From the gut to the lung: microbiota-associated metabolites as regulators of respiratory immunometabolism

Abstract

The development and progression of respiratory diseases are influenced by both the local pulmonary microenvironment and the intestinal ecosystem. Research on the gut-lung axis has shown that diverse small-molecule metabolites produced or modified by the gut microbiota can cross the intestinal barrier and enter the systemic circulation, where they may modulate immune-cell response thresholds, functional polarisation, and inflammatory dynamics in the distal lung. The local respiratory microbiota may also contribute to the pulmonary metabolic microenvironment, although its role in metabolite production and immune regulation remains less clearly defined. This review summarises the metabolic features of the gut and respiratory microbiota, focusing on the production, systemic distribution, and immunomodulatory mechanisms of microbiota-associated metabolites, including short-chain fatty acids, other short-chain carboxylic acids, and amino acid-derived metabolites, with attention to their effects on respiratory immune-cell populations. These mechanisms include metabolite-sensing G protein-coupled receptor signalling, histone deacetylase inhibition, and aryl hydrocarbon receptor-dependent mucosal immune programmes. At the disease level, current evidence suggests that these metabolites mainly influence viral infections, bacterial infections, and chronic inflammatory lung diseases by regulating immune-response intensity, persistence, and tissue tolerance, rather than directly mediating pathogen clearance. Finally, this review discusses the key challenges and future directions for moving from associative studies to causal validation and translational applications.