Mechanisms of fungal involvement during intestinal disease

摘要 共生微生物区系对寄主生理和健康的重要影响才刚刚开始 已澄清。然而，大多数目前的研究只集中在细菌微生物区系上，尽管存在 真菌、古生菌和病毒的成员。抗酿酒酵母(ASCA)抗体的存在 作为克罗恩病(CD)的诊断工具，并提示微生物区系中的真菌成员 会加重疾病的严重程度。此外，在IBD患者中发现的常见基因多态， 如NOD2、Dectin-1和CARD9等已知识别真菌细胞壁成分。我们最近做了 证明了霉菌群中最重要的成员之一，酿酒酵母，可以加剧 肠道内宿主嘌呤代谢上调所致的肠炎。嘌呤的最终产品 人体的新陈代谢是尿酸。最近的研究表明，尿酸可以有显著的 对自噬的影响。巧合的是，许多与人类IBD相关的基因都会影响自噬 流程。有大量临床文献将自噬、酵母菌和尿酸的产生联系起来， 然而，这些关系还有待探索。在这里，我们建议确定真菌成员是如何 微生物区系诱导肠上皮细胞嘌呤代谢及其影响 肠道免疫使疾病恶化。我们已经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来探索酵母如何 在功能上影响肠道疾病。

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.