Abstract

The gut-brain axis enables communication between the central nervous system and the gut, with certain microbial metabolites influencing neurodegeneration. Using genome-scale metabolic modeling, we designed and tested a synthetic microbial consortium with predicted capacity to produce GABA and other neurometabolites in a Drosophila melanogaster model of neurodegeneration of Parkinson’s Disease (PD). The consortium (Levilactobacillus brevis, Lacticaseibacillus paracasei, Bacteroides thetaiotaomicron) produced GABA in bioreactors. Female PD flies receiving the consortium exhibited protection from locomotor impairment at 10 and 25 days upon consortium administration. Head metabolomics revealed partial restoration of PD-associated alterations in energy balance, amino acid and neurotransmitter metabolism, and disease-related biomarkers. Early administration increased microbiome diversity and Lactobacillus abundance. These findings suggest that rationally designed microbial consortia targeting neurometabolite production can modulate brain physiology and confer neuroprotection, supporting their potential for microbiome-based interventions in neurodegenerative disease. © The Author(s) 2025.