PR002462 (Project)

Description:Gut microbial metabolites influence immune responses and play a key role in regulating host metabolism. Inflammatory bowel diseases (IBD) patients have altered gut microbial metabolic signatures driven by shifts in the microbiome. However, the microbial metabolites driving inflammation and remission and their immunomodulatory roles remain largely uncharacterized. We prioritized metabolic features from untargeted IBD fecal metabolomics and selected candidate features based on their microbial association for structural elucidation. We uncovered four acylated putrescines that are IBD-associated and microbially-dependent and investigated their bioactivity. One acylated putrescine, N-oleoylputrescine (NOP), has anti-inflammatory activity and suppressed type 1 immune responses. NOP ameliorated inflammation in several colitis models, modulating myeloid and lymphocyte cell populations and dampening proinflammatory responses, relevant for resolution of inflammation and maintenance of remission in IBD. We present an approach to identify clinically-relevant microbial metabolites from untargeted metabolomics useful for the discovery of bioactive molecules in IBD and other diseases involving host-microbial interactions.