Targeting the Mycobiome in Genetically Defined Patients with Crohns Disease

针对基因明确的克罗恩病患者的分枝菌组

• 批准号: 10598044
• 负责人: Gil Y Melmed
• 金额: $ 63.31万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598044
• 关键词: Affect; Alleles; Antibody Formation; Antifungal Agents; Antifungal Therapy; Bacteria; Behavior; Biopsy; Blood; Blood specimen; Caring; Cell physiology; Chemistry; Chronic; Clinical; Clinical Data; Clinical Trials; Colitis; Colon; Colonoscopy; Crohn' s disease; Data; Disease; Disease model; Double-Blind Method; Epithelial Cells; Evaluation; Feces; Gastrointestinal tract structure; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Transcription; Goals; Health system; Human; Immune; Immune response; Immune system; Immunity; Immunologics; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intestinal Mucosa; Intestines; Laboratories; Link; Malassezia; Mediating; Metabolic; Minority; Mucous Membrane; Oral; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Placebos; Population; Proteins; Randomized; Reporting; Research; Ribosomal DNA; Risk; Role; Sampling; Signal Pathway; Signaling Molecule; Skin; Symptoms; Systems Analysis; T cell response; Testing; Translating; Ulcerative Colitis; Variant; Yeasts; clinical remission; conventional therapy; design; disorder risk; fungal microbiota; fungus; genome wide association study; gut microbiome; health related quality of life; immunoregulation; improved; improved outcome; inflammatory marker; mRNA Expression; metabolome; microbial; microbiome; microbiota; mouse model; mucosal microbiota; mycobiome; patient subsets; placebo controlled study; posaconazole; primary endpoint; risk variant; screening; secondary endpoint; stool sample; symptomatic improvement; treatment effect; treatment response; week trial

ABSTRACT Inflammatory bowel disease (IBD), divided largely into Crohn’s Disease (CD) and ulcerative colitis, is a chronic and serious disease that results from dysregulated inflammatory immune activity in the mucosa of the gastrointestinal tract. There has been much progress defining genetic, intestinal microbiome, host pathway, and environmental roles in disease, and a major goal in IBD research and care is to translate these observations into strategies to improve outcomes by better matching disease treatment with patients’ specific underlying mechanisms of disease. Studies on the role of the microbiome in influencing IBD have focused largely on the bacterial microbiota, while the potential role for commensal fungal microbiota to influence disease has been largely overlooked. We recently reported a strong association of the yeast Malassezia with Crohn’s Disease. Specifically, intestinal mucosa- associated Malassezia are elevated in patients carrying a previously described IBD risk polymorphism (S12N) in the gene for CARD9, a signaling molecule require for antifungal inflammatory immune responses. In mouse models, Malassezia exacerbates colitis via a mechanism requiring CARD9. This project is designed to test the hypothesis that oral antifungal treatment can reduce the burden of Malassezia spp. in CD patients with the CARD9 S12N allele and improve disease symptoms. The approach includes a two-center randomized, double- blind, placebo-controlled study of antifungal drug treatment in genetically defined patients with active Crohn’s disease. We will evaluate the consequences of antifungal drug treatment on the overall microbiome and metabolites it produces as well as regulation of immune cell function in the mucosa.

抽象的 炎症性肠病（IBD）主要分为克罗恩病（CD）和溃疡性结肠炎，是一种慢性 和严重的疾病，是由于粘膜中炎症免疫反应失调而导致的严重疾病 胃肠道。定义遗传，肠道微生物组，宿主途径和 环境在疾病中的作用，以及IBD研究和护理的主要目标是将这些观察结果转化为 通过更好地匹配疾病治疗与患者的特定潜在的策略 疾病机制。 关于影响IBD的微生物组作用的研究主要集中在细菌菌群上，而 共生真菌微生物群对影响疾病的潜在作用已在很大程度上被忽略了。我们最近 报道说，酵母菌马拉西亚与克罗恩病有很强的联系。具体而言，肠粘膜 - 携带先前描述的IBD风险多态性的患者（S12N），相关的Malassezia升高 在Card9的基因中，信号分子需要抗真菌炎症免疫反应。在鼠标中 模型，Malassezia通过需要Card9的机制加剧了结肠炎。该项目旨在测试 假设口服抗真菌治疗可以减少马拉西亚属的伯宁。在CD患者中 Card9 S12N等位基因并改善疾病症状。该方法包括一个两中心的随机，双重 - 盲目的，安慰剂对照的抗真菌药物治疗研究中，有活性Crohn的患者 疾病。我们将评估抗真菌药物治疗对整体微生物组的后果和 它产生的代谢物以及粘膜中免疫功能的调节。