Investigating Immune-Microbiome interactions during treatment of Clostridioides difficile with fecal microbiome transplantation

项目摘要 接受抗生素治疗的住院患者经历肠道微生物群的破坏 使艰难梭状芽胞杆菌等机会性病原体能够在肠道内定居。并发症 艰难梭菌引起的疾病是医疗保健系统的主要负担， 估计为10亿美元，每年导致12,000-20,000人死亡(11，13)。当前使用的抗生素 治疗方案复发率高，凸显了制定替代治疗策略的必要性。 粪便微生物组移植(FMT)已被证明是一种治疗慢性粒细胞白血病的显著有效策略。 艰难梭菌反复感染(21例)。然而，导致FMT成功的宿主和微生物因素 仍然没有明确的定义。艰难梭菌感染的小鼠模型提供了对艰难梭菌作用机制的洞察 FMT。这项提案中提供的数据显示了宿主免疫系统的重要作用， 特别是CD4T调节(Treg)细胞，支持FMT的疗效。在本提案的目标1中，我们将 研究Treg细胞塑造肠道环境的免疫调节机制 促进FMT植入和艰难梭菌溶解。相反，目标2将评估先天免疫 影响肠道环境以抑制FMT植入和艰难梭菌的炎性介质 决议。在老鼠研究的同时，我们将对人类免疫细胞群体进行纵向分析 艰难梭菌严重感染患者在FMT前后。这些目标将确定免疫机制， 支持艰难梭菌感染的成功的FMT治疗，并有可能在 治疗艰难梭菌相关疾病。 1

Project Summary Hospitalized patients receiving antibiotic treatment experience a disruption in the intestinal microbiome enabling opportunistic pathogens, such as Clostridioides difficile to colonize the intestinal tract. Complications resulting from C. difficile associated disease are a major burden on the health care system costing an estimated one billion dollars and resulting in 12,000-20,000 deaths per year (11, 13). Current antibiotic treatment options have a high recurrence rate highlighting the need to develop alternative treatment strategies. Fecal microbiome transplantation (FMT) has proven to be a remarkable effective strategy for treatment of recurrent C. difficile infection (21). However, the host and microbial factors that contribute to FMT success remain poorly defined. The murine model of C. difficile infection offers insights into the mechanism of action of FMT. Data presented in this proposal demonstrates an important role for the host’s immune system, specifically CD4+ T-regulatory (TReg) cells, in supporting FMT efficacy. In aim 1 of this proposal we will investigate the immunoregulatory mechanisms through which TReg cells shape the intestinal environment to promote FMT engraftment and C. difficile resolution. Conversely, aim 2, will assess the innate immune inflammatory mediators that shape the intestinal environment to inhibit FMT engraftment and C. difficile resolution. In parallel to murine studies, we will conduct longitudinal profiling of human immune cell populations in severe C. difficile infected patients before and after FMT. These aims will identify immune mechanisms that support successful FMT therapy in C. difficile infection and potentially identify novel therapeutic targets in treating C. difficile associated disease. 1