Faculty, Staff and Student Publications

Language

English

Publication Date

1-1-2026

Journal

PLOS Biology

DOI

10.1371/journal.pbio.3003627

PMID

41616251

PMCID

PMC12872002

PubMedCentral® Posted Date

1-30-2026

PubMedCentral® Full Text Version

Post-print

Abstract

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.

Keywords

Animals, Caenorhabditis elegans, Amyotrophic Lateral Sclerosis, Probiotics, Enterococcus faecium, Caenorhabditis elegans Proteins, Disease Models, Animal, Cytochrome P-450 Enzyme System, Oxidative Stress, Neuroprotective Agents, Receptors, Cytoplasmic and Nuclear, Reactive Oxygen Species, Motor Neurons, Animals, Genetically Modified, Neuroprotection, Signal Transduction

Published Open-Access

yes

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