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<p>Eco-friendly poly(butylene adipate-co-terephthalate) (PBAT) is widely marketed as biodegradable, yet the neurotoxicity of derived PBAT microplastics (PBAT-MPs) and their underlying mechanisms remain poorly characterized. Here we identify a previously unrecognized “gut microbiota–butyrate–neuro-lipid” axis linking intestinal PBAT-MPs exposure to hippocampal microglial lipotoxicity and cognitive impairment. By integrating fecal microbiota transplantation (FMT) with multi-omics analyses, we demonstrate that orally administered PBAT-MPs preferentially accumulate in the colon, impair epithelial barrier integrity, deplete butyrate-associated taxa, including <i>Muribaculaceae</i> and <i>Alloprevotella</i>, and enrich <i>Escherichia–Shigella</i>. Butyrate depletion elevates systemic lipopolysaccharide (LPS) levels and, via the gut–brain inflammatory route, activates mTORC1–integrated stress response (ISR) signaling in microglia. Consequently, microglia acquire a lipotoxic phenotype characterized by transcriptional up-regulation of <i>DGAT</i>- and <i>ACSL</i>-dependent lipid droplet (LD) biogenesis genes, accumulation of toxic lipids and inflammatory mediators, synaptic stripping, and memory loss. In vivo butyrate supplementation in PBAT-MP-exposed mice alleviates hippocampal pathology, normalizes microglial lipid accumulation, suppresses neuroinflammation, reduces ceramide levels, and improves cognitive performance. Mechanistically, butyrate inhibits mTORC1, attenuates eIF2α–ATF4-dependent ISR signaling, and represses DGAT/ACSL-dependent LD biogenesis, whereas microglial Rptor overexpression abolishes these protective effects, identifying mTORC1 as an upstream metabolic checkpoint. Collectively, our findings establish the microbiota–butyrate–mTORC1–ISR relay as a core driver of PBAT-MPs-induced neurotoxicity and highlight restoration of butyrate signaling as a promising microbiota-based strategy for preventing microplastic-induced brain lipotoxic injury.</p> Graphical Abstract <p></p>

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Butyrate-producing gut bacteria restrain PBAT microplastic-triggered brain microglial lipotoxicity via a microbiota–butyrate–mTORC1–ISR relay along the gut–brain axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月13日

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  • Ming-Zhu Wang,
  • Ze-Bang Du,
  • Wen-Qi Xu,
  • Yu-Han Xie,
  • Lei-Lei Wang,
  • Xin-Xin He,
  • Yu-Han Wang,
  • Han-Ying Zheng,
  • You-Liang Yao,
  • Ya-Bin Song,
  • Zhong-Ning Lin,
  • Yu-Chun Lin

摘要

Eco-friendly poly(butylene adipate-co-terephthalate) (PBAT) is widely marketed as biodegradable, yet the neurotoxicity of derived PBAT microplastics (PBAT-MPs) and their underlying mechanisms remain poorly characterized. Here we identify a previously unrecognized “gut microbiota–butyrate–neuro-lipid” axis linking intestinal PBAT-MPs exposure to hippocampal microglial lipotoxicity and cognitive impairment. By integrating fecal microbiota transplantation (FMT) with multi-omics analyses, we demonstrate that orally administered PBAT-MPs preferentially accumulate in the colon, impair epithelial barrier integrity, deplete butyrate-associated taxa, including Muribaculaceae and Alloprevotella, and enrich Escherichia–Shigella. Butyrate depletion elevates systemic lipopolysaccharide (LPS) levels and, via the gut–brain inflammatory route, activates mTORC1–integrated stress response (ISR) signaling in microglia. Consequently, microglia acquire a lipotoxic phenotype characterized by transcriptional up-regulation of DGAT- and ACSL-dependent lipid droplet (LD) biogenesis genes, accumulation of toxic lipids and inflammatory mediators, synaptic stripping, and memory loss. In vivo butyrate supplementation in PBAT-MP-exposed mice alleviates hippocampal pathology, normalizes microglial lipid accumulation, suppresses neuroinflammation, reduces ceramide levels, and improves cognitive performance. Mechanistically, butyrate inhibits mTORC1, attenuates eIF2α–ATF4-dependent ISR signaling, and represses DGAT/ACSL-dependent LD biogenesis, whereas microglial Rptor overexpression abolishes these protective effects, identifying mTORC1 as an upstream metabolic checkpoint. Collectively, our findings establish the microbiota–butyrate–mTORC1–ISR relay as a core driver of PBAT-MPs-induced neurotoxicity and highlight restoration of butyrate signaling as a promising microbiota-based strategy for preventing microplastic-induced brain lipotoxic injury.

Graphical Abstract