Butyrate modulates the epigenetic landscape of human natural killer cells and affects their regulatory function

Abstract

Gut bacteria-derived metabolites, such as butyrate (BUT), shape the function of T 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 and response to viruses, 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^bright and CD56^dim NK cells, and represses genes specific for non-classical NK cells. Through flow cytometry, we observed that BUT induces CD69 + NK cells and decreases CD56^bright NK cells. Finally, we found that the suppressor function of CD56^bright NK cells towards autologous CD4 + T cells was decreased by BUT. In conclusion, we show that BUT affects the epigenetic landscape of human NK cells, their phenotype and regulatory function.