The gut microbiome promotes mitochondrial respiration in the brain of a Parkinson's disease mouse model.

The pathophysiology of Parkinson's disease (PD) involves gene-environment interactions that impair various cellular processes including mitochondrial dysfunction. Mitochondria-associated mutations increase PD risk, respiration is altered in the PD brain, and mitochondria-damaging toxicants cause PD-like motor and gastrointestinal symptoms in animal models. The gut microbiome is altered in PD, representing an environmental risk, however a relationship between mitochondrial function and the microbiome in PD has not been previously established. Herein, we discover that dysregulation of mitochondria-associated genes and hyperactive striatal mitochondria are induced by the microbiome in α-synuclein-overexpressing (Thy1-ASO) mice. Thy1-ASO mice elaborate increased reactive oxygen species in the striatum whereas germ-free counterparts express increased oxygen scavenging proteins. Indeed, treatment with an antioxidant drug improves motor performance in Thy1-ASO mice and blocking oxidant scavenging in germ-free mice enhances motor deficits in an α-synuclein dependent manner. Thus, the gut microbiome promotes motor symptoms in a mouse model of PD via increased mitochondrial respiration and oxidative stress in the brain.