Butyrate reverts Chlamydia pneumoniae -induced transcriptional suppression of macrophage polarization markers and promotes chlamydial clearance in macrophages

Short-chain fatty acids (SCFAs) are generated by gut microbiota through fermentation of dietary fibers. SCFAs contribute to human health through immunomodulation, metabolic regulation and other extra intestinal functions. The aim of this study was to investigate the effects of SCFAs on the survival and antibiotic susceptibility of the intracellular bacteria Chlamydia pneumoniae and Chlamydia trachomatis, both representing prevalent human pathogens associated with chronic sequelae. Despite earlier reports on their direct antimicrobial activity, none of the three major SCFAs acetate, propionate nor butyrate affected the growth of C. pneumoniae or C. trachomatis in epithelial cells. However, butyrate decreased C. pneumoniae genome copy numbers and infectious progeny production in THP-1 macrophages harbouring antibiotic-refractory infection phenotype. In addition, butyrate enhanced the chlamydiocidal efficacy of azithromycin in the macrophages. Similar results were obtained with C. trachomatis-infected macrophages. To elucidate the underlying molecular changes, impact of chlamydial infection, butyrate treatment and the combination theirof on macrophage polarization and antimicrobial peptide expression was investigated. C. pneumoniae suppressed the expression of macrophage polarization markers CD80, TLR4, CD64, CD204 and CD206, and the antimicrobial peptide LL37, while butyrate treatment reverted the expression of both the polarization markers and LL37 in the infected macrophages. These findings suggest that butyrate may play a role in modulating immune responses in macrophages during Chlamydia infections, highlighting the role of diet-derived metabolites in shaping Chlamydia-host interactions and antichlamydial treatment efficacy.