A comprehensive platform for novel therapy development from the microbiome

肠道微生物区系与许多胃肠道疾病密切相关，包括炎性肠炎。 疾病(IBD)、糖尿病和结直肠癌。然而，肠道运动的许多分子机制 微生物及其代谢产物扰乱宿主免疫尚不清楚。活细胞和 微生物衍生的小分子干预已被证明可以预防或改善胃肠道炎症，但对 在很大程度上，微生物组的靶向成分的治疗潜力尚未实现。 作为对RFA-DK-15-012的响应，我们建议建立一个社区研究资源，其中包括已确定的 微生物群和他们阐述的调节人类生理或病理生理学的因素与… 消化系统疾病。“人类微生物生物活性资源(HMBR)将提供一个全面的平台 用于微生物组衍生的新疗法的发现、验证和早期翻译： 1.一种高效的端到端采样和多组分群系统 胃肠道疾病。 2.来自数千个IBD微生物组和数万个肠道微生物组的数据，跨越 数十个数据集和荟萃分析多个国家、队列和临床中心。 3.确定IBD肠道微生物组潜在生物活性成分的优先顺序，包括A)微生物种类 和菌株，B)微生物基因产品(蛋白质、分泌肽、生物合成基因簇等)， 和C)小分子(例如代谢物或信号分子)。 4.使用哺乳动物细胞和组织模型在体外筛选高优先级生物活性物质以表征 潜在的作用机制和确定宿主-微生物-代谢物的相互作用。 5.成功的表型读数(细胞种群、基于细胞功能的模型和临床前IBD模型) 在常规小鼠和诺生菌小鼠中评估活体活性的生物活性。 6.所有HMBR数据、方案、计算工具、微生物分离物、化合物、细胞系、小鼠、 筛选结果，并通过统一的基于网络的门户网站向社区提供培训材料。 7.通过验证和表征新的应用来利用驱动生物应用的资源 IL-10抗炎和肿瘤坏死因子α促炎反应的调节物。 这一资源将在布罗德研究所的背景下开发，布罗德研究所是肠道微生物组图谱和 哈佛大学公共卫生学院，一个受到严格监控的灵生小鼠设施的所在地； 以及马里兰大学，该大学目前支持全球最大的微生物群资源 人类微生物组项目1和2数据协调中心的形式。通过这种组合 调查人员、环境、资源和生物应用，我们将建立并提供给 社区是首个端到端微生物组治疗发现和验证的平台。

The gut microbiota is closely linked with many gastrointestinal disorders, including inflammatory bowel diseases (IBD), diabetes, and colorectal cancer. However, many of the molecular mechanisms by which gut microorganisms and their metabolic products perturb host immunity are not yet understood. Both live cell and microbially-derived small molecule interventions have proven to prevent or ameliorate GI inflammation, but to a large degree, the therapeutic potential of targeted components of the microbiome has not yet been realized. In response to RFA-DK-15-012, we thus propose a “community research resource of identified members of the microbiome and factors they elaborate which modulate human physiology or pathophysiology related to... digestive diseases.” The Human Microbial Bioactives Resource (HMBR) will provide a comprehensive platform for discovery, validation, and early-stage translation of novel therapeutics derived from the microbiome: 1. An efficient end-to-end sampling and multi’omic profiling system for the host and microbiota in gastrointestinal disease. 2. Data from thousands of IBD microbiomes and tens of thousands of gut microbiome profiles, spanning dozens of datasets and meta-analyzing multiple countries, cohorts, and clinical centers. 3. Prioritized potentially bioactive elements of the gut microbiome in IBD, including A) microbial species and strains, B) microbial gene products (proteins, secreted peptides, biosynthetic gene clusters, etc.), and C) small molecules (e.g. metabolites or signaling molecules). 4. Screens for high-priority bioactives in vitro using mammalian cell and tissue models to characterize potential mechanisms of action and identify host-microbe-metabolite interactions. 5. Phenotypic readouts (cell population, cellular function-based, and preclinical IBD models) for successful bioactives in conventional and gnotobiotic mice to assess activity in vivo. 6. All HMBR data, protocols, computational tools, microbial isolates, compounds, cell lines, mice, screening results, and training material provided to the community through a unified web-based portal. 7. Exercising the resource with a driving biological application by verifying and characterizing novel modulators of the IL-10 anti-inflammatory and TNFα pro-inflammatory responses. This resource will be developed in the context of the Broad Institute, a leader in gut microbiome profiling and analysis in IBD; the Harvard School of Public Health, home to a rigorously monitored gnotobiotic mouse facility; and the University of Maryland, which currently supports the largest human microbiome resource worldwide in the form of the Human Microbiome Project 1 and 2 Data Coordinating Centers. Through this combination of investigators, environments, resources, and biological applications, we will establish and provide to the community the first platform of its kind for end-to-end microbiome therapeutic discovery and validation.