A comprehensive platform for novel therapy development from the microbiome

肠道微生物群与许多胃肠道疾病密切相关，包括炎症性肠病 疾病（IBD）、糖尿病和结直肠癌。然而，许多消化道的分子机制， 微生物及其代谢产物干扰宿主免疫的机制尚不清楚。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GI炎症，但对 在很大程度上，微生物组的靶向组分的治疗潜力尚未实现。 作为对RFA-DK-15-012的回应，我们因此提出了一个“社区研究资源， 微生物组和因素，他们阐述了调节人体生理学或病理生理学相关... 消化系统疾病”人类微生物生物活性物质资源（HMBR）将提供一个全面的平台， 用于发现、验证和早期转化来自微生物组的新型疗法： 1.一个有效的端到端采样和多组学分析系统，用于宿主和微生物群， 胃肠道疾病 2.来自数千种IBD微生物组和数万种肠道微生物组的数据， 数十个数据集，并对多个国家、队列和临床中心进行荟萃分析。 3. IBD中肠道微生物组的优先级潜在生物活性元素，包括A）微生物物种 和菌株，B）微生物基因产物（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，并确定宿主-微生物-代谢物相互作用。 5.表型读数（细胞群、基于细胞功能的和临床前IBD模型），用于成功的 在常规小鼠和无菌小鼠中测定生物活性物质以评估体内活性。 6.所有HMBR数据、方案、计算工具、微生物分离株、化合物、细胞系、小鼠， 筛选结果，并通过统一的网络门户向社区提供培训材料。 7.通过验证和表征新的生物学应用， IL-10抗炎和TNFα促炎反应的调节剂。 该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分析的领导者， 哈佛公共卫生学院，拥有严格监控的gnotobiotic小鼠设施; 以及马里兰州大学，该大学目前支持全球最大的人类微生物组资源， 人类微生物组项目1和2数据协调中心。通过这种结合， 调查人员，环境，资源和生物应用，我们将建立并提供给 社区是首个用于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.