Impact of immunosuppression therapy on commensal fungi and intestinal disease

 描述（由申请人提供）：最近的研究表明，除了细菌和病毒外，哺乳动物肠道是多种真菌群落（真菌生物群）的家园。与细菌类似，真菌可能参与形成宿主粘膜免疫，但也提供了一个潜在的感染性生物体库。虽然真菌生物群不会导致健康个体的病理，但由于更多的人生活在免疫系统受抑制的情况下，如艾滋病毒，癌症和其他免疫抑制患者，真菌感染的患病率正在增加。然而，真菌在免疫抑制过程中的作用尚未被探索。这部分是由于缺乏标准化的方法，数据库和实验模型来支持真菌组研究。免疫抑制治疗是许多患有自身免疫性和慢性炎症性疾病（包括炎症性肠病（IBD））的患者的标准治疗。这些患者人群经常接受免疫调节治疗，并提供了一个个体库，在这些条件下可以研究肠道菌群。我们的初步研究确定了与溃疡性结肠炎（IBD的一种形式）相关的真菌分类群和在接受免疫抑制药物治疗的患者中扩增的特定机会性真菌（包括白色念珠菌和西氏曲霉菌）。在小鼠结肠炎模型中，我们确定了免疫抑制后，真菌可以过度生长，并且C。白色念珠菌，在治疗停止后不久发展为严重的结肠炎（模拟患有炎性病症的患者中皮质类固醇逐渐减少）。在这项提案中，我们将探讨免疫抑制治疗可以影响肠道菌群组成，导致可能导致IBD和其他炎症性疾病患者疾病的潜在有害真菌过度生长的假设。采用定制开发的真菌生物信息学管道和结肠炎和免疫抑制的小鼠模型，我们将在两个特定目标中测试我们的假设。在具体目标1中，我们将评价IBD（UC和克罗恩病）患者在皮质类固醇、6 MP/AZA和抗TNF治疗期间的真菌菌群组成。我们将进一步使用结肠炎治疗的小鼠模型，以区分疾病相关的炎症和免疫抑制作为影响肠道菌群的两个潜在独立因素。在具体目标2中，我们将探讨是否肠道定植特定真菌（C。albicans和A. sydowii），其在免疫抑制期间扩展加重肠道疾病。我们还将评估抗真菌治疗是否可以改善结肠炎，并作为一种潜在的联合治疗。本研究的结果将提供与IBD相关的真菌群分布图，使用免疫抑制剂，以及结肠炎治疗期间特定真菌的体内作用。这将是鉴定真菌分类群的进一步步骤，所述真菌分类群将用作生物标志物以定义处于真菌过度生长的较高风险的免疫抑制患者的亚组，其可能受益于抗真菌联合治疗。

 DESCRIPTION (provided by applicant): Recent studies suggest that in addition to bacteria and viruses, mammalian gut is a home of diverse fungal community (mycobiota). Similar to bacteria, fungi might be involved in shaping the host mucosal immunity, but also provide a pool of potentially infectious organisms. Although commensal mycobiota do not lead to pathologies in healthy individuals, fungal infections are increasing in prevalence owing to more people living with suppressed immune systems, such as HIV, cancer and other immunosuppressed patients. However, the role of mycobiota during immunosuppression has not been explored yet. This is partially due to lack of standardized approaches, databases and experimental models to support the mycobiome studies. Immunosuppression therapy is a standard-of-care for many patients with autoimmune and chronic inflammatory conditions including Inflammatory Bowel Disease (IBD). These patient populations are frequently receiving immunomodulatory therapy and provide a pool of individuals, where gut mycobiota can be investigated under such conditions. Our preliminary studies identified fungal taxa associated with Ulcerative Colitis (a form of IBD) and specific opportunistic fungi (including Candida albicans and Aspergillus sydowii) that expand in patients treated with immunosuppressive drugs. In a mouse model of colitis, we determined that upon immunosuppression, fungi can overgrow and that mice colonized with C. albicans, develop severe colitis soon after treatment withdrawal (modeling corticosteroid tapering in patients with inflammatory conditions). In this proposal, we will explore the hypothesis that immunosuppression therapy can affect the intestinal mycobiota composition leading to the overgrowth of potentially harmful fungi that may contribute to disease in patients with IBD and other inflammatory conditions. Employing a custom developed mycobiome bioinformatics pipeline and mouse models of colitis and immunosuppression, we will test our hypothesis in two specific aims. In Specific Aim 1, we will evaluate the mycobiota composition in patients with IBD (UC and Crohn's disease) during treatment with Corticosteroids, 6MP/AZA and Anti-TNF. We will further use a mouse model of colitis therapy, to differentiate between disease-related inflammation and immunosuppression as two potentially independent factors affecting the gut mycobiota. In Specific Aim 2, we will explore whether intestinal colonization with specific fungi (C. albicans and A. sydowii) that expand during immunosuppression aggravate intestinal disease. We will also assess whether anti-fungal treatment can ameliorate colitis and be used as a potential co-therapy. The results of this study will provide a map of mycobiota profiles associated with IBD, with the use of immunosuppression, as well as the in vivo effect of specific fungi during colitis therapy. This will be a step further in the identificaion of fungal taxa to be used as biomarkers to define subgroups of immunosuppressed patients, at a higher risk of fungal overgrowth, which might benefit from anti-fungal co- therapy.