Atg2 coordinates microbial metabolite signaling and epigenetic remodeling to maintain intestinal lipid homeostasis in Drosophila

Abstract Background The autophagy-related protein Atg2 maintains intestinal homeostasis by preventing lipid accumulation and microbial dysbiosis; however, the mechanisms by which these pathologies interconnect remain unknown. Results We identify a microbiota‒metabolite‒epigenome axis through which Atg2 deficiency triggers metabolic‒immune cascades in the Drosophila intestine. Tissue-specific Atg2 depletion disrupts autophagic flux, provoking commensal overgrowth and pathogenic overproduction of short-chain fatty acids (SCFAs). Elevated SCFAs drive acetyl-CoA overflow, inducing global protein hyperacetylation that simultaneously activates lipogenic programs and primes innate immunity. Crucially, microbiota ablation or SCFAs restriction fully reverses lipid–immune dysregulation, mechanistically linking microbial metabolites to host pathophysiology. Conclusions Our work establishes Atg2 as a guardian of microbiota-derived metabolite signaling, demonstrating that autophagy constrains microbial byproducts to prevent acetyl-CoA-mediated epigenetic hijacking of metabolic and immune networks. These findings reveal protein acetylation as a convergent regulator linking commensal ecology to host physiology, suggesting metabolite-centric therapies for dysbiosis-associated disorders.