Mechanisms of fungal involvement during intestinal disease

肠道疾病期间真菌参与的机制

• 批准号: 10358640
• 负责人: June Louise Round
• 金额: $ 44.93万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-08 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10358640
• 关键词: Address; Affect; Allopurinol; Animals; Antibodies; Archaea; Area; Autophagocytosis; Cell Wall; Cells; Clinical; Colitis; Communities; Complex; Crohn' s disease; Data; Defect; Development; Diagnostic; Disease; Disease Progression; Environmental Risk Factor; Epithelial; Exposure to; Genes; Genetic; Genetic Polymorphism; Genetic Risk; Health; Human; Immune; Immune response; Immune system; Immunity; Immunology; Individual; Inflammatory Bowel Diseases; Intestinal Diseases; Intestines; Knowledge; Lead; Link; Literature; Maintenance; Metabolic Pathway; Metabolism; Microbe; Molecular; Mucous Membrane; Mutation; Myelogenous; Myeloid Cells; Pathway interactions; Patient Care; Patients; Permeability; Pharmaceutical Preparations; Physiology; Play; Population; Process; Production; Publishing; Purines; Reporting; Research Personnel; Role; Saccharomyces cerevisiae; Serum; Severity of illness; Signal Transduction; Susceptibility Gene; Testing; Up-Regulation; Uric Acid; Viral; Work; Yeasts; commensal microbes; dectin 1; diagnostic tool; disorder risk; experimental study; fungal genetics; fungal microbiota; fungus; genetic risk factor; gut health; high risk; human microbiota; improved; intestinal epithelium; intestinal homeostasis; member; microbiota; mycobiome; neglect; purine metabolism; receptor; response; therapeutic target; trafficking

Abstract The commensal microbiota has important impacts on host physiology and health that are only beginning to be elucidated. Most current studies, however, have focused only on the bacterial microbiota despite the presence of fungal, archaeal and viral members. The presence of anti-Saccharomyces cerevisiae (ASCA) antibodies serves as a diagnostic tool for Crohn’s disease (CD) and suggests that fungal members of the microbiota contribute to disease severity. Moreover, common genetic polymorphisms identified in individuals with IBD, such as Nod2, Dectin-1, and Card9 are known to recognize fungal cell wall components. We have recently demonstrated that one of the most prominent members of the mycobiota, S. cerevisiae, can exacerbate intestinal colitis through upregulation of host purine metabolism in the gut. The end product of purine metabolism in humans is uric acid. Recent studies have demonstrated that uric acid can have significant impacts on autophagy. Coincidentally, many of the genes associated with IBD in humans, impact autophagic processes. There is a significant body of clinical literature that links autophagy, yeast, and uric acid production, yet these relationships have yet to be explored. Here we propose to identify how fungal members of the microbiota induce purine metabolism from intestinal epithelia and determine how purine metabolism influences intestinal immunity to worsen disease. We have brought together an inter-disciplinary team of investigators with combined expertise in autophagy, fungal genetics and mucosal immunology to explore how yeast can functionally influence intestinal disease.

摘要 肠道微生物群对宿主生理和健康具有重要影响，这些影响才刚刚开始。 阐明。然而，目前的大多数研究都只关注细菌微生物群， 真菌、古菌和病毒的成员。抗酿酒酵母（ASCA）抗体的存在 作为克罗恩病（CD）的诊断工具，并表明微生物群中的真菌成员 有助于疾病的严重性。此外，在IBD个体中鉴定的常见遗传多态性， 例如Nod 2、Dectin-1和Card 9已知识别真菌细胞壁组分。我们最近 证明了真菌生物群中最重要的成员之一，S.酿酒酵母，可以加剧 通过上调肠道中宿主嘌呤代谢而导致肠结肠炎。嘌呤的终产物 尿酸是人体的代谢产物。最近的研究表明，尿酸可以有显着的 对自噬的影响巧合的是，许多与人类IBD相关的基因， 流程.有大量的临床文献将自噬、酵母和尿酸产生联系起来， 然而，这些关系还有待探讨。在这里，我们提出要确定如何真菌成员的 微生物群诱导肠上皮细胞的嘌呤代谢，并确定嘌呤代谢如何影响 肠道免疫恶化疾病。我们召集了一个跨学科的调查小组 结合自噬，真菌遗传学和粘膜免疫学的专业知识，探索酵母如何 功能性影响肠道疾病。