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: 9900774
• 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/9900774
• 关键词: 16S ribosomal RNA sequencing; Affect; Amphotericin; Antibiotic Therapy; Antibiotics; Antifungal Agents; Aspergillus; Bacteria; Candida; Cells; Colitis; Colon; Communities; Complex; Computer Models; Custom; Dangerousness; Data; Data Set; Development; Diet; Disease; Eukaryota; Exposure to; 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; Interleukin-10; Interleukin-17; Intestinal Diseases; Intestinal Mucosa; Intestines; Lead; Lung; Lung Inflammation; Maps; Mediating; Modeling; Molds; Mucosal Immune System; Mucous Membrane; Mus; Pathology; Pharmaceutical Preparations; Process; Prokaryotic Cells; Pyroglyphidae; Rag1 Mouse; Regulation; Reporting; Research; Resources; Role; Severities; Severity of illness; Structure; Surface; T-Lymphocyte; Trichosporon; Ulcerative Colitis; Virus; Voriconazole; acrosome stabilizing factor; bacterial community; bioinformatics pipeline; commensal bacteria; computational pipelines; cytokine; dectin 1; dust mite allergy; dysbiosis; fungal microbiota; fungus; gut bacteria; gut microbiota; in vivo; in vivo Model; inflammatory disease of the intestine; interleukin-22; intestinal homeostasis; member; microbiota; mouse model; new therapeutic target; novel; novel therapeutics; oral supplementation; pathogenic fungus; 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.

摘要 数十年的研究表明，肠道细菌对调节体内平衡和保护人体健康至关重要 免疫反应。然而，最近的研究表明，真菌和病毒等其他因素也 影响这些进程的潜力。目前尚不清楚肠道真菌群落，也就是所谓的“真菌生物群”如何 受到肠道病理、抗生素治疗、免疫和饮食变化的影响 据报道，这会导致“细菌失调”。我们已经证明，人类基因编码的多态 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， 在结肠炎的小鼠模型中，条件真菌如念珠菌和毛孢子菌的过度生长。 会导致肠道发炎。这表明，健康真菌群落中的干扰 (“霉菌群失调”)可能是肠道疾病发生或发展的一个重要因素。在……里面 在这项提议中，我们将探索肠道真菌菌群失调可能通过以下方式影响肠道炎症的假设 促进“不良”真菌与宿主粘膜免疫系统和肠道的异常相互作用 细菌。我们的初步数据显示，常用的抗真菌药物可以诱导真菌菌群失调。 氟康唑可影响肺部过敏(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)。口服三种非生物丝状真菌(曲霉) 在氟康唑治疗期间扩张的阿司特洛达米、黑表皮藻和墙病)概述 氟康唑对炎症的有害影响，而与生物失调无关的真菌(腓肠链霉菌)则没有。 我们发现，除了影响真菌区系外，药物诱导的生物失调还会影响肠道细菌群落。 在一个没有本土真菌的新的“真菌区系定义”模型中，单一肠道真菌的引入导致了 肠道细菌的明显变化，表明真菌和细菌在肠道中可以相互影响 直觉。利用新的活体工具、高通量平台和计算管道，我们将专注于 描述：(1)真菌失调影响肠道真菌区系和肠道炎症的机制，(2) Dectin-1和适配分子CARD9在真菌菌群炎症反应中的相对作用 (3)在一个新的“真菌生物群”中，非生物真菌与细菌和寄主的特定相互作用 定义了“鼠标模型”。目前尚不清楚肠道微生物区系失调是否被单独视为 “细菌失调”，实际上是原核生物和细菌之间更复杂的相互作用的集体特征。 真核生物群落。我们预计将定义常见的抗真菌药物和非生物真菌如何导致 肠道跨王国群落生物失调，影响免疫并导致肠道疾病。结果是 这项研究将绘制与真菌生物失调相关的真菌生物群分布图，并将进一步朝着 确定肠道内异常的跨王国相互作用，这可能是靶向治疗的基础 炎症性疾病。