HKBU researchers identify gut bacteria-produced metabolites provide a new therapeutic strategy for IBS-D with insulin resistance

Irritable bowel syndrome with diarrhoea (IBS-D) is one of the most common functional gastrointestinal disorders, affecting millions of people worldwide. Increasing evidence suggests that IBS-D is not only associated with intestinal dysfunction but also accompanied by metabolic abnormalities, including insulin resistance. However, the molecular mechanisms connecting gastrointestinal symptoms and metabolic dysfunction remain poorly understood, and effective therapies targeting both conditions are currently lacking.

A recent study titled “Gut bacteria that produce fatty acid ethanolamides alleviate diarrhea-predominant IBS with insulin resistance,” published in Cell Host & Microbe by a research team led by Professor Bian Zhaoxiang, Professor Zhai Lixiang, and Professor Xavier Wong Hoi-leong from Hong Kong Baptist University¹. The study shows that fatty acid ethanolamides (FAE)-producing gut bacteria alleviate the gastrointestinal symptoms and metabolic abnormalities of patients with IBS-D and insulin resistance through activation of the PPARα-SERT signaling pathway, providing new insights into microbiota-based interventions for complex metabolic gastrointestinal disorders.

This study reveals that FAE- producing gut bacteria may improve IBS-D associated insulin resistance by restoring serotonin homeostasis. FAE produced by the gut microbiota activates PPARα signalling, promotes SERT expression in the gut, and enhances serotonin reuptake capacity, thereby reducing peripheral serotonin levels and improving diarrhoea, visceral hypersensitivity and metabolic abnormalities.

Gut microbial FAE deficiency links IBS-D with insulin resistance

IBS-D is increasingly recognised as a disorder involving both gastrointestinal dysfunction and metabolic abnormalities. In this study, the researchers identified altered FAE in IBS-D patients with insulin resistance. Compared with healthy individuals, these patients exhibited reduced circulating FAE levels, which were associated with greater gastrointestinal symptom severity.

Functional studies demonstrate that FAE supplementation, particularly oleoylethanolamide (OEA), alleviate diarrhoea-like symptoms and visceral hypersensitivity in experimental IBS-D models, while improving glucose intolerance and insulin resistance in a dual-disease model of IBS-D and metabolic dysfunction. These findings identify FAE as important regulators linking intestinal dysfunction and metabolic disorders.

The PPARα-SERT pathway mediates the therapeutic effects of FAE

To elucidate the mechanism underlying FAE-mediated protection, the researchers investigated its regulation of intestinal serotonin signalling. OEA activates peroxisome proliferator-activated receptor alpha (PPARα), leading to an increased expression of the serotonin transporter (SERT) in intestinal tissues.

Enhanced SERT expression raises serotonin reuptake and reduces peripheral serotonin availability, thereby alleviating serotonin-associated gastrointestinal abnormalities. Blocking SERT activity abolishes the beneficial effects of OEA, confirming the essential role of the PPARα-SERT pathway in mediating FAE-induced therapeutic effects.

FAE-producing bacteria provide a microbiota-based therapeutic strategy for IBS-D

To translate these findings into microbiota-based interventions, the researchers investigated whether FAE-producing bacteria could reproduce the effects of FAE supplementation. Natural FAE-producing bacteria, Eubacterium rectale, improved IBS-D-related phenotypes, while engineered FAE-producing bacteria further demonstrated the therapeutic potential of enhancing beneficial metabolite production in vivo.

These findings highlight bacterial engineering as a promising strategy for developing next-generation microbiota-based therapies.

Pathogenic role of gut microbial metabolites in IBS-D and insulin resistance

Building on prior research published in Cell Host & Microbe, the team identified that Ruminococcus gnavus (R. gnavus)-derived aromatic trace amines, such as phenethylamine and tryptamine, contribute to IBS-D pathogenesis by activating TAAR1 signaling in intestinal enterochromaffin cells. This enhances serotonin biosynthesis, resulting in elevated peripheral serotonin, accelerated gastrointestinal transit, and diarrhoea-like symptoms—revealing a pathogenic microbiota–metabolite–serotonin axis². Furthermore, in a follow-up study published in Nature Communications, the team demonstrated that tryptamine and phenethylamine derived from R. gnavus contribute to insulin resistance associated with IBS and metabolic disorders. These metabolites impair insulin signalling through the TAAR1-ERK pathway, leading to reduced insulin sensitivity and impaired glucose regulation³.

Together, these studies establish a comprehensive framework showing that gut microbial metabolites can either promote disease progression or restore physiological balance, depending on their biological functions.

Conclusion

Through a series of integrated studies, the research team has revealed a complex regulatory network connecting gut microbiota, microbial metabolites, serotonin signalling, gastrointestinal dysfunction, and metabolic health.

From identifying pathogenic microbial metabolites that disrupt serotonin homeostasis to discovering beneficial microbial metabolites that restore intestinal and metabolic balance, this research highlights the importance of targeting microbial functions rather than simply microbial composition.

The findings provide new perspectives for developing precision microbiota-based therapies for IBS-D and other complex disorders involving interactions between the gut and systemic metabolism.