Melatonin supplementation in preclinical colitis models: A systematic review and dose-response meta-analysis on inflammation, oxidative stress, and colon repair

Abstract

Background: Ulcerative colitis (UC), an autoimmune form of inflammatory bowel disease (IBD), leads to chronic inflammation of the colon. Existing treatments often fall short, highlighting the need for alternative or supplementary therapies. Melatonin, known for its antioxidant and anti-inflammatory effects, shows promise in this context. Thus, this study conducts a dose-response meta-analysis and systematic review of preclinical models to evaluate melatonin's effectiveness in UC. Methods: Extensive searches in PubMed, Scopus, Embase, and Web of Science were performed, adhering to SYRCLE's risk of bias guidelines, and registered with PROSPERO (CRD42024511595). Random-effects models calculated standard mean differences (SMD) and 95 confidence intervals (CI) for disease activity indices, inflammatory markers, and antioxidant defenses. Results: Out of 860 screened records, 72 studies met the inclusion criteria. Melatonin was found to significantly lower the ulcer index (SMD = -3.19) and malondialdehyde levels (SMD = -2.31). It also notably suppressed key pro-inflammatory mediators, including TNF-alpha (SMD = -1.14), IL-6 (SMD = -1.44), IL-1 beta (SMD = -1.63) and IL17 (SMD = -1.77), while enhancing antioxidant defenses, particularly glutathione levels (SMD = 2.80). Furthermore, melatonin effectively modulated critical inflammatory regulators including nuclear factor kappa B (SMD = -1.97) and cyclooxygenase-2 (SMD = -1.34). The optimal therapeutic dose was identified as up to 10 mg/kg, with the highest efficacy observed via intraperitoneal and intracolonic administration routes. Conclusion: Melatonin showed significant anti-inflammatory, antioxidant and tissue-repairing benefits in preclinical UC models, supporting clinical trials to confirm its therapeutic potential and optimal dosing.