Sodium Butyrate Therapy in Ulcerative Colitis: A Systematic Review of Preclinical and Clinical Evidence.

Background/Objectives: Sodium butyrate, a short-chain fatty acid produced by gut microbial fermentation of dietary fiber, has attracted increasing interest as a potential adjunctive therapy for ulcerative colitis (UC) because of its anti-inflammatory, barrier-protective, and immunomodulatory properties. This systematic review aimed to evaluate the current clinical and preclinical evidence regarding the efficacy and mechanisms of sodium butyrate in UC. Methods: A systematic review was conducted in accordance with the PRISMA 2020 guidelines and registered in PROSPERO (CRD420261437741). PubMed/MEDLINE, Scopus, Web of Science, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched from February through April 2026. Eligible clinical and experimental studies investigating oral or rectal administration of sodium butyrate in UC or experimental colitis were included. Risk of bias was assessed using RoB 2, ROBINS-I, or the SYRCLE tool according to study design. Results: Twenty-two studies were included, comprising ten clinical trials, one prospective observational study and eleven preclinical animal studies. In adults diagnosed with UC, oral sodium butyrate, particularly microencapsulated formulations, demonstrated encouraging effects as an adjunct to standard therapy by improving clinical remission rates, quality of life and reducing disease activity and inflammatory biomarkers. Evidence in pediatric inflammatory bowel disease remained inconsistent. Studies evaluating rectal sodium butyrate enemas reported variable clinical efficacy despite evidence of local biological activity. Preclinical studies consistently demonstrated reduced intestinal inflammation, improved epithelial barrier integrity, modulation of oxidative stress, favorable alterations of the gut microbiota, and regulation of several mechanistic pathways identified across individual preclinical studies, including PI3K/AKT/mTOR, WNT/ERK, ERK/STAT3, autophagy and ferroptosis. Conclusions: Current evidence suggests that sodium butyrate represents a promising adjunctive therapeutic strategy for UC, supported by consistent mechanistic findings and encouraging clinical results, particularly with oral formulations. However, the available clinical evidence remains heterogeneous, and larger, well-designed randomized controlled trials with standardized formulations and treatment protocols are required before its routine clinical implementation can be considered.