The Intestinal Mycobiome and IBD

肠道真菌组和 IBD

• 批准号: 10154754
• 负责人: Luca Di Martino
• 金额: $ 12.33万
• 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/10154754
• 关键词: Affect; Antibiotics; Antifungal Therapy; Bacteria; Biological; Blocking Antibodies; Candida; Candidiasis; Chemicals; 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; commensal microbes; design; dextran sulfate sodium induced colitis; dysbiosis; experimental group; experimental study; germ free condition; gut microbiome; human data; improved; in vivo; inflammatory disease of the intestine; 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）代表了超过100万人的重大公共卫生挑战 在美国受到这种情况的影响。迄今为止，尚无CD的完整治疗。 CD具有多因素 病因，其特征是环境和遗传因素之间的复杂相互作用，尤其是 对受遗传影响个体的共生微生物的不当炎症反应。 真菌感染 代表最严重的健康危害之一，尤其是对于免疫受损的患者。 c Andidiasis 在全球范围内急剧增加，尤其是中立患者或肠道微生物组改变的患者 由于抗生素的使用增加。我们小组进行的最近进行的研究表明，抽象 与非疾病的一级亲属相比，CD患者的热带梭菌明显更高。 C 热带和白色念珠菌已被认为是最常见的致病真菌，是人类的一部分 Comensal Flora。 C. tropicalis和C. bilicans通常在胃肠道中发现。但是， 念珠菌感染在CD患者肠道感染中的作用尚未完全阐明。所以， 需要进行机械研究，以描述念珠菌的分子机制 感染可能导致CD恶化。本文提出的研究利用了独特的资源 CD样回肠炎（SAMP1/YITFC或SAMP）的赞助鼠模型，以破译机械作用 实验性回肠炎的念珠菌病。来自我们小组的强大初步数据表明C57BL/6（B6） 感染了热带梭菌的小鼠更容易发生硫酸钠（DSS） - 与未感染的同窝仔相比，诱导结肠炎，密钥Th1反应的基因表达增加 相关基因，例如TNF和IFN，并扩大了与Th2响应相关基因的表达，此类 如IL4和IL13。对感染和未感染小鼠的粪便样品的16S rRNA分析表明C. 热带症显着改变了B6小鼠的微生物组群体，并增加了粘蛋白的丰度 降解细菌，例如akkermansia（A。）粘膜和ruminococcus（R。）gnavus。 基于它的 生物学影响，我们假设念珠菌感染可能会改变肠道微生物组社区，从而导致 营养不良反过来增加了宿主发展IBD或CD患者触发的敏感性。这 该提案的目标是：（1）证明念珠菌感染有助于更糟糕的实验性肠道 炎; （2）确定肠道增加的特定微生物和机制 B6和SAMP小鼠的炎症。了解念珠菌病影响肠道的机制 微生物组对于维持CD患者的缓解和设计新型抗菌疗法至关重要 提高效率和增加的副作用。