Gut Microbiome Species Levilactobacillus brevis Protects Dopaminergic Neurons from α-Synuclein Toxicity In Vivo

Background/Objectives: Parkinson’s disease (PD) is characterized by progressive degeneration of dopaminergic neurons and aggregation of the protein α-synuclein. Growing evidence suggests that α-synuclein aggregation may originate in the gut, and dysbiosis of the gut microbiome has been observed in PD patients. Levilactobacillus brevis (L. brevis) is increased in the PD gut microbiome; however, the role of specific host–microbiota interactions and direct causal links with PD pathology remain unclear. We therefore examined the effects of L. brevis on disease phenotypes in PD models driven by α-synuclein toxicity. Methods: Using Caenorhabditis elegans (C. elegans), a rapidly aging and highly genetically tractable model system with simple gut anatomy and orthologs for 60–80% of human genes, we investigated the impact of L. brevis on dopamine neuron structure, dopamine-dependent behavior, and α-synuclein aggregation in PD models. Additionally, we tested candidate regulators of L. brevis-induced effects and conducted dopaminergic neuron-specific transcriptional profiling to gain further mechanistic understanding. Results: In adult C. elegans, feeding with L. brevis protected against pathological features associated with α-synuclein toxicity, including dopaminergic degeneration, dopamine-dependent motor dysfunction, and α-synuclein aggregation. RNAi knockdown of candidate genes vps-35 and ifd-2 in dopaminergic neurons was associated with altered patterns of dopamine-dependent behavior, motivating further investigation of potential genetic contributors. Transcriptional analysis of dopamine neurons revealed changes in gene expression and functional pathways in response to L. brevis. Conclusions: These findings highlight L. brevis as a gut microbial factor capable of protecting dopaminergic neurons in the context of α-synuclein toxicity, and demonstrate the utility of C. elegans for establishing causal roles of host–microbiota interactions in disease. Moreover, this study offers potential therapeutic targets to be validated in vertebrate systems, with the goal of promoting dopamine neuron resilience in PD.