ERIN CRC: Host-microbiota-pathogen interactions govern enteric health and disease

描述（由申请人提供）：密歇根州立大学肠道研究调查网络，合作研究中心（MSU ERIN CRC）是一个多学科研究中心，旨在研究健康和疾病中的肠道微生物组，其总体目标是阐明其与最重要的全球健康问题之一的关系，即肠道疾病。MSU ERIN CRC是一个由来自多个学科的科学家组成的协同小组，包括微生物生态学，微生物学，免疫学，流行病学和工程学，与传染病，外科和儿科医生合作。我们的长期目标是确定微生物组在增强肠道疾病易感性或提供抵抗力方面的作用。我们将专注于介导肠道疾病的因素之间的关系：肠道细菌病原体，肠道微生物组，控制易感性，耐药性或自身免疫性的宿主反应。我们的总体假设是：（1）肠道微生物组保护宿主免受管腔、上皮和侵入性病原体的侵害，（2）微生物组的多样性控制扰动后的弹性，（3）群落代谢组有助于病原体侵入期间的病变，以及（4）常驻微生物群通过表现出分子模拟的细菌基序加强自身免疫应答。我们将使用（1）生物反应器和在1区和2区定植有人类微生物群的小鼠，以及（2）来自3区实验室确诊腹泻病例流行病学研究的样本来解决这些假设。在区域1，微生物生态学和发病机制中，我们的总体目标是确定（1）肠道微生物群落的多样性降低是否允许具有不同生活方式（管腔，上皮相关和侵入性）的肠道病原体在生物反应器和人源化小鼠中的人类粪便微生物群落中建立，以及（2）竞争性排斥的一般生态学原理是否控制该过程。在区域2，宿主反应中，我们的总体目标是确定具有“人源化”微生物组的鼠模型是否会发展继发于C的自发性自身免疫后遗症。空肠感染A级LOS;这些模型将用于剖析自身免疫机制，并作为GBS/MFS患者的治疗和预防替代品。在区域3，临床研究中，我们的总体目标是确定增加宿主对肠道疾病易感性的肠道微生物组的变化是否与（1）对肠道病原体活动产生负面影响的群落成员的丧失或抑制相关，或（2）与宿主相互作用以促进对肠道病原体耐药性的群落成员的丧失或抑制相关。

DESCRIPTION (provided by applicant): The Michigan State University Enterics Research Investigational Network, Cooperative Research Center (MSU ERIN CRC) is a multidisciplinary Research Center proposal to study the enteric microbiome in health and disease with the overarching objective to elucidate its relationship to one of the most important global health problems, diarrheal illness. MSU ERIN CRC is a synergistic group of scientists from multiple disciplines, including microbial ecology, microbiology, immunology, epidemiology, and engineering, with cooperation from physicians working in infectious diseases, surgery, and pediatrics. Our long term goal is to determine the role of the microbiome in enhancing susceptibility or providing resistance to enteric diseases. We will focus on relationships between factors mediating diarrheal disease: enteric bacterial pathogens, the enteric microbiome, and host responses controlling susceptibility, resistance, or autoimmunity. Our overarching hypotheses are: (1) the enteric microbiome protects the host from luminal, epithelial and invasive pathogens, (2) diversity of the microbiome controls resiliency after perturbations, (3) the community metabolome contributes to lesions during pathogen invasion, and (4) resident microbiota intensify autoimmune responses by bacterial motifs exhibiting molecular mimicry. We will address these hypotheses using (1) bioreactors and mice colonized with human microbiota in Areas 1 and 2, and (2) samples from an epidemiological study of laboratory-confirmed cases of diarrhea in Area 3. In Area 1, Microbial Ecology and Pathogenesis, our overall objectives are to determine if (1) reduced diversity of the intestinal microbial community allows enteric pathogens with different lifestyles (luminal, epithelium-associated, and invasive) to become established in human fecal microbial communities in bioreactors and humanized mice, and (2) if the general ecological principle of competitive exclusion governs this process. In Area 2, Host Response, our overall objectives are to determine if murine model(s) with a "humanized" microbiome will develop spontaneous autoimmune sequelae secondary to C. jejuni infection with class A LOS; these models will then be used to dissect mechanisms of autoimmunity and to serve as treatment and prevention surrogates for GBS/MFS patients. In Area 3, Clinical Research, our overall objectives are to determine if shifts in the intestinal microbiome that increase host susceptibility to enteric disease are associated with (1) loss or inhibition of community members that negatively impact activities of an enteric pathogen, or (2) loss or inhibition of community members that interact with the host to promote resistance to enteric pathogens.