Differential regulatory mechanisms of gut-derived SCFAs (acetate, propionate, butyrate) on the pulmonary TLR2 signaling pathway and their roles in the inflammatory balance of bacterial pneumonia

Gut microbiota-derived short-chain fatty acids (SCFAs), key mediators in gut-lung axis interactions, profoundly influence pulmonary immune homeostasis. Toll-like receptor 2 (TLR2) is crucial for initiating innate immunity against bacterial pneumonia by recognizing bacterial molecular patterns, but its signaling requires precise regulation to balance pathogen clearance and prevent excessive inflammation-induced tissue damage. The major SCFAs-acetate, propionate, and butyrate-modulate immune responses via distinct mechanisms, including G protein-coupled receptor (GPR) activation and histone deacetylase (HDAC) inhibition. However, direct evidence on how these SCFAs differentially regulate the pulmonary TLR2 signaling pathway in pulmonary cells is critically lacking. This review reviews current knowledge, examining TLR2's role in pulmonary immune defense and bacterial pneumonia, along with its regulatory network, and the molecular details of SCFA immunomodulation through GPR activation and HDAC inhibition. Crucially, we propose and thoroughly discuss a central hypothesis based on indirect evidence and molecular understanding: acetate and propionate likely inhibit early TLR2 signaling activation via GPR-mediated rapid pathways, while butyrate predominantly promotes late-stage inflammation resolution and tissue homeostasis by remodeling gene expression through its HDAC inhibitory activity. We further analyze the potential biological significance of this postulated differential regulatory pattern in maintaining inflammatory balance during bacterial pneumonia. This review integrates literature and mechanistic analysis, highlights critical knowledge gaps in SCFA-pulmonary TLR2 axis research (such as lack of direct evidence, unclear in vivo differential effects, and local concentration influence), and outlines future research directions to deepen understanding of gut-lung axis-mediated pulmonary immune regulation, providing a theoretical foundation for innovative bacterial pneumonia prevention and treatment strategies.