Gut homeostasis is a dynamically balanced state to maintain intestinal health. Vacuolar ATPases (V-ATPases) are multi-subunit proton pumps that were driven by ATP hydrolysis. Several subunits of V-ATPases may be involved in the maintenance of intestinal pH and gut homeostasis in Drosophila. However, the specific role of each subunit in this process remains to be elucidated. Here, we knocked down the Drosophila gene VhaAC39-1 encoding the V0d1 subunit of V-ATPases to assess its function in gut homeostasis. Knockdown of VhaAC39-1 resulted in the loss of midgut acidity, the increase of the number of gut microbiota and the impairment of intestinal epithelial integrity in flies. The knockdown of VhaAC39-1 led to the hyperproliferation of intestinal stem cells, increasing the number of enteroendocrine cells, and activated IMD signaling pathway and JAK-STAT signaling pathway, inducing intestinal immune response of Drosophila. In addition, knockdown of VhaAC39-1 caused the disturbance of many physiological indicators such as food intake, triglyceride level and fecundity of flies, which ultimately led to the shortening of the life span of Drosophila. These results shed light on the gut homeostasis mechanisms which would help to identify interventions to promote healthy aging.

肠道稳态是维持肠道健康的动态平衡状态。液泡 ATP 酶 (V-ATP 酶) 是由 ATP 水解驱动的多亚基质子泵。V-ATP酶的几个亚基可能参与果蝇肠道pH和肠道稳态​​的维持。然而，每个亚基在这一过程中的具体作用仍有待阐明。在这里，我们敲除编码 V-ATP 酶的 V0d1 亚基的果蝇基因VhaAC39-1，以评估其在肠道稳态中的功能。敲除 VhaAC39-1导致果蝇中肠酸度丧失、肠道微生物群数量增加和肠上皮完整性受损。VhaAC39-1的击倒导致肠道干细胞过度增殖，增加肠内分泌细胞数量，激活IMD信号通路和JAK-STAT信号通路，诱导果蝇肠道免疫反应。此外，VhaAC39-1的敲低引起果蝇摄食量、甘油三酯水平和繁殖力等多项生理指标的紊乱，最终导致果蝇寿命缩短。这些结果揭示了肠道稳态机制，这将有助于确定促进健康衰老的干预措施。