Severe Clostridiodes difficile infection (CDI) is life-threatening and responds poorly to treatment. Obesity is associated with development of severe CDI. Therefore, to define the mechanisms that exacerbate disease severity, we examined CDI pathogenesis in high-fat diet (HFD)-fed obese mice. Compared to control mice, HFD-fed mice failed to clear C. difficile bacteria which resulted in protracted diarrhea, weight loss and colonic damage. After infection, HFD-induced obese mice had an intestinal bile acid (BA) pool that was dominated by primary BAs which are known promoters of C. difficile spore germination, and lacked secondary BAs that inhibit C. difficile growth. Concurrently, synthesis of primary BAs from liver was significantly increased in C. difficile-infected HFD-fed mice. A key pathway that regulates hepatic BA synthesis is via feedback inhibition from intestinal Farnesoid X receptors (FXRs). Our data reveal that the proportion of FXR agonist BAs to FXR antagonist BAs in the intestinal lumen was significantly reduced in HFD-fed mice after CDI. Treatment of HFD-fed mice with an FXR agonist Obeticholic acid, resulted in decreased primary BA synthesis, fewer C. difficile bacteria and better CDI outcomes. Thus, OCA treatment holds promise as a therapy for severe CDI.

严重的艰难梭菌感染 (CDI) 会危及生命，并且治疗效果不佳。肥胖与严重 CDI 的发生有关。因此，为了确定加剧疾病严重程度的机制，我们研究了高脂饮食 (HFD) 喂养的肥胖小鼠的 CDI 发病机制。与对照小鼠相比，HFD 喂养的小鼠未能清除艰难梭菌，导致长期腹泻、体重减轻和结肠损伤。感染后，HFD 诱导的肥胖小鼠的肠道胆汁酸 (BA) 库以初级 BA 为主，初级 BA 是已知的艰难梭菌孢子萌发促进剂，并且缺乏抑制艰难梭菌生长的次级 BA。同时，感染艰难梭菌的 HFD 喂养小鼠肝脏中初级 BA 的合成显着增加。调节肝脏 BA 合成的关键途径是通过肠道 Farnesoid X 受体 (FXR) 的反馈抑制。我们的数据显示，在 CDI 后，HFD 喂养的小鼠肠腔中 FXR 激动剂 BA 与 FXR 拮抗剂 BA 的比例显着降低。用 FXR 激动剂奥贝胆酸治疗 HFD 喂养的小鼠，导致初级 BA 合成减少、艰难梭菌减少和 CDI 结局改善。因此，OCA 治疗有望成为治疗严重 CDI 的方法。