The gut microbiome has been implicated in multiple human chronic gastrointestinal (GI) disorders . Determining its mechanistic role in disease has been difficult due to apparent disconnects between animal and human studies and lack of an integrated multi-omics view of disease-specific physiological changes . We integrated longitudinal multi-omics data from the gut microbiome, metabolome, host epigenome, and transcriptome in the context of irritable bowel syndrome (IBS) host physiology . We identified IBS subtype-specific and symptom-related variation in microbial composition and function . A subset of identified changes in microbial metabolites correspond to host physiological mechanisms that are relevant to IBS . By integrating multiple data layers, we identified purine metabolism as a novel host-microbial metabolic pathway in IBS with translational potential . Our study highlights the importance of longitudinal sampling and integrating complementary multi-omics data to identify functional mechanisms that can serve as therapeutic targets in a comprehensive treatment strategy for chronic GI diseases . VIDEO ABSTRACT.