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This disorder is characterized pathologically by the prion-like spread of misfolded neuronal alpha-synuclein proteins in specific brain regions leading to Lewy body formation, neurodegeneration, and progressive neurological impairment. It is unclear what triggers Parkinson\u2019s and where \u03b1-synuclein protein aggregation begins, although proposed induction sites include the olfactory bulb and dorsal motor nucleus of the vagus nerve. Within the last 20\u00a0years, there has been increasing evidence that Parkinson\u2019s could be triggered by early microbiome changes and \u03b1-synuclein accumulation in the gastrointestinal system. Gut microbiota dysbiosis that alters gastrointestinal motility, permeability, and inflammation could enable prion-like spread of \u03b1-synuclein from the gut-to-brain via the enteric nervous system. Individuals with isolated rapid eye movement sleep behavior disorder have a high likelihood of developing Parkinson\u2019s and might represent a prodromal \u2018gut-first\u2019 subtype of the condition. The gut-first model of Parkinson\u2019s offers novel gut-based therapeutic avenues, such as anti-, pre-, and pro-biotic preparations and fecal microbiota transplants. Crucially, gut-based interventions offer an avenue to treat Parkinson\u2019s at early prodromal stages with the aim of mitigating evolution to clinically recognizable Parkinson\u2019s disease characterized by motor impairment.<\/jats:p>","DOI":"10.1007\/s00415-025-13138-5","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T01:07:08Z","timestamp":1747789628000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["The gut\u2013brain axis in early Parkinson\u2019s disease: from prodrome to prevention"],"prefix":"10.1007","volume":"272","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-7818-7820","authenticated-orcid":false,"given":"Patrick James","family":"Oliver","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2399-1436","authenticated-orcid":false,"given":"Livia","family":"Civitelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6382-5841","authenticated-orcid":false,"given":"Michele T.","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,21]]},"reference":[{"key":"13138_CR1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.neuropsych.14.2.223","author":"J Parkinson","year":"2002","unstructured":"Parkinson J (2002) An essay on the shaking palsy. 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