Gut bacteria that produce fatty acid ethanolamides alleviate diarrhea-predominant IBS with insulin resistance.

Individuals with diarrhea-predominant irritable bowel syndrome (IBS-D) are at an increased risk of insulin resistance. Here, we identify a critical role for gut-microbe-derived fatty acid ethanolamides (FAEs) in the treatment of IBS-D with insulin resistance. In IBS-D patients with insulin resistance, serum levels of FAE are significantly reduced compared with healthy controls, and lower FAE levels negatively correlate with the severity of GI symptoms. Oral administration of FAE, specifically oleoylethanolamide (OEA), alleviates diarrhea and visceral hypersensitivity in murine IBS-D-like models. Mechanistically, OEA acts as a PPARα agonist to upregulate the serotonin transporter (SERT), limiting peripheral serotonin availability. Furthermore, fecal microbiota transplantation from high-FAE donors or treatment with FAE-producing bacteria (Escherichia coliereT+ or Eubacterium rectale) elevates fecal FAE and alleviates symptoms via the PPARα-SERT axis. Our findings reveal a microbial FAE-driven pathway linking IBS-D and insulin resistance, presenting a therapeutic target for this comorbidity. This study was registered at ClinicalTrials.gov (NCT02822677 and NCT03457324) and Chinese Clinical Trial Registry (ChiCTR2300069830 and ChiCTR2300067254).