Butyrate ameliorates lung inflammation in chronic obstructive pulmonary disease in association with the regulation of histone lactylation: A mechanistic study.

Abstract

AIMS: This study investigates the role and mechanism of butyrate in modulating lung inflammation in a murine model of chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS: A COPD mouse model was established via chronic cigarette smoke exposure and treated with sodium butyrate or a vehicle. Lung function, histopathology, gut microbiota, and SCFA (short-chain fatty acid) levels were assessed. RNA sequencing, chromatin immunoprecipitation sequencing, Western blot, immunofluorescence, and flow cytometry were employed to analyze transcriptomic changes, histone H3K18 lactylation (H3K18la), and immune cell infiltration. Human peripheral blood mononuclear cells from COPD patients and healthy controls were analyzed for H3K18la levels. KEY FINDINGS: Butyrate treatment improved lung function and ameliorated histopathological damage, which was associated with restored SCFA levels and altered gut microbiota. Transcriptomic analysis revealed butyrate downregulated genes in immune-inflammatory pathways (e.g., Th17 differentiation, MAPK) and upregulated metabolic genes. Moreover, butyrate treatment was accompanied by a suppression of global lactylation and H3K18la levels, manifested as reduced H3K18la enrichment on pro-inflammatory genes (e.g., in MAPK/JAK-STAT pathways) and increased enrichment on SOCS2. Butyrate reduced lung ILC2 cell numbers and inhibited H3K18la modification within remaining ILC2s. Clinically, H3K18la was significantly elevated in peripheral blood mononuclear cells from COPD patients. SIGNIFICANCE: Butyrate ameliorates COPD, an effect associated with the regulation of histone lactylation, leading to improved lung function and reduced inflammation. The findings highlight gut-derived metabolites' role in modulating epigenetic landscapes and offer potential therapeutic strategies for COPD.