Microbial-associated acylated putrescines as immunomodulatory molecules in inflammatory bowel diseases

The gut microbiota profoundly shapes intestinal immunity through the production of small-molecule metabolites; yet in inflammatory bowel diseases (IBD), where the microbial metabolome is substantially altered, the identities and immunological functions of most disease-associated metabolites remain unknown. Here, we integrate untargeted fecal metabolomics from two independent IBD patient cohorts with gnotobiotic mouse metabolomic data to identify N-acyl putrescines as a class of microbiome-associated metabolites consistently enriched in both Crohn’s disease (CD) and ulcerative colitis (UC). Among these, N-oleoylputrescine (NOP) induces potent and selective transcriptional responses in bone marrow-derived dendritic cells (BMDCs) and colonic organoids, establishing it as the primary immunomodulatory candidate in this metabolite class. Enterocloster species harboring nonribosomal peptide synthetase (NRPS) biosynthetic gene clusters produce NOP via conjugation of oleic acid with putrescine, confirmed by isotope-tracing in vitro and germ-free mouse mono-colonization in vivo. NOP suppresses five core IBD-associated inflammatory pathways in mouse dendritic cells and human monocytes, reduces gene signatures of histologic inflammation and IBD therapy non-response, and ameliorates colitis in four murine models. NOP dampens NF-κB activation and iNOS expression in myeloid cells and suppresses type 1 immune responses through a T cell-intrinsic mechanism. The enrichment of NOP in IBD despite its anti-inflammatory activity supports a holobiont defense hypothesis: that the gut microbiota mounts a compensatory metabolic response to intestinal inflammation that may contribute to the restoration of organismal homeostasis.