Butyrate enhances CD56 NK cell-driven killing of activated T cells and modulates NK cell chromatin accessibility.

Gut bacteria-derived metabolites, such as butyrate (BUT), induce T regulatory cells through inhibition of histone deacetylases (HDAC). Natural killer (NK) cells are innate lymphocytes with important effector and regulatory functions; little is known on the effect of BUT on NK cells. Here we aimed at evaluating whether BUT affects the epigenetic landscape of human NK cells. We found that BUT inhibits HDAC on human NK cells. Through ATAC sequencing, we demonstrated that BUT affects the chromatin accessibility of human NK cells, influencing, among others, genetic pathways related to immune regulation, response to viruses, chromatin remodeling and genes encoding for micro-RNAs. We identified, through analysis of published transcriptomic data, genes specific for NK-cell functional clusters, and we overlapped results of ATAC-sequencing, finding that BUT activates genes specific for CD56 and CD69+CD56 NK cells, and represses genes specific for non-classical NK cells. Through flow cytometry, we observed that BUT induces CD69+CD56 NK cells. Finally, we found increased cytotoxicity of BUT-treated CD56 NK cells towards CD25+ and CD69+ T cells, despite a trend towards decreased suppressor function towards total autologous CD4+ T cells. In conclusion, we show that BUT affects the epigenetic landscape of human NK cells, their phenotype and regulatory function.