What question did this study set out to answer?

This study aims to evaluate the effects of glucagon-like peptide-1 receptor agonists on inflammatory bowel disease severity and understand the underlying mechanisms.

June 7, 2026

2462-P: Glucagon-Like Peptide 1 Receptor Agonism Ameliorates Colonic Inflammation in a Murine Model of Inflammatory Bowel Disease via Central and Peripheral Mechanisms

Key Points

This study aims to evaluate the effects of glucagon-like peptide-1 receptor agonists on inflammatory bowel disease severity and understand the underlying mechanisms.
C57BL/6 mice were fed a high-fat diet to induce obesity for 12-14 weeks.
Mice received either subcutaneous Semaglutide or vehicle, or intracerebroventricular Semaglutide infusion.
Colitis was induced using 2% dextran sodium sulfate after 14 days of treatment.
Subcutaneous Semaglutide led to a significant weight loss of 18.44% compared to vehicle (p<0.0001).
Intracerebroventricular Semaglutide reduced colitis severity by 18.3% clinically and 17.6% histopathologically (p<0.0001 for each).
Subcutaneous Semaglutide reduced colitis by 35.9% clinically and 12.9% histopathologically (p<0.0001 for each), affecting proinflammatory cytokine levels.

Abstract

Introduction and Objective: Type 2 diabetes (T2D), obesity, and inflammatory bowel disease (IBD) are increasingly common inflammatory disorders. Additionally, comorbid obesity and T2D are linked to more severe IBD. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as Semaglutide (Sema), are thought to promote weight loss and improve glycemic control through peripheral and central nervous system (CNS) pathways, while also exerting anti-inflammatory effects. This study examined whether Sema reduces IBD severity in diet-induced obese (DIO) mice and whether this involves a central mechanism of action. Methods: Adult male C57BL/6 mice consumed a high-fat diet for 12-14 wks to induce DIO, then underwent subcutaneous (subQ) implantation of an osmotic minipump containing either Sema or vehicle (veh). In separate studies, Sema was delivered either subQ (40 μg/kg bw), or infused directly into the brain via an intracerebroventricular (ICV) cannula at a much lower dose (4 μg/kg bw; a dose with no peripheral effect). After 14d, 2% dextran sodium sulfate (DSS) was given in drinking water for 10d to induce colitis. Results: Peripheral and central Sema both caused weight loss before DSS, with a greater effect from peripheral dosing (peripheral Sema: -18.44%, p0.0001 vs veh. Central Sema: -8.62%, p0.0001 vs veh, p0.0001 peripheral vs central). Sema reduced both clinical and histopathologic DSS colitis severity given centrally (18.3% and 17.6%, respectively; p0.0001 for each) or SubQ (35.9% and 12.9%, respectively; p0.0001 for each). Systemic Sema also lowered colonic proinflammatory cytokine expression, an effect not seen with ICV Sema. Conclusion: We report that DSS colitis is ameliorated by Sema administration, whether given centrally or systemically. Additional mechanistic studies are needed, but we conclude that activation of GLP1 receptors in the brain is sufficient to improve outcomes in a mouse model of IBD. Disclosure B. Desai: None. K. Francis: None. C. Bryan: None. J.N. Connolly: None. T. Karunagaran: None. S.A. Mathan: None. K. Sharma: None. C.A. Watts: None. P. Choi: None. K.H. Kadlec: None. B.N. Phan: None. M.C. Pacheco: Research Support; Current; Taisho Pharmaceutical Holdings Co., Ltd. G. Morton: None. M.W. Schwartz: Consultant; Current; Eli Lilly and Company. J. Scarlett: None. Funding National Institutes of Health (2T32DK007247-46)

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2462-P: Glucagon-Like Peptide 1 Receptor Agonism Ameliorates Colonic Inflammation in a Murine Model of Inflammatory Bowel Disease via Central and Peripheral Mechanisms

Key Points

Abstract

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