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

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. Video Abstract.