Commensal fungal communities in the regulation of immunity and intestinal inflammation.

摘要 几十年的研究表明，肠道细菌对调节体内平衡和保护至关重要。 免疫反应。然而，最近的研究表明，真菌和病毒等其他参与者也 影响这些过程的潜力。目前尚不清楚肠道真菌群落，所谓的“真菌生物群”， 受肠道病变、抗生素治疗、免疫和饮食变化的影响， 导致“细菌生态失调”我们已经证明，人类基因编码的多态性 抗真菌受体Dectin-1（CLEC 7A）与溃疡性结肠炎（UC）的严重程度密切相关， 在结肠炎的小鼠模型中，机会性真菌如假丝酵母属和丝孢酵母属的过度生长。 导致肠道炎症。这表明健康真菌群落的紊乱 真菌生物群生态失调（“mycobiota dysbiosis”）可能是肠道疾病发展或进展的重要因素。在 在这项提议中，我们将探讨肠道菌群失调可能通过以下方式影响肠道炎症的假设： 促进“生态失调”真菌与宿主粘膜免疫系统和肠道免疫系统的异常相互作用 细菌我们的初步数据表明，常用的抗真菌药物诱导的真菌菌群失调 氟康唑可影响肺过敏（屋尘螨过敏模型）和肠道炎症的严重程度 (DSS和T细胞转移小鼠模型）。口服补充三种生态失调的丝状真菌（曲霉属 amsterodami、黑附球菌和沙壁菌），这些菌在氟康唑治疗期间扩增， 氟康唑对炎症的有害作用，而与生态失调无关的真菌（S. fibuligera）没有。 我们发现，除了影响菌群，药物诱导的生态失调影响肠道细菌群落。 在一种缺乏本土真菌的新型“真菌生物群定义”模型中，引入单一肠道真菌导致 肠道细菌的独特变化，表明真菌和细菌可以相互影响， 直觉采用新的体内工具，高通量平台和计算管道，我们将专注于 描述：（1）真菌生态失调影响肠道菌群和肠道炎症的机制，（2） Dectin-1和衔接分子CARD 9对真菌生物群的炎症作用的相对贡献 微生态失调，（3）微生态失调真菌与细菌和宿主在新的“真菌生物群”中的特异性相互作用 定义“鼠标模型”。目前尚不清楚肠道微生物群生态失调，这仅仅被认为是 “细菌生态失调”，实际上是原核生物和 真核生物群落我们期望确定常见的抗真菌药物和微生态失调的真菌是如何导致 肠道界间群落生态失调影响免疫力并导致肠道疾病。结果 这项研究的结果将绘制与真菌生态失调相关的真菌生物群图谱， 定义肠道中异常的王国间相互作用，这可以成为靶向新疗法的基础， 炎症性疾病。

Abstract Decades of research have revealed that intestinal bacteria are critical for regulating homeostatic and protective immune responses. However, recent studies suggest that additional players such as fungi and viruses have also the potential to influence these processes. It is unknown how gut fungal communities, so called “mycobiota”, can be influenced by intestinal pathologies, antibiotic treatment, immune and dietary changes that have been reported to lead to “bacterial dysbiosis”. We have shown that a polymorphism in the human gene encoding the anti-fungal receptor Dectin-1 (CLEC7A) is strongly associated with the severity of ulcerative colitis (UC) and that, in a mouse model of colitis, the overgrowth of opportunistic fungi such as Candida and Trichosporon spp. contribute to intestinal inflammation. This suggests that disturbances in the healthy fungal community (“mycobiota dysbiosis”) may be an important factor in the development or progression of intestinal disease. In this proposal, we will explore the hypothesis that gut mycobiota dysbiosis might affect intestinal inflammation by promoting aberrant interaction of “dysbiotic” fungi with the host mucosal immune system and with intestinal bacteria. Our preliminary data show that mycobiota dysbiosis induced with the commonly used antifungal drug fluconazole can affect the severity of lung allergy (house dust mite allergy model) and intestinal inflammation (DSS and T cell transfer mouse models). Oral supplementation with three dysbiotic filamentous fungi (Aspergillus amstelodami, Epicoccum nigrum, and Wallemia sebi) that expanded during fluconazole treatment recapitulated the detrimental effects of fluconazole on inflammation, while fungi unrelated to dysbiosis (S. fibuligera) did not. We found that, in addition to influencing the mycobiota, drug-induced dysbiosis affects gut bacterial communities. In a novel “mycobiota defined” model that lacks indigenous fungi, introduction of a single intestinal fungus led to distinctive changes in the intestinal bacteria, suggesting that fungi and bacteria can influence each other in the gut. Employing new in vivo tools, high-throughput platforms and computational pipelines, we will focus on delineating: (1) the mechanisms by which fungal dysbiosis affects gut mycobiota and intestinal inflammation, (2) the relative contribution of Dectin-1 and adaptor molecule CARD9 on the inflammatory effects of mycobiota dysbiosis, (3) the specific interactions of dysbiotic fungi with bacteria and with the host in a novel “mycobiota defined” mouse model. It is currently unknown whether gut microbiota dysbiosis, which is solely viewed as “bacterial dysbiosis”, is actually a collective feature of more complex interactions between prokaryotic and eukaryotic communities. We anticipate defining how common antifungal drugs and dysbiotic fungi lead to intestinal inter-kingdom community dysbiosis that affect immunity and contribute to intestinal disease. The results of this study will map mycobiota profiles associated with fungal dysbiosis and will be a further step towards defining aberrant inter-kingdom interactions in the gut which can be the basis for targeted novel therapies for inflammatory diseases.