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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
Original title: Butyrate-producing gut bacteria restrain PBAT microplastic-triggered brain microglial lipotoxicity via a microbiota–butyrate–mTORC1–ISR relay along the gut–brain axis
Summary
Researchers found that "biodegradable" PBAT plastic particles—found in some eco-friendly packaging—can harm gut bacteria in mice, wiping out helpful microbes that produce butyrate, a compound that normally keeps the gut lining and brain healthy. This triggers a chain reaction leading to brain inflammation, fatty buildup in brain immune cells, and memory problems, but giving mice butyrate supplements reversed much of the damage. While this study was done in mice, it suggests that even "green" plastics may pose hidden risks to brain health through the gut, and that protecting or restoring gut bac
Abstract 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 Proposed molecular mechanism underlying poly(butylene adipate-co-terephthalate) microplastics (PBAT-MPs) neurotoxicity via gut–brain immunoinflammatory axis: PBAT-MPs exposure disrupts gut microbial homeostasis, depletes the protective metabolite butyrate, and activates microglial mTORC1–integrated stress response (ISR) signaling, thereby driving lipid-droplet (LD) biogenesis. These events culminate in lipotoxicity-associated neuroinflammation and neurodegenerative injury. (Created with BioRender.com).