Mechanisms of Protection by Commensal Fungi in Colitis

结肠炎中共生真菌的保护机制

• 批准号: 8635702
• 负责人: ILIYAN Dimitrov ILIEV
• 金额: $ 9万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-04 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8635702
• 关键词: Acute; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antifungal Agents; Antigens; Arts; Bacteria; Cell Wall; Cells; Citrobacter rodentium; Colitis; Colon; Communities; Data; Development; Disease; Equilibrium; Etiology; Evaluation; Exhibits; Feces; Fungal DNA; Glucans; Health; Homeostasis; Host Defense Mechanism; Human; Immune; Immune response; Immune system; Immunity; Immunologic Receptors; Indigenous; Infection; Inflammatory; Inflammatory disease of the intestine; Intestinal Diseases; Intestines; Lead; Life; Mediating; Microbe; Modeling; Molecular; Mucosal Immune Responses; Mus; Mycoses; Natural Immunity; Pathway interactions; Pharmaceutical Preparations; Population; Population Heterogeneity; Predisposition; Prevention; Property; Rag1 Mouse; Regulatory T-Lymphocyte; Reporting; Research; Role; Saccharomyces; Saccharomyces cerevisiae; Saccharomycopsis; Supplementation; System; T cell regulation; T-Lymphocyte; Technology; Testing; Tissues; adaptive immunity; arm; commensal microbes; dectin 1; deep sequencing; fungus; gut microflora; intestinal epithelium; intestinal homeostasis; microbiome; microorganism; mouse model; particle; protective effect; public health relevance; response

Project summary/ abstract A diverse community of commensal bacteria colonizes the mammalian gut. Interactions between the commensal microflora and the gut immune system are critical for establishing a proper balance between immune host defense mechanisms and tissue health. Although a few studies have reported the presence of fungal DNA in human and murine feces, gut fungi have been largely overlooked and their interactions with the gut immune system have not been investigated. We have recently reported an abundant and highly diverse population of fungal species (gut mycobiome) to be a significant component of the murine intestinal microbiota. We found that gut fungi interact with the immune system through the innate immune receptor Dectin-1 and that mice lacking Dectin-1 exhibit increased susceptibility to chemically-induced colitis, which is a result of altered responses to indigenous fungi. However not all fungi are "bad". We found that a mouse commensal strain of Saccharomycopsis fibuligera (S. fibuligera ID1) was protective against intestinal inflammation in a DSS- induced model of colitis. Certain species of commensal bacteria have long been known to modulate mucosal immune responses, dictate the balance between Th1, Th2, Th17 and Treg cells and have been widely used for prevention and treatment of intestinal disorders. Only a few studies have reported that fungi can have similar protective properties, although the mechanism behind such "protection" is largely unknown. This proposal focuses on defining protective gut fungi and their mechanisms of protection by studying their interaction with bacteria and the intestinal epithelium as well as with the innate and adaptive immune systems in the gut. We hypothesize that commensal fungi interact with gut bacteria and with the mucosal immune system to induce tolerogenic mechanisms, leading to suppression of intestinal inflammation and colitis. We will test our hypothesis in three specific aims. In Specific Aim 1 we will evaluate commensal and related fungi for protective properties using a mouse model of DSS induced colitis. In Specific Aim 2 we will extend the analysis to look at protection by S. fibuligera ID1 and other fungi in models targeting different arms of colitis etiology including T cell-mediated and infectious microbe-mediated disease. In Specific Aim 3 we will explore mechanisms of protection including fungal-induced alterations in the bacterial microbiome, interaction of gut fungi with the intestinal epithelium and the innate immune system, and regulation of T cell bias in the intestine.

项目概要/摘要 哺乳动物肠道内栖息着多种共生细菌。之间的相互作用 共生微生物区系和肠道免疫系统对于在两者之间建立适当的平衡至关重要 免疫宿主防御机制和组织健康。尽管一些研究报告了存在 人类和小鼠粪便中的真菌 DNA、肠道真菌在很大程度上被忽视了，而且它们与肠道真菌的相互作用 肠道免疫系统尚未被研究。我们最近报道了丰富且高度多样化的 真菌物种（肠道菌群）种群是小鼠肠道微生物群的重要组成部分。 我们发现肠道真菌通过先天免疫受体 Dectin-1 与免疫系统相互作用，并且 缺乏 Dectin-1 的小鼠表现出对化学诱导的结肠炎的易感性增加，这是由于 对本土真菌的反应。然而，并非所有真菌都是“坏”的。我们发现小鼠共生菌株 Saccharomycopsis fibuligera (S. fibuligera ID1) 在 DSS- 中对肠道炎症具有保护作用 诱导结肠炎模型。人们早就知道某些种类的共生细菌可以调节粘膜 免疫反应，决定 Th1、Th2、Th17 和 Treg 细胞之间的平衡，并已广泛用于 预防和治疗肠道疾病。只有少数研究报道真菌可以具有类似的功能 保护特性，尽管这种“保护”背后的机制很大程度上未知。这个提议 重点是通过研究它们与肠道真菌的相互作用来定义保护性肠道真菌及其保护机制。 细菌和肠上皮以及肠道中的先天性和适应性免疫系统。 我们假设共生真菌与肠道细菌和粘膜免疫系统相互作用， 诱导耐受机制，从而抑制肠道炎症和结肠炎。 我们将在三个具体目标上检验我们的假设。在具体目标 1 中，我们将评估共生性和相关性 使用 DSS 诱导的结肠炎小鼠模型研究真菌的保护特性。在具体目标 2 中，我们将扩展 分析以观察 S. fibuligera ID1 和其他真菌在针对不同结肠炎分支的模型中的保护作用 病因包括 T 细胞介导的疾病和感染性微生物介导的疾病。在具体目标 3 中，我们将探讨 保护机制，包括真菌引起的细菌微生物组改变、肠道相互作用 真菌与肠上皮和先天免疫系统的关系，以及肠道中 T 细胞偏向的调节。