Microbe-derived acetate activates the Drosophila immunodeficiency (IMD) pathway in a subset of enteroendocrine cells (EECs) of the anterior midgut. In these cells, the IMD pathway co-regulates expression of antimicrobial and enteroendocrine peptides including tachykinin, a repressor of intestinal lipid synthesis. To determine whether acetate acts on a cell surface pattern recognition receptor or an intracellular target, we asked whether acetate import was essential for IMD signaling. Mutagenesis and RNA interference revealed that the putative monocarboxylic acid transporter Tarag was essential for enhancement of IMD signaling by dietary acetate. Interference with histone deacetylation in EECs augmented transcription of genes regulated by the steroid hormone ecdysone including IMD targets. Reduced expression of the histone acetyltransferase Tip60 decreased IMD signaling and blocked rescue by dietary acetate and other sources of intracellular acetyl-CoA. Thus, microbe-derived acetate induces chromatin remodeling within enteroendocrine cells, co-regulating host metabolism and intestinal innate immunity via a Tip60-steroid hormone axis that is conserved in mammals.

微生物来源的醋酸盐激活果蝇前中肠的一部分肠内分泌细胞 (EEC) 中的免疫缺陷 (IMD) 通路。在这些细胞中，IMD 通路共同调节抗菌肽和肠内分泌肽的表达，包括速激肽，一种肠道脂质合成的阻遏物。为了确定醋酸盐是否作用于细胞表面模式识别受体或细胞内靶标，我们询问醋酸盐输入是否对 IMD 信号传导至关重要。诱变和 RNA 干扰表明推定的单羧酸转运蛋白 Tarag 对于膳食乙酸盐增强 IMD 信号传导至关重要。干扰 EEC 中的组蛋白去乙酰化增强了由类固醇激素蜕皮激素调节的基因的转录，包括 IMD 靶标。组蛋白乙酰转移酶 Tip60 的表达降低会降低 IMD 信号传导并阻止膳食醋酸盐和其他细胞内乙酰辅酶 A 来源的拯救。因此，微生物来源的醋酸盐可诱导肠内分泌细胞内的染色质重塑，通过哺乳动物中保守的 Tip60 类固醇激素轴共同调节宿主代谢和肠道先天免疫。