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<p>Probiotics exert neuroprotective effects against Alzheimer’s disease (AD) through modulation of gut-brain axis signaling pathways, yet disease-modifying therapies remain elusive. In this study, we demonstrate that <i>Stenotrophomonas maltophilia</i> (<i>S. maltophilia</i>) ameliorates AD-associated pathological and behavioral phenotypes in <i>Caenorhabditis elegans</i> (<i>C. elegans</i>) models, including learning deficits and paralysis. Mechanistically, <i>S. maltophilia</i> suppresses β-amyloid (Aβ) peptide aggregation by orchestrating the activation of conserved cellular pathways: autophagy, innate immune signaling, and unfolded protein responses in the mitochondria (UPRmt) and endoplasmic reticulum (UPRer). Specifically, <i>S. maltophilia</i> induces UPRmt in an <i>atfs-1</i>-dependent manner and activates UPRer via the PERK kinase PEK-1. Further mechanistic analysis suggests that <i>S. maltophilia</i> initiates a signaling cascade: activation of ATF-7 immune pathways enhanced autophagy and subsequent clearance of Aβ aggregates. Metabolomic screening further pinpointed pizotifen as a bioactive metabolite that might inhibit Aβ aggregation through immune modulation.</p><p></p>

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Stenotrophomonas maltophilia alleviates Alzheimer’s disease model phenotype by inhibiting Aβ aggregation via autophagy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月30日

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  • Chuyu Song,
  • Wei Yao,
  • Xiaotong Hu,
  • Ruixi Song,
  • Dapeng Li,
  • Xiangming Wang

摘要

Probiotics exert neuroprotective effects against Alzheimer’s disease (AD) through modulation of gut-brain axis signaling pathways, yet disease-modifying therapies remain elusive. In this study, we demonstrate that Stenotrophomonas maltophilia (S. maltophilia) ameliorates AD-associated pathological and behavioral phenotypes in Caenorhabditis elegans (C. elegans) models, including learning deficits and paralysis. Mechanistically, S. maltophilia suppresses β-amyloid (Aβ) peptide aggregation by orchestrating the activation of conserved cellular pathways: autophagy, innate immune signaling, and unfolded protein responses in the mitochondria (UPRmt) and endoplasmic reticulum (UPRer). Specifically, S. maltophilia induces UPRmt in an atfs-1-dependent manner and activates UPRer via the PERK kinase PEK-1. Further mechanistic analysis suggests that S. maltophilia initiates a signaling cascade: activation of ATF-7 immune pathways enhanced autophagy and subsequent clearance of Aβ aggregates. Metabolomic screening further pinpointed pizotifen as a bioactive metabolite that might inhibit Aβ aggregation through immune modulation.