Glucagon-like peptide-1 (GLP-1) receptor agonists in inflammatory bowel disease: mechanisms, clinical implications, and therapeutic potential

Abstract

Glucagon-like peptide-1 receptor agonists are increasingly recognized for their potential dual benefit in inflammatory bowel disease (IBD), offering metabolic advantages alongside emerging anti-inflammatory, immunomodulatory, and gut barrier-enhancing effects. Pre-clinical data demonstrate attenuation of inflammation, preservation of epithelial integrity, and modulation of the microbiome in colitis models. Early retrospective studies in patients with IBD suggest improved clinical outcomes, such as reduced hospitalization and surgery rates, particularly in those with obesity. Glucagon-like peptide-1 receptor agonists are already widely used for obesity and diabetes, including increasing self-administration by patients outside medical supervision. Their impact on drug absorption, safety in gastrointestinal disease, and interactions with existing IBD therapies require further exploration. This review synthesizes the mechanistic rationale, pre-clinical evidence, and clinical data to date, highlighting the potential utility and safety considerations of glucagon-like peptide-1 receptor agonists in IBD and emphasizes the need for robust prospective trials to ascertain their safety and efficacy in this patient population.

Keywords: Crohn’s disease; glucagon-like peptide-1 receptor agonists; inflammatory bowel disease; ulcerative colitis.

Figure 1.

(A) Classical GLP-1 signaling in the pancreas and stomach. (B) Multi-organ effects of GLP-1 signaling. Figures created in BioRender. Povlsen, S. (2025), https://BioRender.com/kygr09l

Figure 2.

(A) Inflammatory stimuli such as interleukin-6 (IL-6) and lipopolysaccharide (LPS) endotoxin trigger secretion of GLP-1 by enteroendocrine L cells in the intestine. GLP-1 signaling, via endogenous GLP-1 or GLP-1RAs, induces M2 macrophage polarization and reduces M1 polarization. M2 macrophages, in turn, promote regulatory T cell (Treg) differentiation through TGF-β signaling and support IL-10 production, further amplifying anti-inflammatory effects. GLP-1 also acts directly on αβ and γδ T cells, reducing pro-inflammatory cytokine and chemokine secretion, altering microbiome–immune cell interactions, and modulating gut microbial composition. Additionally, GLP-1 signaling exerts intestinotrophic effects by stimulating crypt fission, enhancing epithelial barrier integrity through increased intercellular adhesion, and promoting mucin production. (B) Intracellular GLP-1 signaling mechanisms in immune cells. T cell receptor (TCR)-mediated signaling is reduced by GLP-1 signaling via induction of cyclic adenosine monophosphate (cAMP), which activates protein kinase A (PKA). This leads to inhibition of zeta-chain-associated protein kinase 70 (ZAP-70), which lies downstream of TCR activation. This in turn reduces signal transduction through SH2 domain containing leukocyte protein 76 (SLP-76) and resulting gene expression. Induced cAMP also inhibits NF-κB activation, nuclear translocation, and resulting gene expression. cAMP induction leads to increased M2 and decreased M1 macrophage polarization via inhibition of c-Jun N-terminal kinases (JNKs) and thereby transcription factor Jun (cJun)-related gene expression, and via activation of signal transducer and activator of transcription 3 (STAT 3). Dashed lines: indirect pathways. Solid lines: direct pathways. Figures created in BioRender. Povlsen, S. (2025), https://BioRender.com/yjxadfx

Figure 3.

Practical advice to clinicians when managing patients with IBD who are taking GLP-1RAs.^,