Mechanisms of Protection by Commensal Fungi in Colitis

项目摘要/摘要 哺乳动物肠道中有一种多样性的共生细菌群落。两国之间的互动 共生微生物区系和肠道免疫系统是建立适当平衡的关键 免疫宿主防御机制与组织健康。尽管有一些研究报告说 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，它们与 肠道免疫系统尚未得到研究。我们最近报道了一种丰富和高度多样化的 真菌种群(肠道真菌生物群)是小鼠肠道微生物区系的重要组成部分。 我们发现，肠道真菌通过天然免疫受体Dectin-1与免疫系统相互作用， 缺乏Dectin-1的小鼠对化学诱导的结肠炎的易感性增加，这是改变的结果 对本土真菌的反应。然而，并不是所有的真菌都是“坏的”。我们发现一种小鼠共栖品系 在DSS中，腓状酵母菌(S.fibuligera ID1)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 免疫应答，决定Th1、Th2、Th17和Treg细胞之间的平衡，已被广泛用于 预防和治疗肠道疾病。只有几项研究报告说真菌可以有类似的 尽管这种“保护”背后的机制在很大程度上是未知的，但这种“保护”的性质并不清楚。这项建议 重点是通过研究肠道真菌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。 细菌和肠道上皮，以及肠道中的先天和适应性免疫系统。 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，导致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，我们将评估共生和相关 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，我们将延长 在针对不同臂结肠炎的模型中观察腓肠杆菌ID1和其他真菌的保护作用的分析 病原学包括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，我们将探索 保护机制包括真菌诱导的细菌微生物群的改变、肠道的相互作用 真菌与肠道上皮和先天免疫系统有关，并调节肠道内T细胞的偏向。

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.