Microbial biochemistry is central to the pathophysiology of inflammatory bowel diseases (IBD). Improved knowledge of microbial metabolites and their immunomodulatory roles is thus necessary for diagnosis and management. Here, we systematically analyzed the chemical, ecological, and epidemiological properties of ~82k metabolic features in 546 Integrative Human Microbiome Project (iHMP/HMP2) metabolomes, using a newly developed methodology for bioactive compound prioritization from microbial communities. This suggested >1000 metabolic features as potentially bioactive in IBD and associated ~43% of prevalent, unannotated features with at least one well-characterized metabolite, thereby providing initial information for further characterization of a significant portion of the fecal metabolome. Prioritized features included known IBD-linked chemical families such as bile acids and short-chain fatty acids, and less-explored bilirubin, polyamine, and vitamin derivatives, and other microbial products. One of these, nicotinamide riboside, reduced colitis scores in DSS-treated mice. The method, MACARRoN, is generalizable with the potential to improve microbial community characterization and provide therapeutic candidates. Synopsis: MACARRoN combines ecological and epidemiological metrics to prioritize metabolic features with potential bioactivity in a phenotype of interest. Its application to inflammatory bowel disease (IBD) prioritizes both previously IBD-linked and less-explored microbiome-associated metabolites. Metabolic features that covary among conditions tend to be closer in mass and chemically homogeneous, pointing to underlying biochemical relationships. MACARRoN integrates metabolic feature prevalence, covariance, abundance with respect to an identified metabolite, and extent of perturbation to prioritize actionable, phenotype-associated features from untargeted metabolomics data. MACARRoN prioritized ~1,000 chemically diverse, stool-derived features as IBD-associated, including known IBD biomarkers and several unannotated features that covary with them. Newly IBD-linked metabolic features included microbial polyamines, nicotinamide riboside (shown here to reduce colitis in DSS-treated mice), and novel putatively microbially-derived bilirubin compounds. MACARRoN combines ecological and epidemiological metrics to prioritize metabolic features with potential bioactivity in a phenotype of interest. Its application to inflammatory bowel disease (IBD) prioritizes both previously IBD-linked and less-explored microbiome-associated metabolites. [ABSTRACT FROM AUTHOR]