拟杆菌属缓解肝纤维化的作用可能是通过调节雄性小鼠肠道胆汁酸代谢和肝细胞焦亡实现的。

Parabacteroides distasonis ameliorates hepatic fibrosis potentially via modulating intestinal bile acid metabolism and hepatocyte pyroptosis in male mice.

机构信息

Laboratory of Metabolomics and Drug-Induced Liver Injury, Department of Gastroenterology & Hepatology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China.

State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China.

出版信息

Nat Commun. 2023 Apr 1;14(1):1829. doi: 10.1038/s41467-023-37459-z.

DOI:10.1038/s41467-023-37459-z

PMID:37005411

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10067939/

Abstract

Parabacteroides distasonis (P. distasonis) plays an important role in human health, including diabetes, colorectal cancer and inflammatory bowel disease. Here, we show that P. distasonis is decreased in patients with hepatic fibrosis, and that administration of P. distasonis to male mice improves thioacetamide (TAA)- and methionine and choline-deficient (MCD) diet-induced hepatic fibrosis. Administration of P. distasonis also leads to increased bile salt hydrolase (BSH) activity, inhibition of intestinal farnesoid X receptor (FXR) signaling and decreased taurochenodeoxycholic acid (TCDCA) levels in liver. TCDCA produces toxicity in mouse primary hepatic cells (HSCs) and induces mitochondrial permeability transition (MPT) and Caspase-11 pyroptosis in mice. The decrease of TCDCA by P. distasonis improves activation of HSCs through decreasing MPT-Caspase-11 pyroptosis in hepatocytes. Celastrol, a compound reported to increase P. distasonis abundance in mice, promotes the growth of P. distasonis with concomitant enhancement of bile acid excretion and improvement of hepatic fibrosis in male mice. These data suggest that supplementation of P. distasonis may be a promising means to ameliorate hepatic fibrosis.

摘要

拟杆菌属（Parabacteroides）中的迪斯托拟杆菌（P. distasonis）在人类健康中发挥着重要作用，包括糖尿病、结直肠癌和炎症性肠病。在这里，我们表明迪斯托拟杆菌在肝纤维化患者中减少，并且给予雄性小鼠迪斯托拟杆菌可改善硫代乙酰胺（TAA）和蛋氨酸胆碱缺乏（MCD）饮食诱导的肝纤维化。迪斯托拟杆菌的给予还导致胆汁盐水解酶（BSH）活性增加、抑制肠道法尼醇 X 受体（FXR）信号传导和肝脏中牛磺胆酸（TCDCA）水平降低。TCDCA 在小鼠原代肝细胞（HSCs）中产生毒性，并诱导小鼠线粒体通透性转换（MPT）和 Caspase-11 焦亡。迪斯托拟杆菌通过减少 HSCs 中的 MPT-Caspase-11 焦亡来改善 HSCs 的激活。化合物塞拉菌素被报道可增加小鼠中迪斯托拟杆菌的丰度，它促进迪斯托拟杆菌的生长，同时增强胆汁酸排泄，并改善雄性小鼠的肝纤维化。这些数据表明，补充迪斯托拟杆菌可能是改善肝纤维化的一种有前途的方法。