The dual role of capsaicin in inflammatory bowel disease: from TRPV1-mediated protection to neurogenic inflammation.

Capsaicin, the pungent vanilloid of chili pepper, is a widely consumed dietary constituent that exerts pleiotropic actions on physiological and pathophysiological processes, including anti-inflammatory, antioxidant, antiproliferative, metabolic and cardioprotective effects. Capsaicin is a small, highly lipophilic molecule that is not appreciably hydrolyzed by digestive enzymes in the gut lumen; it is absorbed across the gastrointestinal epithelium largely in its intact form, mainly by passive diffusion, and enters the portal circulation, where it undergoes extensive first-pass metabolism in the intestinal epithelium and liver before reaching the systemic circulation. Its principal molecular target, transient receptor potential vanilloid 1 (TRPV1), is upregulated in the inflamed colonic mucosa of patients with inflammatory bowel disease (IBD), a chronic relapsing disorder in which current therapies remain limited by incomplete efficacy, loss of response and cumulative toxicity. Because capsaicin activates TRPV1 on capsaicin-sensitive sensory neurons and can thereby evoke burning pain and neurogenic inflammation, its potential relevance to IBD was long overlooked. In recent years, however, a growing body of preclinical evidence has shown that capsaicin can attenuate experimental colitis through multiple pathways, including anti-inflammatory action, mucosal protection, microbiota regulation and microcirculation regulation, whereas higher doses, certain routes of administration and an already-inflamed mucosa favour adverse effects-consistent with the bell-shaped dose-response relationship reported for capsaicin. This review summarizes the evidence for the protective effects of capsaicin in IBD, outlines its gastrointestinal adverse effects and the TRPV1-dependent mechanisms that underlie them, and discusses how dose, route, duration of exposure and disease stage determine whether capsaicin acts as friend or foe.