REPOSITIONING DUAL GLP-1/GIP RECEPTOR AGONISTS FOR THE TREATMENT OF COLITIS AND COLITIS-ASSOCIATED TUMORIGENESIS

Abstract Chronic colitis in patients with ulcerative colitis (UC) and Crohn’s disease (CD) predisposes patients to debilitating symptoms and an increased risk of colorectal cancer (CRC). Despite advances in biologics, only 30–40% of patients achieve sustained remission, underscoring the need for novel agents with complementary mechanisms of action and reduced toxicity. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist originally developed for type 2 diabetes, has demonstrated favorable metabolic and anti-inflammatory effects, suggesting potential utility in gastrointestinal disease. While GLP-1 receptor agonists have shown promise in acute colitis models and epidemiological studies indicate reduced CRC incidence among exposed individuals, the effects of dual agonists in chronic colitis-associated cancer (CAC) remain unknown. We evaluated Tirzepatide in the Winnie mouse, a model of spontaneous UC-like colitis and CAC. Weekly administration of Tirzepatide (30 nmol/kg, 8 weeks) markedly reduced colitis severity and tumor burden compared to vehicle controls. Treated mice exhibited improved weight stability independent of obesity, reflecting attenuation of inflammation and tumorigenesis rather than metabolic effects. Histologic analyses confirmed reduced inflammatory scores, preservation of crypt architecture, and fewer dysplastic lesions. At the molecular level, Tirzepatide suppressed transcription of colon cancer-associated genes (Axin2, Myc, Cdkn1a, Lgr5) and reduced pro-survival and proliferative signaling proteins (p-AKT, p-PFK2, Cyclin D1). Inflammatory cytokine transcripts (Il6, Il1β, Tnf) and stool lipocalin-2 levels were significantly decreased, corroborating broad anti-inflammatory activity. These findings align with reports of Tirzepatide suppressing tumor growth in patient-derived CRC xenografts, reinforcing a potential direct effect on epithelial oncogenic pathways rather than an indirect consequence of weight loss. Our results support Tirzepatide as a promising therapeutic candidate that bridges metabolic and immune pathways to mitigate colitis and CAC. Its dual receptor activity may synergize with existing therapies such as mesalamine or biologics, offering an advanced combination therapeutic approach to IBD management and cancer prevention. Future studies are warranted to define dosing strategies that dissociate metabolic from anti-inflammatory effects and to evaluate long-term outcomes in translational and clinical settings.