Evaluation of potential therapeutic effects of GLP-1 receptor agonists on the state of secondary bile acid loss in mice

Introduction: Chronic inflammatory bowel diseases may lead to severe diarrhea that is difficult to manage despite effective anti-inflammatory treatments. For some forms of diarrhea, secondary bile acid loss may be one contributing mechanism. One form of diarrhea that is particularly difficult to treat is the diarrhea inherent to an ileoanal pouch. Recent evidence has pointed to a role for GLP-1 analogues in reducing diarrhea in patients with an ileoanal pouch. Recent evidence has shown efficacy for GLP-1 analogues in treating primary bile acid diarrhea. Patients with a high output pouch have a deficiency in secondary bile acids. While GLP-1 analogues primarily slow gastric and small intestinal transit, their effect on enterohepatic circulation and bile acid signalling pathways is unknown.

Objectives: This study aimed to investigate the therapeutic effects of GLP-1 receptor agonists on the state of secondary bile acid loss in mice.

Methodology: Secondary bile acid loss was induced in C57BL/6 mice with a colestyramine supplemented diet. Mice were randomized into treatment groups receiving either vehicle, low or high doses of short-acting or long-acting GLP-1 receptor agonists. Body weight and stool water content were monitored. mRNA expression of genes involved in bile acid synthesis and transport was assessed in hepatic and ileal tissues.

Results: Colestyramine-treated mice experienced weight loss to a small degree, while controls maintained stable body weight. Co-treatment with the long-acting agonist led to significant weight reduction.Colestyramine treatment caused a marked increase in stool volume and water content, indicating bile acid-induced diarrhea. High-dose co-treatment with either GLP-1 receptor agonist significantly reduced stool volume and water content. Low-dose co-treatment produced a modest reduction in stool water content. Molecular analysis showed that colestyramine significantly downregulated FXR-dependent bile acid transporter genes in the ileum (p<0.05). Co-administration of the long-acting GLP-1 receptor agonist upregulated Fgf15 expression in the ileum. Colestyramine significantly increased Cyp7a1 expression in the liver (p<0.05), which was suppressed by both GLP-1 receptor agonists.

Conclusion: GLP-1 receptor agonists counteract colestyramine-induced diarrhea and associated molecular disturbances by promoting fluid reabsorption, reducing intestinal motility, and restoring bile acid regulatory pathways.

 

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Publication History

Article published online:
04 September 2025