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.