Discovery of new bioactive microbial metabolites in inflammatory bowel disease

The gut microbiota and associated bioactive compounds have been implicated as causal and as protective factors in gastrointestinal disorders, including the inflammatory bowel diseases (IBD). Both host immune interactions with gut microbes and microbial small molecule products are likely responsible for these bioactivities. Several gut microbial metabolites, e.g. short-chain fatty acids and a subset of omega-3 fatty acids depleted in GI inflammation, have demonstrated therapeutic potential in IBD by attenuating gut inflammation. However, discovery of new bioactive compounds from the gut microbiome relevant to IBD or inflammation is challenging due to the vast numbers of uncharacterized metabolites produced by the microbiome. To address this challenge, we investigated two IBD cohorts with integrated metagenomic and metabolomic profiles of the gut microbiome: PRISM, the Prospective Registry in IBD Study at MGH, and the Integrative Human Microbiome Project (HMP2). Putrescine and a potentially novel family of metabolites microbially derived from it were among the ~10,000 metabolites differentially abundant (PRISM n=8,792 and HMP2 n=9,444) during gut inflammation, of which only ~100 were characterized (PRISM n=157 and HMP2 n=99). We validated the dependence of these putrescine derivatives on the gut microbiome and their bioactivity in vivo by treating germ-free, gnotobiotic and conventional mice with dietary putrescine, which induced changes in immune system activity in a microbial community-dependent manner. This included that putrescine selectively affects host colonic and ileum M2 macrophage cell populations only in conventional mice. These results underscore the power of combined computational and experimental approaches for identifying microbially derived metabolites with general immunomodulatory activity and specific relevance for IBD patient care.