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

共生真菌群落调节免疫和肠道炎症。

• 批准号: 9287841
• 负责人: ILIYAN Dimitrov ILIEV
• 金额: $ 38.14万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9287841
• 关键词: Affect; Amphotericin; Antibiotic Therapy; Antibiotics; Antifungal Agents; Aspergillus; Bacteria; Bioinformatics; Candida; Cells; Colitis; Colon; Communities; Complex; Computer Simulation; Custom; Dangerousness; Data; Data Set; Development; Diet; Disease; Eukaryota; Feces; Fluconazole; Genes; Genetic Polymorphism; Germ-Free; Health; Home environment; Human; Hypersensitivity; Immune; Immune response; Immune system; Immunity; Implant; Indigenous; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Interleukin-10; Interleukin-17; Intestinal Diseases; Intestinal Mucosa; Intestines; Lead; Lung; Lung Inflammation; Maps; Mediating; Modeling; Molds; Mus; Pathology; Pharmaceutical Preparations; Process; Prokaryotic Cells; Pyroglyphidae; Rag1 Mouse; Regulation; Reporting; Research; Resources; Role; Severities; Severity of illness; Structure; Surface; Symbiosis; T-Lymphocyte; Trichosporon; Ulcerative Colitis; Virus; Voriconazole; acrosome stabilizing factor; commensal microbes; cytokine; dectin 1; fungus; gut microbiota; in vivo; in vivo Model; interleukin-22; intestinal homeostasis; member; microbiota; mouse model; new therapeutic target; novel; novel therapeutics; oral supplementation; pathogen; pyrosequencing; receptor; tool; transcriptome sequencing

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.

抽象的 数十年的研究表明，肠道细菌对于控制稳态和受保护至关重要 免疫反应。但是，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。尚不清楚肠道真菌社区如何称为“ Mycobiota” 受肠道病理，抗生素治疗，免疫和饮食变化的影响 据报道导致“细菌性营养不良”。我们已经表明，编码人类基因的多态性 抗真菌受体Dectin-1（CLEC7A）与溃疡性结肠炎（UC）的严重程度密切相关，并且 在结肠炎的小鼠模型中，机会性真菌（如念珠菌和trichosporon spp）的过度生长。 有助于肠道炎症。这表明健康真菌社区的干扰 （“霉菌蛋白营养不良”）可能是肠道疾病发展或进展的重要因素。在 这项提议，我们将探讨肠道霉菌营养不良的假设可能会影响肠道炎症 促进“不良生物”真菌与宿主粘膜免疫系统的异常相互作用以及肠道 细菌。我们的初步数据表明，菌根营养不良症诱导了常用的抗真菌药物 氟康唑可能会影响肺过敏的严重程度（房屋尘埃过敏模型）和肠炎 （DSS和T细胞转移鼠标模型）。口服三种失调丝状真菌（曲霉）的口服补充 在氟康唑治疗期间扩展的Amstelodami，Epicoccum nigrum和Wallemia sebi） 氟康唑对炎症的有害作用，而与营养不良无关的真菌却没有。 我们发现，除了影响霉菌群外，药物诱导的营养不良会影响肠道细菌群落。 在缺少本地真菌的小说“ Mycobiota定义”模型中，引入了单一肠真菌导致 肠道细菌的明显变化，表明真菌和细菌可以在 肠。采用新的体内工具，高通量平台和计算管道，我们将重点关注 描述：（1）真菌营养不良影响肠道菌菌和肠炎的机制，（2） Dectin-1和衔接子分子Card9对菌根炎症作用的相对贡献 营养不良，（3）不植物真菌与细菌的特定相互作用以及与新颖的“ Mycobiota”中的宿主相互作用 定义的“小鼠模型”。目前尚不清楚肠道微生物群是否仅被视为 “细菌性营养不良”实际上是原核生物和核之间更复杂相互作用的集体特征 真核生物群落。我们预计可以确定常见的抗真菌药物和失调真菌如何导致 肠间界社区营养不良，影响免疫力并导致肠道疾病。结果 这项研究将绘制与真菌营养不良相关的Mycobiota概况，这将是迈向 定义肠道中的异常界间相互作用，这可能是针对性的新型疗法的基础 炎症性疾病。