Mechanisms of Protection by Commensal Fungi in Colitis

项目概要/摘要 哺乳动物的肠道内有多种细菌群落。之间的交互 肠道微生物区系和肠道免疫系统对于在肠道和肠道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。虽然有一些研究报告说， 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，它们与人类和小鼠粪便中的真菌DNA的相互作用， 肠道免疫系统尚未被研究。我们最近报道了一个丰富的和高度多样化的 真菌物种的群体（肠道真菌生物群）是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， 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，并非所有的真菌都是“坏”的。我们发现一种老鼠的肌肉组织 扣囊拟大蚊（S. fibuligera ID 1）对DSS-1小鼠的肠道炎症具有保护作用。 结肠炎模型。长期以来，人们就知道某些种类的肠道细菌可以调节粘膜 免疫应答，决定了Th 1、Th 2、Th 17和Treg细胞之间的平衡，并已被广泛用于 预防和治疗肠道疾病。只有少数研究报告说，真菌可以有类似的 保护特性，尽管这种“保护”背后的机制在很大程度上是未知的。这项建议 重点是定义保护性肠道真菌和他们的保护机制，通过研究他们的相互作用， 细菌和肠上皮以及肠道中的先天性和适应性免疫系统。 我们假设肠道真菌与肠道细菌和粘膜免疫系统相互作用， 诱导致耐受性机制，从而抑制肠道炎症和结肠炎。 我们将在三个具体目标中检验我们的假设。在具体目标1中，我们将评估 使用DSS诱导的结肠炎的小鼠模型，对真菌的保护特性进行了研究。在具体目标2中，我们将扩展 分析了S. fibuligera ID 1和其他真菌在靶向结肠炎不同分支的模型中的作用 病原学包括T细胞介导的和感染性微生物介导的疾病。在第三章中，我们将探索 保护机制，包括真菌诱导的细菌微生物组的改变， 真菌与肠上皮和先天免疫系统的关系，以及肠内T细胞偏好的调节。

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.