The Sulfate-Reducing Bacteria Hypothesis in Parkinson’s Disease: From Desulfovibrio-Derived Hydrogen Sulfide to Alpha-Synuclein Aggregation

The conceptualization of Parkinson’s disease (PD) has shifted from a strictly central neurodegenerative disorder to a systemic synucleinopathy that may, in some patients, originate in the enteric nervous system. This review synthesizes recent evidence highlighting the potential role of sulfate-reducing Desulfovibrio (DSV) bacteria as candidate pathobionts in the proposed “gut-first” pathogenic cascade. By colonizing anaerobic niches within the colon and metabolizing dietary sulfur compounds, DSV generate hydrogen sulfide (H2S), a gaseous metabolite that may compromise intestinal barrier integrity and impair mitochondrial function through the inhibition of cytochrome c oxidase. These processes have been associated with ATP depletion, cytochrome c release, and iron-dependent oxidative stress, creating conditions that may favor α-synuclein misfolding and aggregation within enteroendocrine cells. We further examine evidence supporting the retrograde propagation of α-synuclein pathology from the gut to the brain via the vagus nerve—a hypothesis strengthened by experimental findings and epidemiological observations, including studies reporting reduced PD risk following truncal vagotomy. Although the increased prevalence of DSV in PD patients suggests potential applications in prodromal diagnostics and microbiome-based risk stratification, a definitive causal relationship has yet to be established. We therefore discuss key methodological limitations, including biases associated with 16S rRNA sequencing and the current lack of robust in vivo metabolomic evidence. Finally, we consider whether targeted modulation of the intestinal environment, including DSV-specific bacteriophages and [FeFe]-hydrogenase inhibitors, could emerge as a future strategy for influencing early disease processes.