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

研究粪便微生物组移植治疗艰难梭菌期间免疫-微生物组的相互作用

• 批准号: 10343845
• 负责人: Michael C. Abt
• 金额: $ 47.62万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-05 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10343845
• 关键词: Ablation; Adoptive Transfer; Antibiotic Therapy; Bacteria; Bile Acids; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Shape; Cells; Cessation of life; Clinical; Clostridium difficile; Complement; Complex; Data; Diarrhea; Disease; Economic Burden; Engraftment; Environment; Exhibits; FOXP3 gene; Failure; Genotype; Health Care Costs; Healthcare Systems; Human; Immune; Immune Targeting; Immune system; Impairment; Incidence; Infection; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-10; Intestines; Longitudinal Studies; Mediating; Mediator of activation protein; Medical Economics; Mus; Nitrogen; Nosocomial Infections; Oxygen; Pathway interactions; Patients; Pharmacology; Population; Production; Rag1 Mouse; Recombinants; Recurrence; Regulatory T-Lymphocyte; Reporter; Resolution; Role; Severities; Shapes; Signal Transduction; Source; Testing; Therapeutic; Toxic Megacolon; Transplantation; Treatment Protocols; United States; Work; alternative treatment; base; cohort; cost estimate; cytokine; disorder control; enteric pathogen; experience; fecal transplantation; gain of function; gut colonization; gut inflammation; gut microbiome; immune activation; immunological status; immunoregulation; impaired capacity; insight; loss of function; metabolome; metabolomics; microbial; microbial community; microbiome; microbiota; monocyte; mouse model; neutrophil; new therapeutic target; novel therapeutics; opportunistic pathogen; prevent; success; transplantation therapy; treatment strategy

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

项目概要 接受抗生素治疗的住院患者肠道微生物群受到破坏 使机会性病原体（例如艰难梭菌）在肠道定殖。 由艰难梭菌相关疾病引起的疾病是医疗保健系统的主要负担，造成了巨大的损失 估计花费 10 亿美元，每年导致 12,000-20,000 人死亡 (11, 13)。 治疗方案的复发率很高，凸显了开发替代治疗策略的必要性。 粪便微生物组移植（FMT）已被证明是治疗以下疾病的一种非常有效的策略： 复发性艰难梭菌感染 (21) 然而，有助于 FMT 成功的宿主和微生物因素。 艰难梭菌感染的小鼠模型仍不清楚。 该提案中提供的数据表明了宿主免疫系统的重要作用， CD4+ T 调节性 (TReg) 细胞，支持 FMT 功效 在本提案的目标 1 中，我们将具体说明。 研究 TReg 细胞塑造肠道环境的免疫调节机制 促进 FMT 植入和离线艰难梭菌消退，目标 2 将评估先天免疫。 炎症介质塑造肠道环境，抑制 FMT 植入和艰难梭菌 与小鼠研究并行，我们将对人类免疫细胞群进行纵向分析。 这些目标将确定 FMT 前后的严重艰难梭菌感染患者的免疫机制。 支持艰难梭菌感染的成功 FMT 治疗，并可能确定新的治疗靶点 治疗艰难梭菌相关疾病。 1