Presented by: Amrisha Bhosle
Microbial community biochemistry is responsible for processing hundreds of thousands of compounds, of which only a few percent are typically identified and even fewer linked to specific functions or phenotypes. This is true even in the relatively well-characterized human gut, in which perturbation of microbial metabolism is an important aspect of the pathophysiology of conditions including the inflammatory bowel diseases (IBD). Improved knowledge of microbial metabolites and their immunomodulatory roles is thus necessary to the understanding of the gut and other ecologies, as well as diagnosis and clinical management of IBD. Here, we systematically analyzed the molecular, ecological, and epidemiological properties of ~82k metabolic features in 546 Integrative Human Microbiome Project (iHMP/HMP2) untargeted fecal metabolomes and prioritized >1,000 metabolic features as potentially bioactive in IBD. This methodology associated 18,699 (~42%) of prevalent but unidentified metabolic features with at least one well-characterized annotated metabolite, thereby ‘de-orphaning’ a significant portion of the fecal metabolome. Prioritized unidentified metabolites were both abundant and significantly perturbed during IBD, and they included known IBD-linked chemical families such as bile acids and short-chain fatty acids, as well as less-explored bilirubin derivatives, polyamines, vitamins, and other microbial products. One of these previously unannotated but highly prioritized compounds, nicotinamide riboside, successfully reduced histological colitis scores in DSS-treated mice. The resulting chemical prioritization and identification strategy, implemented as MACARRoN, is generalizable to untargeted metabolomes from other environments, with the potential to improve microbial community characterization and provide new therapeutic candidates in the human microbiome.