Microbe-dependent inter-organ communication regulates germline stem cell proliferation in Drosophila

Animals integrate environmental cues with internal physiological states through inter-organ communication to regulate reproduction. However, how environmental microbes are incorporated into these systemic pathways to control reproductive stem cell proliferation remains poorly understood. Here, we demonstrate that environmental microbes colonizing the gut promote stem cell-mediated oogenesis in Drosophila melanogaster by increasing germline stem cell (GSC) number. This process requires microbial activation of gut metabolic pathways, including glycolysis and the pentose phosphate pathway (PPP), linking microbial cues to organismal physiology. We further show that microbial cues modulate circadian clock gene expression in both the gut and brain, and that circadian gene activity in these tissues is required for microbe-induced increases in GSCs. These metabolic changes promote ecdysone and juvenile hormone signaling in ovarian somatic cells, and single-cell transcriptomic analyses further reveal cell type-specific metabolic and hormonal responses across germline and follicle cell populations. Together, our findings establish that microbe-dependent gut-mediated inter-organ communication integrates metabolism, circadian gene expression, and endocrine signaling to regulate stem cell-mediated reproduction in Drosophila.