Butyrate Regulating Inflammatory Responses in Chronic Obstructive Pulmonary Disease via the Gut-Lung Axis

Chronic obstructive pulmonary disease (COPD) poses a major global health challenge, yet current pulmonary-directed therapies offer only symptomatic relief without modifying the underlying systemic inflammatory pathology. The gut-lung axis has emerged as a pivotal cross-organ regulatory circuit in COPD progression, and butyrate-a key microbial short-chain fatty acid derived from dietary fibre fermentation-mediates pleiotropic immunomodulatory effects that bridge intestinal homeostasis and pulmonary inflammation. This narrative review synthesises preclinical and limited clinical evidence to elucidate the regulatory functions of butyrate in COPD inflammation via the gut-lung axis, organising its core mechanisms into four major modules: strengthening intestinal mucosal barrier integrity, suppressing type 2 innate lymphoid cell overactivation, restoring the Th17/Treg homeostatic balance, and interrupting pathological endothelial-macrophage inflammatory crosstalk. Importantly, the therapeutic potential of butyrate is phenotype-restricted; its anti-inflammatory actions are primarily validated in the type 2 inflammatory COPD subtype, which affects only 20-40% of patients, whereas robust evidence for efficacy in the predominant neutrophilic phenotype remains scarce. Translational hurdles further impede clinical application, including poor oral bioavailability due to first-pass hepatic metabolism, insufficient human clinical verification, and the theoretical risk of excessive immunosuppression at elevated concentrations. Moreover, most mechanistic inferences are drawn from in vitro studies and cigarette smoke-induced animal models that incompletely recapitulate the heterogeneous pathophysiology of human COPD. This review critically appraises the current theoretical framework of butyrate-mediated gut-lung co-regulation, delineates the applicable patient subsets and core limitations of butyrate intervention, and highlights priority research directions encompassing phenotype-stratified clinical trials, optimised targeted delivery systems, and comparative analyses of multiple short-chain fatty acids. Although butyrate offers a promising theoretical foundation for developing novel gut-lung coordinated disease-modifying strategies, rigorous stratified clinical validation remains essential to ascertain its genuine therapeutic value in practice.