The Intestinal Mycobiome and IBD

肠道真菌组和 IBD

• 批准号: 10337333
• 负责人: Luca Di Martino
• 金额: $ 12.18万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10337333
• 关键词: Affect; Antibiotics; Antifungal Therapy; Bacteria; Biological; Blocking Antibodies; Candida; Candidiasis; Colitis; Colonoscopy; Communities; Complex; Coupled; Crohn' s disease; Data; Development; Disease remission; Etiology; First Degree Relative; Flare; Flow Cytometry; Functional disorder; Gastrointestinal tract structure; Gene Expression; Genes; Genetic; Germ-Free; Goals; Health Hazards; Histology; Human; Ileitis; Immune response; Immunocompromised Host; In Vitro; Individual; Infection; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Interleukin-17; Intestines; Intraperitoneal Injections; Knowledge; Link; Lymphocyte; Mediating; Metagenomics; Microbe; Molecular; Mucins; Mus; Mycoses; Outcome Measure; Patients; Phenotype; Play; Population; Predisposition; Public Health; Resources; Ribosomal RNA; Role; Ruminococcus; Saccharomycopsis; Sampling; Sodium Dextran Sulfate; T-Lymphocyte Subsets; Testing; Yeasts; antimicrobial; base; chemically induced colitis; commensal microbes; design; dextran sulfate sodium induced colitis; dysbiosis; experimental group; experimental study; germ free condition; gut inflammation; gut microbiome; human data; improved; in vivo; mesenteric lymph node; microbiome alteration; microbiome composition; mouse model; mycobiome; nano-string; novel; pathogenic fungus; response; side effect

PROJECT SUMMARY Crohn’s disease (CD) represents a significant public health challenge with more than 1 million individuals affected by this condition in the US. To date, a complete cure of CD is not available. CD has a multifactorial etiology, characterized by a complex interplay between environmental and genetic factors, particularly an inappropriate inflammatory response to commensal microbes in genetically affected individuals. Fungal infection represents one of the most serious health hazards, especially for immuno-compromised patients. C andidiasis has dramatically increased worldwide, especially in neutropenic patients or patients with altered gut microbiome due to increased antibiotic use. Recent studies performed by our group have demonstrated that the abundance C. tropicalis is significantly higher in patients with CD compared to their non-diseased first-degree relatives. C. tropicalis and C. albicans have been recognized as the most common pathogenic fungi and are part of the human commensal flora. C. tropicalis and C. albicans are commonly found in the gastrointestinal tract. However, the role of Candida infections in intestinal inflammation in patients with CD has not been fully elucidated. Therefore, there is a need for mechanistic studies aimed at delineating the molecular mechanisms by which Candida infection may result in exacerbation of CD. Studies proposed herein take advantage of a unique resource, a spontaneous murine model of CD-like ileitis (SAMP1/YitFc or SAMP), to decipher the mechanistic role of candidiasis in experimental ileitis. Strong preliminary data from our group have demonstrated that C57BL/6 (B6) mice infected with C. tropicalis are significantly more susceptible to develop dextran sodium sulfate (DSS)- induced colitis compared to uninfected littermates, with increased gene expression of key Th1 response- associated genes, such as Tnf and Ifn, and decreased expression of Th2 response-associated genes, such as Il4 and Il13. 16S rRNA analysis of fecal samples from infected and uninfected mice have shown that C. tropicalis significantly altered the microbiome population of B6 mice, with increased abundance of mucin degrading bacteria, such as Akkermansia (A.) muciniphila and Ruminococcus (R.) gnavus. Based on its biological effects, we hypothesized that Candida infection may alter the gut microbiome community resulting in dysbiosis that, in turn, increases the susceptibility of the host to develop IBD, or triggers flare in CD patients. The goals of this proposal are: (1) demonstrate that Candida infections contribute to worsen experimental intestinal inflammation; and (2) identify the specific microbes and mechanisms responsible for the increased intestinal inflammation in B6 and SAMP mice. Understanding the mechanisms by which candidiasis affects the gut microbiome is essential to maintain remission in CD patients and the design of novel antimicrobial therapies with increased efficacy and decreased side-effects.

项目摘要 克罗恩病（CD）是一项重大的公共卫生挑战，感染人数超过100万 在美国受到这种情况的影响。到目前为止，CD的完全治愈还没有。CD具有多因素 病因学，以环境和遗传因素之间的复杂相互作用为特征，特别是 对肠道微生物的不适当的炎症反应。 真菌感染 是最严重的健康危害之一，特别是对于免疫功能低下的患者。 C 虫体病 在全球范围内急剧增加，特别是在贫血患者或肠道微生物组改变的患者中 由于抗生素使用的增加。我们小组最近的研究表明， C.与其未患病的一级亲属相比，CD患者中的Tropicalis显著更高。C. tropicalis和C.白色念珠菌被认为是最常见的致病真菌， 水生植物群。C. tropicalis和C.白色念珠菌常见于胃肠道。但 念珠菌感染在CD患者肠道炎症中的作用尚未完全阐明。因此，我们认为， 需要进行机制研究，旨在阐明念珠菌感染的分子机制， 感染可导致CD恶化。本文提出的研究利用了一种独特的资源， CD样回肠炎的自发鼠模型（SAMP 1/YitFc或SAMP），以解释 实验性回肠炎中的念珠菌病来自我们小组的强有力的初步数据表明，C57 BL/6（B6） 感染C.热带的人更容易产生葡聚糖硫酸钠（DSS）- 与未感染的同窝仔相比，诱导的结肠炎，关键Th 1反应的基因表达增加- 相关基因，如TNF α和IFN α，以及Th 2应答相关基因，如 如I14和I13。对感染和未感染小鼠粪便样品的16 S rRNA分析表明，C. tropicalis显著改变了B6小鼠的微生物群，增加了粘蛋白的丰度 降解菌如阿克曼氏菌（A.）muciniphila和Ruminococcus（R.）gnavus。 基于其 生物学效应，我们假设念珠菌感染可能会改变肠道微生物群落， 这反过来增加了宿主发展IBD的易感性，或触发CD患者的发作。的 本提案的目的是：（1）证明念珠菌感染有助于恶化实验性肠道 炎症;（2）确定负责增加肠道炎症的特定微生物和机制 在B6和SAMP小鼠中的炎症。了解念珠菌病影响肠道的机制 微生物组对于维持CD患者的缓解至关重要， 提高疗效，减少副作用。