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

Overview

1. State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiang’an Hospital of Xiamen University, Xiamen University, Xiamen, 361102 China
2. Fujian Medical University, Fuzhou, Fujian, China
3. Department of Neurology, Xiang’an Hospital of Xiamen University, Xiamen, Fujian China

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.

Supplementary Information: The online version contains supplementary material available at 10.1186/s12974-026-03869-1.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE261007, at NCBI GEO; found in the text, “Butyrate alleviates microglial lipotoxic…”

Data availability

All data supporting the findings of this study are available from the corresponding author upon reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 12 authors, 5 keywords, 11 MeSH terms, 7 funders, 53 references.

Cite

This paper

Wang, M.-Z., Du, Z.-B., Xu, W.-Q., Xie, Y.-H., Wang, L.-L., He, X.-X., Wang, Y.-H., Zheng, H.-Y., Yao, Y.-L., Song, Y.-B., Lin, Z.-N., & Lin, Y.-C. (2026). Butyrate-producing gut bacteria restrain PBAT microplastic-triggered brain microglial lipotoxicity via a microbiota-butyrate-mTORC1-ISR relay along the gut-brain axis. Journal of neuroinflammation, 23(1), 233. https://doi.org/10.1186/s12974-026-03869-1

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