Carlini Federico, Squillario Margherita, Casella Valentina, Capaia Matteo, Lusi Valeria, Bagnara Davide, Colombo Monica, Palmeri Serena, Ivaldi Federico, Loiacono Fabrizio, Uccelli Antonio, Piana Michele, Laroni Alice
IRCCS Ospedale Policlinico San Martino, Genova, Italy.
Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy.
Genes Immun. 2025 Jun 12. doi: 10.1038/s41435-025-00338-2.
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.
肠道细菌衍生的代谢产物，如丁酸盐（BUT），通过抑制组蛋白脱乙酰酶（HDAC）诱导调节性T细胞。自然杀伤（NK）细胞是具有重要效应和调节功能的固有淋巴细胞；关于BUT对NK细胞的影响知之甚少。在这里，我们旨在评估BUT是否会影响人类NK细胞的表观遗传格局。我们发现BUT抑制人类NK细胞上的HDAC。通过ATAC测序，我们证明BUT会影响人类NK细胞的染色质可及性，尤其会影响与免疫调节、病毒应答、染色质重塑以及微小RNA编码基因相关的遗传途径。我们通过分析已发表的转录组数据，确定了NK细胞功能簇特有的基因，并将ATAC测序结果进行比对，发现BUT激活CD56和CD69+CD56 NK细胞特有的基因，并抑制非经典NK细胞特有的基因。通过流式细胞术，我们观察到BUT可诱导CD69+CD56 NK细胞。最后，我们发现经BUT处理的CD56 NK细胞对CD25+和CD69+ T细胞的细胞毒性增加，尽管对总自体CD4+ T细胞的抑制功能有下降趋势。总之，我们表明BUT会影响人类NK细胞的表观遗传格局、其表型和调节功能。
