Goto Kana, Kani Koudai, Kato Miyuna, Igarashi Naoya, Tada Yuki, Kasai Kaichi, Ichimura-Shimizu Mayuko, Watanabe Shiro, Tsuneyama Koichi, Furusawa Yukihiro, Nagai Yoshinori
Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama, 939-0398, Japan.
Department of Pathology and Laboratory Medicine, Tokushima University Graduate School of Biomedical Sciences, 3-8-15 Kuramoto-Cho, Tokushima, 770-8503, Japan.
Inflammation. 2025 Jun 9. doi: 10.1007/s10753-025-02294-5.
A high-fat/cholesterol/cholate-based (iHFC) diet induces pathological changes in Tsumura-Suzuki non-obese (TSNO) mice, resembling human metabolic dysfunction associated steatohepatitis (MASH), along with advanced liver fibrosis. In this study, we investigated the role of cholic acid (CA) in the development of iHFC diet-induced MASH development. In mice receiving an iHFC diet without CA (CA(-) iHFC diet), both lobular inflammation and fibrosis progression in the liver were attenuated compared to those on the standard iHFC diet. Notably, hepatocyte ballooning was significantly improved in the CA(-) iHFC diet group. The expression levels of genes associated with inflammation and fibrosis were lower in the livers of CA(-) iHFC diet-fed mice compared to those fed the iHFC diet. Furthermore, there were no significant changes in the proportion and number of monocyte-derived macrophages in the livers of CA(-) iHFC diet-fed mice relative to those in the ND (normal diet)-fed group. The co-localization of CD11c macrophages with collagen fibers in the livers of CA(-) iHFC diet-fed mice did not significantly differ from that of the ND-fed group. Moreover, the CA(-) iHFC-fed mice exhibited a distinct microbial composition relative to both ND- and iHFC-fed mice. Finally, the increase in deoxycholic acid in fecal samples and the reduced hepatic expression of Cyp27a1 and Cyp7a1 induced by the iHFC diet were less in the CA(-) iHFC-fed group. These results suggest that CA modulates iHFC diet-induced MASH development by influencing the accumulation of monocyte-derived macrophages in the liver and shaping the gut microbiota composition and bile acid profile.
基于高脂肪/胆固醇/胆酸盐的（iHFC）饮食会在津村-铃木非肥胖（TSNO）小鼠中诱发病理变化，类似于人类代谢功能障碍相关脂肪性肝炎（MASH），并伴有晚期肝纤维化。在本研究中，我们调查了胆酸（CA）在iHFC饮食诱导的MASH发展中的作用。在接受不含CA的iHFC饮食（CA(-) iHFC饮食）的小鼠中，与标准iHFC饮食组相比，肝脏中的小叶炎症和纤维化进展均有所减轻。值得注意的是，CA(-) iHFC饮食组的肝细胞气球样变得到了显著改善。与喂食iHFC饮食的小鼠相比，喂食CA(-) iHFC饮食的小鼠肝脏中与炎症和纤维化相关的基因表达水平较低。此外，相对于喂食正常饮食（ND）的组，喂食CA(-) iHFC饮食的小鼠肝脏中单核细胞衍生巨噬细胞的比例和数量没有显著变化。喂食CA(-) iHFC饮食的小鼠肝脏中CD11c巨噬细胞与胶原纤维的共定位与喂食ND的组没有显著差异。此外，相对于喂食ND和iHFC的小鼠，喂食CA(-) iHFC的小鼠表现出独特的微生物组成。最后，CA(-) iHFC喂食组粪便样本中脱氧胆酸的增加以及iHFC饮食诱导的肝脏中Cyp27a1和Cyp7a1表达的降低较少。这些结果表明，CA通过影响单核细胞衍生巨噬细胞在肝脏中的积累以及塑造肠道微生物群组成和胆汁酸谱来调节iHFC饮食诱导的MASH发展。
