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: 10398911
• 负责人: Gil Y Melmed
• 金额: $ 64.05万
• 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/10398911
• 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; 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，是一种慢性疾病 以及由于粘膜炎症免疫活性失调而导致的严重疾病 胃肠道的定义已取得很大进展，肠道微生物组、宿主途径和 环境在疾病中的作用，IBD 研究和护理的一个主要目标是将这些观察结果转化为 通过更好地将疾病治疗与患者的具体基础相匹配来改善结果的策略 疾病机制。 关于微生物组在影响 IBD 中的作用的研究主要集中在细菌微生物群上，而 最近，我们很大程度上忽视了共生真菌微生物群影响疾病的潜在作用。 具体来说，肠粘膜—— 携带先前描述的 IBD 风险多态性 (S12N) 的患者中，相关的马拉色菌水平升高 CARD9 基因是小鼠抗真菌炎症免疫反应所需的信号分子。 模型中，马拉色菌通过需要 CARD9 的机制加重结肠炎。 假设口服抗真菌治疗可以减轻 CD 患者的马拉色菌负担。 CARD9 S12N 等位基因和改善疾病症状的方法包括两中心随机、双研究。 对基因明确的活动性克罗恩病患者进行抗真菌药物治疗的盲法安慰剂对照研究 我们将评估抗真菌药物治疗对整体微生物组和疾病的影响。 它产生的代谢物以及粘膜免疫细胞功能的调节。