The effect of the microbiome on the development and severity of uveitis

描述（由申请人提供）：越来越多的证据表明，在自身免疫性疾病中出错的免疫耐受的形成受到肠道微生物群的严重影响。尽管已经针对自身免疫性疾病如类风湿性关节炎、炎症性肠病和多发性硬化症研究了微生物组和自身免疫性之间的这种关系，但尚未针对自身免疫性葡萄膜炎进行研究，这是一种潜在的免疫性疾病。 影响眼睛的失明炎症。研究微生物组与葡萄膜炎的关系可能会揭示这种疾病发病机制的重要见解，但更重要的是，可能会通过使用新的治疗策略进行潜在的干预。 这项研究的假设是，改变肠道植物群将影响葡萄膜炎的临床严重程度。检验这一假设的第一个目的是使用广谱抗生素减少肠道植物群，并确定这如何以及为什么会影响葡萄膜炎疾病的严重程度。为此，将测试两种自身免疫性葡萄膜炎动物模型，实验性自身免疫性葡萄膜炎（EAU）和聚集蛋白聚糖诱导的葡萄膜炎。将评估疾病严重程度、肠道微生物的相对丰度和调节性T淋巴细胞的贡献。为了评估微生物群，将使用一种成熟的快速但稳健的技术来定量表征复杂生物环境（如肠道）的微生物组（生物组代表性计算机核型分析或BRISK）。在第二个和第三个目标中，将研究益生菌（可以调节自身耐受性的肠道微生物）和益生元（以特定方式影响先天微生物组的饮食）对临床疾病严重程度的影响以及改变上述疾病模型中肠道植物群的能力。

DESCRIPTION (provided by applicant): There is increasing evidence that the shaping of the immunological tolerance that goes awry in autoimmune disease is heavily influenced by commensal microbiota. Although this relationship between the microbiome and autoimmunity has been studied for autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis, it has not been investigated for autoimmune uveitis, a potentially blinding inflammatory condition affecting the eyes. Studying the relationship of the microbiome with uveitis may reveal important insights into the pathogenesis of this disease, but more importantly, may result in potential intervention through the use of novel treatment strategies. The hypothesis of this study is that altering the gut flora will affect the clinical severity of uvitis. The first aim to test this hypothesis involves administering broad-spectrum antibiotics to reduce gut flora and to determine how and why this affects uveitis disease severity. Two animal models of autoimmune uveitis, experimental autoimmune uveitis (EAU), and aggrecan-induced uveitis will be tested for this purpose. Disease severity, relative abundances of bowel microorganisms, and the contribution of regulatory T lymphocytes will be assessed. To evaluate the microbiota, a well-developed rapid but robust technique to quantitatively characterize the microbiome of complex biological environments, such as the gut, will be used (Biome representational in silico karyotyping or BRISK). In the second and third aims, the effects of probiotics (commensal microrganisms that can regulate self-tolerance) and prebiotics (diets that affect the innate microbiome in a specific way) will be investigated for their effects on clinical disease severity and the ability to alter gut flora in the disease models above.