Strains used in the study.

Neurodegenerative diseases are often associated with oxidative stress, and while probiotics may influence neuronal health, the underlying mechanisms remain poorly understood. Using the sod-1 A4VM amyotrophic lateral sclerosis (ALS) model in Caenorhabditis elegans, we investigated the protective effects of the probiotic Enterococcus faecium against oxidative stress-induced neurodegeneration. Animals fed E. faecium showed reduced motor neuron degeneration under oxidative stress compared to those maintained on a standard Escherichia coli diet. Transcriptome analysis revealed a significant enrichment of oxidoreductase genes, including cytochrome P450 (cyp) genes. RNAi-mediated knockdown of cyp genes impaired E. faecium-mediated neuroprotection, and this loss correlated with increased reactive oxygen species (ROS) levels. We identified the conserved nuclear hormone receptor NHR-86 as a key regulator of cyp gene expression and neuroprotection. Loss of nhr-86 abolished the probiotic’s protective benefits, while transgenic expression of nhr-86 restored cyp induction and neuronal resilience. Importantly, intestinal expression of NHR-86 was sufficient to restore CYP induction and neuronal resilience, whereas neuronal knockdown had no effect, indicating that gut NHR-86 activity is essential for this protective pathway. These findings reveal a previously uncharacterized NHR-CYP regulatory axis activated by an intestinal probiotic, highlighting a mechanistic link between microbial signals and host neuroprotection.神经退行性疾病常与氧化应激相关，尽管益生菌或可影响神经元健康，但其背后的分子机制仍尚未被充分阐明。本研究以秀丽隐杆线虫（Caenorhabditis elegans）的sod-1 A4VM型肌萎缩侧索硬化症（ALS）模型为研究对象，探究了屎肠球菌（Enterococcus faecium）对氧化应激诱导的神经退行性变的保护作用。与以标准大肠杆菌（Escherichia coli）为食的线虫相比，喂食屎肠球菌的线虫在氧化应激状态下的运动神经元退行性变程度显著降低。转录组分析显示，包括细胞色素P450（cyp）基因在内的氧化还原酶基因出现显著富集。RNA干扰（RNAi）介导的cyp基因敲低会削弱屎肠球菌介导的神经保护作用，且该效应与活性氧（ROS）水平升高显著相关。本研究鉴定出保守型核激素受体NHR-86是cyp基因表达与神经保护作用的关键调控因子。nhr-86基因的缺失会完全消除益生菌的保护益处，而nhr-86的转基因表达则可恢复cyp基因的诱导表达与神经元抗逆性。值得注意的是，仅在肠道中表达NHR-86即可恢复CYP的诱导表达与神经元抗逆性，而神经元内的基因敲低则无此效果，这表明肠道NHR-86的活性是该保护通路的核心要素。本研究揭示了一条由肠道益生菌激活的、此前未被表征的NHR-CYP调控轴，阐明了微生物信号与宿主神经保护作用之间的机制性联系。