霉酚酸酯
医学
毒性
胆酸
霉酚酸
药理学
维生素D与神经学
胆汁酸
骨化三醇受体
肠道菌群
胃肠道
内科学
免疫学
移植
作者
Song Zeng,Wei Lv,Yan Xu,Zijian Zhang,Song Zeng,Weixun Zhang,Lian Gong,Limei Shao,Min Zhang,He Tian,Yingying Liu,Yuxuan Wang,Ling Liu,Xiaopeng Hu
标识
DOI:10.1016/j.ajt.2024.02.029
摘要
Abstract
Mycophenolate mofetil (MMF) is one of the most used immunosuppressive drugs in organ transplantation, but frequent gastrointestinal (GI) side effects through unknown mechanisms limit its clinical use. Gut microbiota and its metabolites were recently reported to play a vital role in MMF-induced GI toxicity, but the specific mechanism of how they interact with the human body is still unclear. Here, we found that secondary bile acids (BAs), as bacterial metabolites, were significantly reduced by MMF administration in the gut of mice. Microbiome data and fecal microbiota transfer model supported a microbiota-dependent effect on the reduction of secondary BAs. Supplementation of the secondary BA lithocholic acid (LCA) alleviated MMF-induced weight loss, colonic inflammation, and oxidative phosphorylation damage. Genetic deletion of the vitamin D3 receptor (VDR), which serves as a primary colonic BA receptor, in colonic epithelial cells (VDRΔIEC) abolished the therapeutic effect of LCA on MMF-induced GI toxicity. Impressively, we discovered that paricalcitol, an FDA-approved VDR agonist that has been used in clinics for years, could effectively alleviate MMF-induced GI toxicity. Our study reveals a previously unrecognized mechanism of gut microbiota, BAs, and VDR signaling in MMF-induced GI side effects, offering potential therapeutic strategies for clinics.
科研通智能强力驱动
Strongly Powered by AbleSci AI