肠道F.prausnitzii通过FXR对抗NF-κB抑制CDI炎症的机制研究

The interaction between gut microbiota and bile acid (BA) metabolism plays important role in the pathogenesis of Clostridium difficile infection (CDI), however, the mechanism is unclear. Our previous data showed that F. prausnitzii (Fp), an anti-inflammatory symbiotic bacteria riches in intestinal tract of healthy people, was decreased significantly in the intestinal tract of CDI children; fecal microbiota transplantation (FMT) could significantly increase the abundance of Fp in the intestinal tract of CDI children and improve the metabolism of bile acid; the increase of Fp abundance was positively correlated with the therapeutic effect of FMT on CDI. We hypothesize that Fp can regulate intestinal bile acid metabolism, restore normal gut microbiota composition, and intestinal immune balance to cure CDI. In this proposed study, we are going to study the therapeutic effect of Fp on CDI mice model induced by antibiotic exposure; the effect of Fp on bile acid metabolism and the mechanism of bile acid in inhibiting intestinal inflammation in CDI mice; and to investigate the molecular mechanism of Fp in regulating bile acid metabolism and curing CDI by FXR gene knockout mice. Our study will provide experimental evidences to reveal the roles of Fp in the pathogenesis of CDI, and suggest the potential application of symbiotic bacteria-based CDI treatment in the future.

肠道菌群与胆汁酸代谢的相互作用参与艰难梭菌感染（CDI）的发生发展过程，但其作用机制尚不明确。我们的前期研究发现健康人肠道含量丰富的抗炎共生菌F. prausnitzii（Fp）在CDI儿童肠道中显著减少；粪菌移植（FMT）可显著增加CDI儿童肠道Fp的丰度和改善肠道胆汁酸代谢；Fp丰度的增加与FMT治疗CDI效果呈正相关。我们假说Fp可调节肠道胆汁酸代谢，恢复正常肠道菌群组成与肠道免疫平衡来治疗CDI。本项目将以抗生素暴露诱导的CDI小鼠模型来研究Fp对CDI的治疗作用；研究Fp对CDI小鼠胆汁酸代谢的影响，以及胆汁酸抑制CDI炎症的作用与机制；并通过法尼醇衍生物X受体（FXR）基因敲除小鼠探讨Fp调节胆汁酸代谢激活FXR信号通路治疗CDI的细胞分子机制，为揭示Fp在CDI发生发展中的重要作用提供理论依据，为开发可调节肠道菌群平衡和胆汁酸代谢治疗CDI的益生菌提供实验基础。

儿童艰难梭菌感染（Clostridium difficile infection, CDI）的发病率呈逐年上升趋势，给全球公共卫生带来严重负担，利用艰难梭菌基因型可用来追踪其传播模式。艰难梭菌被成为病原监测和流行病学研究的重点，尤其儿童艰难梭菌研究较成人少，需引起临床医生的重视。特殊的艰难梭菌菌株可能与临床严重程度、是否复发和/或抗生素耐药性有关，但特定的基因型并不总是与疾病的严重程度明确相关。肠道菌群与胆汁酸代谢的相互作用参CDI的发生发展过程，但其作用机制尚不明确。本项目以抗生素暴露诱导的CDI小鼠模型来研究Fp对CDI的治疗作用，探讨Fp参与调节CDI的炎症过程，通过儿童艰难梭菌的基因分型、耐药及毒力特点，了解儿童CDI的流行情况，为CDI的治疗开辟新思路，并探索儿童艰难梭菌基因分型与耐药机制及临床结局的关系，为指导儿童CDI的治疗和预后评估提供依据。