膀胱传入神经信号异常是膀胱过度活动症（OAB）的主要发病机制之一，而膀胱上皮功能受损是介导异常传入神经信号形成的重要原因。既往研究聚焦于膀胱本身，未关注到泌尿道微环境的影响。我们发现OAB患者泌尿道存在“专性厌氧菌减少/兼性厌氧菌增多”的菌群紊乱模式及丁酸盐含量显著降低。已知丁酸盐可通过激动核受体PPAR-γ，增强上皮屏障和线粒体β氧化功能。因此提出假设：泌尿道菌群紊乱介导丁酸盐减少和PPAR-γ激动不足，造成膀胱上皮功能障碍和β氧化受损，局部微环境发生改变，从而诱发OAB。本项目拟从菌群与宿主相互作用的角度入手，在人体、动物、细胞三个层次，通过高通量测序进行菌群结构和代谢功能谱分析、分离特异菌株进行菌株移植和共培养、补充丁酸盐、调控PPAR-γ等体内外实验，进一步研究菌群紊乱介导丁酸盐减少和膀胱上皮屏障受损的具体机制，从微生态视角为阐明OAB发病机制和寻找新治疗靶标提供依据。

Abnormalities of afferent sensory nerve signaling mediated by the urothelial dysfunction is thought to be a main pathogenesis of overactive bladder (OAB). Previous researches of OAB were focus on bladder but ignored the effects of urinary tract microenvironment. In our previous work, the aberrant urinary microbiome with increased facultative anaerobes and decreased obligate anaerobes were observed distinctly in OAB patients, and we also demonstrated that butyrate concentrations in urine of OAB group were significantly decreased compared to controls. It has been known that reduction of butyrate may result in insufficient activation of PPAR-γ, inducing impaired epithelial barrier. Therefore, we propose a hypothesis that decreased butyrate mediated by aberrant urinary microbiome may cause insufficient activation of PPAR-γ and sequentially impair bladder epithelial barrier. Then infiltration of harmful substances may lead to abnormalities of afferent sensory nerve signaling and finally trigger the initiation of OAB. This project is aimed specifically at the connections between urinary microbiome and host. At human, animal, and cell levels, we plan to further study the concrete mechanism how urinary microbiome decreases butyrate and consequently impairs bladder epithelial barrier. We will perform a series of experiments in vivo and vitro, including high-throughput sequencing for the analysis of microbiome composition and metabolic function, isolating specific strains for transplantation and co-culture, supplementing with butyrate and regulating PPAR-γ and PKC signaling pathway. We hope to provide experimental and theoretical basis for clarifying the pathogenesis of OAB and finding novel therapeutic targets ultimately.