A gut-activated NHR-86–CYP pathway mediates the neuroprotective effects of Enterococcus faecium probiotics in a nematode model of amyotrophic lateral sclerosis

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 A4V^M 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.