Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Sci Adv. 2022 Aug 26;8(34):eabo2794. doi: 10.1126/sciadv.abo2794.
Altered host-microbe interactions and increased intestinal permeability have been implicated in disease pathogenesis. However, the mechanisms by which intestinal microbes affect epithelial barrier integrity remain unclear. Here, we investigate the impact of bacterial metabolism of host-produced bile acid (BA) metabolites on epithelial barrier integrity. We observe that rats fed a choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD) exhibit reduced intestinal abundance of host-produced conjugated BAs at early time points, coinciding with increased gut permeability. We show that in vitro, conjugated BAs protect gut epithelial monolayers from damage caused by bacterially produced unconjugated BAs through micelle formation. We then demonstrate that inhibition of bacterial BA deconjugation with a small-molecule inhibitor prevents the development of pathologic intestinal permeability and hepatic inflammation in CDAHFD-fed rats. Our study identifies a signaling-independent, physicochemical mechanism for conjugated BA-mediated protection of epithelial barrier function and suggests that rational manipulation of microbial BA metabolism could be leveraged to regulate gut barrier integrity.
宿主-微生物相互作用的改变和肠道通透性的增加与疾病的发病机制有关。然而，肠道微生物影响上皮屏障完整性的机制尚不清楚。在这里，我们研究了细菌对宿主产生的胆汁酸（BA）代谢物的代谢作用对上皮屏障完整性的影响。我们观察到，给予胆碱缺乏、l-氨基酸定义的高脂肪饮食（CDAHFD）的大鼠在早期时间点表现出肠道中宿主产生的结合型 BA 丰度降低，同时肠道通透性增加。我们表明，在体外，结合型 BA 通过胶束形成保护肠道上皮单层免受细菌产生的未结合型 BA 引起的损伤。然后，我们证明用小分子抑制剂抑制细菌 BA 去结合可防止 CDAHFD 喂养的大鼠发生病理性肠道通透性和肝炎症。我们的研究确定了一种信号非依赖的、物理化学机制，用于结合型 BA 介导的上皮屏障功能保护，并表明合理操纵微生物 BA 代谢可以用来调节肠道屏障完整性。
