Significance Obesity is associated with enhanced colonic inflammation, which is a major risk factor for colorectal cancer. To date, the mechanisms by which obesity increases colonic inflammation are not well-understood, and there are few effective strategies for controlling obesity-induced colonic inflammation and associated diseases. Here, using LC-MS/MS–based metabolomics, we report that soluble epoxide hydrolase (sEH) could be a novel therapeutic target for obesity-induced colonic inflammation. This could lead to rapid human translation, as pharmacological inhibitors of sEH are being evaluated in human clinical trials targeting multiple disorders.