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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 \u03b1-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 \u03b1-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.<\/jats:p>","DOI":"10.1038\/s41531-025-01142-5","type":"journal-article","created":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T11:19:06Z","timestamp":1760959146000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The gut microbiome promotes mitochondrial respiration in the brain of a Parkinson\u2019s disease mouse model"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5738-2658","authenticated-orcid":false,"given":"Livia H.","family":"Morais","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linsey","family":"Stiles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milla","family":"Freeman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8473-6378","authenticated-orcid":false,"given":"Anastasiya D.","family":"Oguienko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3762-9596","authenticated-orcid":false,"given":"Jonathan D.","family":"Hoang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeff","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baiyi","family":"Quan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack","family":"Devine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin S.","family":"Bois","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsui-Fen","family":"Chou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne","family":"Trinh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Picard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5868-348X","authenticated-orcid":false,"given":"Viviana","family":"Gradinaru","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2713-1513","authenticated-orcid":false,"given":"Sarkis K.","family":"Mazmanian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,20]]},"reference":[{"key":"1142_CR1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.13","volume":"3","author":"W Poewe","year":"2017","unstructured":"Poewe, W. et al. 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