Gut Microbial Metabolism of 5-ASA Diminishes Its Clinical Efficacy in Inflammatory Bowel Disease

For decades, the variable clinical efficacy of the widely used inflammatory bowel disease (IBD) drug, 5-aminosalicylic acid (5-ASA), has been attributed in part to its acetylation and inactivation by gut microbes. Identification of the responsible microbes and enzyme(s), however, has proved elusive. To uncover the source of this metabolism, we created an integrated workflow combining metagenomics, metatranscriptomics, and metabolomics data from a longitudinal cohort of patients with IBD and controls. This identified 12 previously uncharacterized microbial acetyltransferases belonging to two protein superfamilies, the thiolases and acyl-CoA N-acyltransferases. In vitro characterization of a representative from the highly conserved thiolase family confirmed the ability of these enzymes to acetylate 5-ASA. A subsequent cross-sectional case-control analysis within the discovery cohort then confirmed that this and other microbial thiolases were associated with an increased risk of treatment failure among 5-ASA users. Together, these data address a long-standing challenge in IBD management, outline a workflow for the discovery of previously uncharacterized gut microbial activities, and advance the possibility of microbiome-based personalized medicine.
One-Sentence Summary: Gut microbial enzymes inactivate a commonly used drug in inflammatory bowel disease, 5-ASA, and, in turn, are associated with treatment failure.