Butyrate silences MUC5ACexpression in airway epithelial cells by mediating histone deacetylation at its transcription start site

Abstract

Abstract Secreted airway mucins form a mucous gel consisting of MUC5AC and MUC5B and maintain airway homeostasis for appropriate mucociliary clearance and airway defense. There is conceivably a global mechanism to counteract excessive mucin production in response to incessant exposure to external and internal stimuli, which otherwise leads to goblet metaplasia and mucus hyperproduction. Here, we report that butyrate, a short-chain fatty acid (SCFA), strongly suppresses MUC5AC production at as low as sub-to micromolar concentrations in NCI-H292, airway epithelial cells. Butyrate transcriptionally inhibits MUC5AC mRNA and protein that are induced by a variety of stimuli including EGF and LPS. In line, butyrate upregulates FOXA2, which is known to block goblet cell metaplasia. The mode of the inhibition by butyrate appears to be independent of the known receptors of butyrate. In addition, butyrate does not alter the EGFR signaling pathway. Chromatin immunoprecipitation analysis demonstrates that histone H3K27 acetylation level is increased upon stimulation with EGF and returns to baseline in the presence of butyrate. We propose that butyrate, a metabolic product of gut microbiota, plays a central role in maintaining homeostasis of airway mucous gel by counteracting mucin production resulting from repeated provocation of airway epithelium. National Research Foundation of Korea (NRF) funded by the Korean government (MSIT), NRF-2022R1A2B5B01002127.