Gut microbiome changes have been associated with several human diseases, but the molecular and functional details underlying these associations remain largely unknown. Here, we performed a meta-analysis of small molecule biosynthetic gene clusters (BGCs) in metagenomic samples of the gut microbiome from inflammatory bowel disease (IBD) patients and matched healthy subjects and identified two Clostridia-derived BGCs that are significantly associated with Crohn's disease (CD), a main IBD type. Using synthetic biology, we discovered and solved the structures of six fatty acid amides as the products of the CD-enriched BGCs, which we subsequently detected in fecal samples from IBD patients. Finally, we show that the discovered molecules disrupt gut permeability and exacerbate disease in chemically or genetically susceptible mouse models of colitis. These findings suggest that microbiome-derived small molecules may play a role in the etiology of IBD and represent a generalizable approach for discovering molecular mediators of disease-relevant microbiome-host interactions.