The Intestinal Mycobiome and IBD

肠道真菌组和 IBD

• 批准号: 10579839
• 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/10579839
• 关键词: Affect; Antibiotics; Antifungal Therapy; Bacteria; Biological; Blocking Antibodies; C57BL/6 Mouse; Candida; Candida albicans; Candida tropicalis; 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; IL17 gene; Ileitis; Immune response; Immunocompromised Host; In Vitro; Individual; Infection; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intestines; Intraperitoneal Injections; Knowledge; Link; Lymphocyte; Mediating; Metagenomics; Microbe; Molecular; Mucins; Mus; Mycoses; Outcome Measure; Patients; Phenotype; Population; Predisposition; Public Health; Resources; Ribosomal RNA; Role; Ruminococcus; Saccharomycopsis; Sampling; Sodium Dextran Sulfate; T-Lymphocyte Subsets; Testing; Yeasts; antimicrobial; 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.

项目总结 克罗恩病(CD)是一个重大的公共卫生挑战，有100多万人 在美国受到这种情况的影响。到目前为止，还没有完全治愈CD的方法。CD有一个多因素的 病因学，以环境和遗传因素之间复杂的相互作用为特征，特别是 受基因影响的个体对共生微生物的不适当炎症反应。 真菌感染 是最严重的健康危害之一，尤其是对免疫功能低下的患者。 C 念珠菌病 在全球范围内急剧增加，特别是在中性粒细胞减少的患者或肠道微生物群改变的患者中 由于抗生素使用量的增加。我们团队最近进行的研究表明，丰富的 CD患者中热带毛滴虫的感染率明显高于其未患病的一级亲属。C。 热带和白色念珠菌被认为是最常见的致病真菌，是人类的一部分。 共生植物区系。热带念珠菌和白色念珠菌常见于胃肠道。然而， 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， 有必要进行机制研究，以描述念珠菌感染的分子机制 感染可能导致CD的恶化。这里提出的研究利用了一种独特的资源，即 自发性CD样回肠炎小鼠模型(SAMP1/YitFc或SAMP)的研究 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，C57BL/6(B6) 感染热带毛滴虫的小鼠更容易患上葡聚糖硫酸钠(DSS)- 诱导的结肠炎与未感染的小鼠相比，关键的Th1反应的基因表达增加- 相关基因，如肿瘤坏死因子和干扰素，以及Th2应答相关基因的表达减少，如 IL-4和IL-13。对感染和未感染小鼠粪便样本的16S rRNA分析表明，C. 热带菌显著改变了B6小鼠的微生物群，增加了粘蛋白的丰度 降解菌，如Akkermansia(A.)粘液球菌和瘤胃球菌(R.)格纳夫斯。 基于ITS 生物学效应，我们假设假丝酵母菌感染可能改变肠道微生物群落，导致 生物失调，反过来，增加宿主患IBD的易感性，或在CD患者中引发红斑。这个 这项提案的目标是：(1)证明念珠菌感染有助于实验性肠道恶化 炎症；以及(2)确定导致肠道增加的特定微生物和机制 B6和SAMP小鼠的炎症反应。了解念珠菌病影响肠道的机制 微生物组是维持CD患者缓解和设计新的抗菌疗法的关键 提高疗效，减少副作用。