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组的破坏 使机会致病菌如艰难梭菌在肠道定植。并发症 由C.艰难梭菌相关疾病是卫生保健系统的主要负担， 估计10亿美元，每年造成12，000 - 20，000人死亡（11，13）。当前抗生素 治疗方案的复发率很高，这突出表明需要开发替代治疗策略。 粪便微生物组移植（FMT）已被证明是治疗肠道疾病的一种非常有效的策略。 复发C.艰难梭菌感染（21）。然而，有助于FMT成功的宿主和微生物因素 定义不明确。小鼠C.艰难梭菌感染提供了深入了解的作用机制， FMT。本提案中提出的数据表明了宿主免疫系统的重要作用， 特别是CD 4 + T调节（TReg）细胞，以支持FMT功效。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;艰难的决议。相反，目标2，将评估先天免疫 影响肠道环境以抑制FMT植入的炎症介质和C.艰难 分辨率在小鼠研究的同时，我们将对人类免疫细胞群进行纵向分析 严重C. FMT前后的艰难梭菌感染患者。这些目标将确定免疫机制， 支持成功的FMT治疗C。艰难梭菌感染，并可能确定新的治疗靶点， 治疗C.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