Gut Microbiome-Dependent Metabolic Remodeling and Its Impact on α-Synuclein Phenotype in Caenorhabditis elegans

Background: Parkinson’s disease (PD), which affects more than six million people, is marked by the aggregation of α-synuclein and the progressive loss of dopaminergic neurons. Most cases are sporadic, and the factors that trigger them are still poorly defined. One proposed contributor is the gut microbiome, which may influence disease through its effects on host metabolism. Here, we used Caenorhabditis elegans to examine how individual gut bacteria shape host metabolism and PD-related phenotypes. Methods: Intestinal colonization was first quantified in wild-type worms and in mutants lacking TOL-1, the only Toll-like receptor homolog in this nematode, and the worm metabolome was then profiled by untargeted LC-MS/MS. Results: Loss of TOL-1 altered the bacterial load in the gut and shortened lifespan only on the pathogen Salmonella enterica. Metabolomic profiling showed that colonization reshaped host metabolism in a TOL-1-dependent way, with retinol metabolism among the most affected pathways; this effect was strongest in worms fed Rhodococcus erythropolis MYb53, a bacterium native to the worm microbiome. In an α-synuclein-expressing strain, R. erythropolis postponed the appearance of aggregates and maintained motility in older animals, although aggregate numbers eventually increased late in life. Conclusions: Motor decline was therefore uncoupled from aggregate load, indicating that this native bacterium protects the motor phenotype rather than preventing aggregation itself. Overall, our results support C. elegans as a tractable system for dissecting how the gut microbiome contributes to PD.