Potential roles of short-chain fatty acids in chronic obstructive pulmonary disease from the gut-lung axis perspective: an exploratory trend summary and discussion on biological mechanisms based on current evidence

Abstract

Short-chain fatty acids (SCFAs) have been proposed as mediators of the gut-lung axis in chronic obstructive pulmonary disease (COPD). However, the human evidence is limited and heterogeneous across disease states and specimen types. We therefore synthesized the available evidence to describe reported associations between fecal or plasma SCFAs and COPD-related phenotypes and to place the proposed biological mechanisms in context. PubMed, Embase, the Cochrane Library, and Web of Science were searched from inception through December 31, 2025. Five studies enrolled 333 participants, of whom 314 contributed SCFA outcome data. Quantitative pooling was not appropriate because the studies differed substantially in disease status, comparison groups, specimen types, interventions, and data formats. We therefore used descriptive statistics and qualitative trend synthesis, stratified findings by population, disease status, and specimen type, and compared interventions narratively. Zhu et al. reported lower levels of all measured fecal SCFAs in 24 patients with acute exacerbation of COPD (AECOPD) than in 18 healthy controls. Li et al. reported lower fecal acetate, isobutyrate, and isovalerate in severe stable COPD, with no significant differences in propionate or butyrate. Kirschner et al. reported lower plasma acetate in stable COPD ( P = 0.001), with no significant differences in propionate or butyrate. Otake et al. found lower plasma total SCFAs and propionate in smokers than in non-smokers; acetate and butyrate did not differ significantly. Because these comparisons were not biologically or methodologically exchangeable, no cross-study effect estimate was calculated. This exploratory synthesis identified study-specific patterns of lower acetate and branched-chain SCFAs, but the patterns varied by disease state, specimen type, and comparison group. They should not be interpreted as evidence of a universal SCFA deficiency in COPD. A high-fiber diet showed beneficial effects in mouse models, whereas a three-month multi-nutrient intervention did not alter gut microbiota composition or systemic inflammation in humans. Larger prospective cohorts and adequately powered, longer-term trials are required before clinical translation can be considered.