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Background <p>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.</p> Results <p>We identify a microbiota‒metabolite‒epigenome axis through which <i>Atg2</i> deficiency triggers metabolic‒immune cascades in the <i>Drosophila</i> intestine. Tissue-specific <i>Atg2</i> 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.</p> Conclusions <p>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.</p> <p><MediaObject ID="MOESM2"> <VideoObject FileRef="MediaObjects/40168_2026_2356_MOESM2_ESM.mp4" VideoID="DhctqdtdvNh4uVJSXzHUZA"> <Caption Language="En" xml:lang="en"> <CaptionContent> <p>Video Abstract</p> </CaptionContent> </Caption> </VideoObject> </MediaObject></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月27日

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  • Ping Wang,
  • Xinran Li,
  • Jiangong Zhang,
  • Jiewei Wang,
  • Li Hua Jin

摘要

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