Microbiota-derived SCFAs modulate Socs36E-mediated feedback to regulate intestinal stem cell proliferation upon Atg4 loss in Drosophila

Microbial metabolites affect host physiology, but how they link genetic defects to abnormal stem cell behavior is unclear. In Drosophila, losing Atg4 in progenitors changes the gut microbiota and raises short-chain fatty acids (SCFAs), such as acetate and propionate. These SCFAs increase intracellular acetyl-CoA, which boosts acetylation by inhibiting histone deacetylases (HDACs) and activating multiple histone acetyltransferases. Chromatin immunoprecipitation identifies Socs36E as a direct acetylation target. Socs36E upregulation serves as a feedback brake on EGFR signaling. However, this brake is too weak to stop sustained proliferation, causing intestinal stem cell overgrowth. These phenotypes are abolished in a germ-free niche and can be recapitulated by SCFA-producing bacteria. Our results support a model where niche-derived metabolites drive locus-specific acetylation of Socs36E, modulating a key homeostatic node and influencing stem cell fate decisions.