gut microbiota-BA crosstalk, which in turn promotes hepatic BA synthesis, thereby ameliorating MS.
代谢综合征（MS）是一种以肥胖和多种代谢紊乱为特征的进行性代谢疾病。色氨酸（Trp）是一种必需氨基酸，其代谢与众多生理功能和疾病相关。然而，色氨酸影响代谢综合征的机制尚未完全明确。在本研究中，通过高脂饮食（HFD）和粪便微生物群移植（FMT）实验，研究色氨酸在调节代谢紊乱中的作用。在小鼠模型中，补充色氨酸可抑制肠道法尼酯X受体（FXR）信号传导，促进肝脏胆汁酸（BA）合成与排泄，同时肝脏和粪便胆汁酸谱中结合型胆汁酸水平升高，非12-羟基胆汁酸与12-羟基胆汁酸的比例增加。由于色氨酸会改变肠道微生物群以及富含胆汁盐水解酶（BSH）的微生物丰度，我们收集了补充色氨酸小鼠的新鲜粪便，并在高脂饮食处理的小鼠中进行粪便微生物群移植和无菌粪便滤液（SFF）接种。粪便微生物群移植和无菌粪便滤液不仅具有降脂作用，还能抑制肠道FXR信号传导并增加肝脏胆汁酸合成。这表明肠道微生物群通过色氨酸在改善胆汁酸代谢中发挥有益作用。此外，非瑟酮胺（一种肠道特异性FXR激动剂）可逆转色氨酸的治疗效果，提示色氨酸通过FXR信号通路发挥作用。最后，在育肥猪模型中的验证表明，色氨酸可改善脂质代谢，扩大肝脏胆汁酸池，并改变肝脏脂质谱中的多种甘油磷脂分子。我们的研究表明，色氨酸抑制由肠道微生物群-胆汁酸相互作用介导的肠道FXR信号传导，进而促进肝脏胆汁酸合成，从而改善代谢综合征。
