Vitamin B6 produced by gut microbiome regulates host behavioral phenotypes through dopaminergic metabolism

The gut microbiome modulates host neuropathology, but the mechanisms linking specific microbial genes and metabolites to host phenotypes remain poorly defined. Here, we identify microbiome-derived vitamin B6 (VB6) and its biosynthesis gene as key regulators of host dopaminergic homeostasis. Metagenomic analysis of fecal samples from Parkinson's disease (PD) patients revealed enrichment of biosynthetic pathways for pyridoxal-5'-phosphate (PLP), the active form of VB6, and tyrosine decarboxylase genes. Using E. coli-C. elegans symbiotic models, we demonstrate that the bacterial pdxJ gene, encoding a key enzyme in de novo VB6 synthesis, is essential in regulating host dopaminergic homeostasis. Colonization with pdxJ-deficient bacteria led to reduced host VB6 and dopamine levels, reduced dopaminergic enzyme activity, and altered motor behavior, which were all rescued by VB6 supplementation. In PD-relevant C. elegans models, bacterial PLP biosynthesis modulated α-synuclein aggregation and behavioral deficits associated with human LRRK2 mutations. In mice, colonization with pdxJ-deficient bacteria reduced serum VB6 levels, decreased tyrosine hydroxylase staining in the substantia nigra, and impaired motor coordination, which were rescued by VB6 supplementation. Overall, our results define a bacterial pdxJ-PLP-dopamine axis that links gut microbial metabolism to host dopaminergic phenotypes and suggest bacterial VB6 biosynthesis as a potential modifier of PD risk and a context-dependent therapeutic target.