Therapeutic potential of butyrate supplementation in sepsis: a review of preclinical evidence and translational perspectives

Sepsis remains a major global health problem and is responsible for millions of deaths annually despite significant progress in antimicrobial therapy and organ support. Increasing evidence highlights the role of the gut-immune axis in shaping host responses during sepsis, with particular interest in microbiota-derived metabolites such as short-chain fatty acids (SCFAs). Among these, butyrate has emerged as a promising candidate due to its anti-inflammatory, immunomodulatory, and intestinal barrier-preserving properties. This narrative review summarizes current evidence regarding the biological activities of butyrate and its potential therapeutic relevance in sepsis and septic shock. A comprehensive literature search of PubMed and additional sources up to April 2025 identified experimental and clinical studies evaluating butyrate supplementation in sepsis. Preclinical studies show that butyrate improves function across organ systems (neurologic, hepatic, intestinal, cardiac, pulmonary, and renal) mainly by reducing inflammation, oxidative stress, and epithelial barrier disruption. In models like cecal ligation and puncture (CLP) or endotoxemia, survival improved by 20-40 % with butyrate administration. Human data are limited: an observational study found higher circulating β-hydroxybutyrate levels in sepsis survivors, while a randomized trial reported fewer gastrointestinal complications and ventilator-associated pneumonia in patients with synbiotic-induced butyrate increases. Overall, current evidence suggests that butyrate may modulate key pathophysiological pathways in sepsis and holds potential as an adjunctive therapy. Nonetheless, dedicated early-phase clinical trials are required to clarify safety, optimal dosing, pharmacodynamics, and clinical effectiveness.