Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1871, Frederiksberg C, Denmark.
School of Science and Technology, Örebro University, 702 81, Örebro, Sweden.
BMC Microbiol. 2022 Dec 1;22(1):287. doi: 10.1186/s12866-022-02704-w.
Gut microbiota dysbiosis is associated with the development of non-alcoholic steatohepatitis (NASH) through modulation of gut barrier, inflammation, lipid metabolism, bile acid signaling and short-chain fatty acid production. The aim of this study was to describe the impact of a choline-deficient amino acid defined high fat diet (CDAHFD) on the gut microbiota in a male Göttingen Minipig model and on selected pathways implicated in the development of NASH.
Eight weeks of CDAHFD resulted in a significantly altered colon microbiota mainly driven by the bacterial families Lachnospiraceae and Enterobacteriaceae, being decreased and increased in relative abundance, respectively. Metabolomics analysis revealed that CDAHFD decreased colon content of short-chain fatty acid and increased colonic pH. In addition, serum levels of the microbially produced metabolite imidazole propionate were significantly elevated as a consequence of CDAHFD feeding. Hepatic gene expression analysis showed upregulation of mechanistic target of rapamycin (mTOR) and Ras Homolog, MTORC1 binding in addition to downregulation of insulin receptor substrate 1, insulin receptor substrate 2 and the glucagon receptor in CDAHFD fed minipigs. Further, the consequences of CDAHFD feeding were associated with increased levels of circulating cholesterol, bile acids, and glucagon but not total amino acids.
Our results indicate imidazole propionate as a new potentially relevant factor in relation to NASH and discuss the possible implication of gut microbiota dysbiosis in the development of NASH. In addition, the study emphasizes the need for considering the gut microbiota and its products when developing translational animal models for NASH.
肠道微生物失调通过调节肠道屏障、炎症、脂质代谢、胆汁酸信号和短链脂肪酸生成，与非酒精性脂肪性肝炎（NASH）的发展有关。本研究旨在描述胆碱缺乏氨基酸定义的高脂肪饮食（CDAHFD）对雄性哥廷根小型猪模型肠道微生物群的影响，以及对 NASH 发生中涉及的选定途径的影响。
CDAHFD 喂养 8 周导致结肠微生物群发生显著改变，主要由细菌家族 Lachnospiraceae 和肠杆菌科驱动，相对丰度分别降低和增加。代谢组学分析显示，CDAHFD 降低了结肠中短链脂肪酸的含量，增加了结肠 pH 值。此外，由于 CDAHFD 喂养，血清中微生物产生的代谢物咪唑丙酸的水平显著升高。肝基因表达分析显示，CDAHFD 喂养的小型猪中，机械性靶标雷帕霉素（mTOR）和 Ras Homolog、MTORC1 结合的 Ras Homolog 上调，胰岛素受体底物 1、胰岛素受体底物 2 和胰高血糖素受体下调。此外，CDAHFD 喂养的后果与循环胆固醇、胆汁酸和胰高血糖素水平升高有关，但与总氨基酸水平无关。
我们的研究结果表明，咪唑丙酸是与 NASH 相关的一个新的潜在相关因素，并讨论了肠道微生物失调在 NASH 发展中的可能影响。此外，该研究强调在开发 NASH 的转化动物模型时，需要考虑肠道微生物群及其产物。
