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

  • Cell Host Microbe. 2026 Jul 8;34(7):1350-1366.e8. doi: 10.1016/j.chom.2026.05.020.
Shujun Xu  1 ,  Junfang Lyu  2 ,  Gengyu Bao  1 ,  Ping Zheng  2 ,  Yaqi Li  1 ,  Ziwan Ning  2 ,  Baohua Li  1 ,  Min Zhuang  1 ,  Hoi Ki Wong  1 ,  Mingchun Wang  1 ,  Yufei Zeng  3 ,  Ya Zheng  4 ,  Jingyuan Luo  1 ,  Qin Liu  2 ,  Lu Zhang  5 ,  Chengyuan Lin  2 ,  Haitao Xiao  3 ,  Chun-Su Yuan  6 ,  Hoi Leong Xavier Wong  7 ,  Zhaoxiang Bian  8 ,  Lixiang Zhai  9
Affiliations
  • 1. Centre for Chinese Medicine Drug Development Limited, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China; School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China.
  • 2. Centre for Chinese Medicine Drug Development Limited, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China.
  • 3. Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, Guangdong, China.
  • 4. School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China.
  • 5. Department of Computer Science, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China.
  • 6. Tang Center for Herbal Medicine Research, Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL, USA.
  • 7. School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China. Electronic address: [email protected].
  • 8. Centre for Chinese Medicine Drug Development Limited, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China; School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China. Electronic address: [email protected].
  • 9. Centre for Chinese Medicine Drug Development Limited, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China. Electronic address: [email protected].
PMID: 42320473 DOI: 10.1016/j.chom.2026.05.020
Abstract

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).

Keywords
Eubacterium rectale; PPARα; disorder of gut-brain interactions; enterochromaffin cells; fatty acid ethanolamides; insulin resistance; irritable bowel syndrome; oleoylethanolamide; serotonin; visceral hypersensitivity.
Products