title: Gut-brain and brain-gut axis in Parkinson's disease models: Effects of a uridine and fish oil diet.
abstract: Recent investigations have focused on the potential role of gastrointestinal (GI) abnormalities in the pathogenesis of Parkinson's disease (PD). The 'dual-hit' hypothesis of PD speculates that a putative pathogen enters the brain via two routes: the olfactory system and the GI system. Here, we investigated (1) whether local exposures of the neurotoxin rotenone in the gut or the brain of mice could induce PD-like neurological and GI phenotypes as well as a characteristic neuropathology in accordance with this 'dual-hit hypothesis' and (2) the effects of a diet containing uridine and fish oil providing docosahexaenoic acid (DHA), in both models. Mice were given rotenone either orally or by an injection in the striatum. Dietary interventions were started 1 week before rotenone exposures. We found that (1) both oral and intrastriatal administration of rotenone induced similar PD-like motor deficits, dopaminergic cell loss, delayed intestinal transit, inflammation, and alpha-synuclein accumulation in the colon; (2) the uridine and DHA containing diet prevented rotenone-induced motor and GI dysfunctions in both models. The models suggest possible bidirectional communication between the gut and the brain for the genesis of PD-like phenotype and pathology. The dietary intervention may provide benefits in the prevention of motor and non-motor symptoms in PD.
authors.affiliation: a Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University , Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
authors.forename: Paula
authors.initials: P
authors.lastname: Perez-Pardo
authors.affiliation: b Department of Internal Medicine, Division of Gastroenterology , Rush University Medical Center , 1725 West Harrison Street, Chicago , IL 60612 , USA.
authors.forename: Hemraj B
authors.initials: HB
authors.lastname: Dodiya
authors.affiliation: a Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University , Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.|c Nutricia Research , Uppsalalaan 12, 3584 CT Utrecht, The Netherlands.
authors.forename: Laus M
authors.identifier: http://orcid.org/0000-0002-4814-2636
authors.initials: LM
authors.lastname: Broersen
authors.affiliation: a Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University , Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
authors.forename: Hidde
authors.initials: H
authors.lastname: Douna
authors.affiliation: c Nutricia Research , Uppsalalaan 12, 3584 CT Utrecht, The Netherlands.
authors.forename: Nick
authors.identifier: http://orcid.org/0000-0003-2272-7182
authors.initials: N
authors.lastname: van Wijk
authors.affiliation: c Nutricia Research , Uppsalalaan 12, 3584 CT Utrecht, The Netherlands.
authors.forename: Sofia
authors.identifier: http://orcid.org/0000-0002-8370-5107
authors.initials: S
authors.lastname: Lopes da Silva
authors.affiliation: a Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University , Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.|c Nutricia Research , Uppsalalaan 12, 3584 CT Utrecht, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: Garssen
authors.affiliation: a Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University , Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.|b Department of Internal Medicine, Division of Gastroenterology , Rush University Medical Center , 1725 West Harrison Street, Chicago , IL 60612 , USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Keshavarzian
authors.affiliation: a Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University , Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
authors.forename: Aletta D
authors.initials: AD
authors.lastname: Kraneveld
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004032:Diet; D004281:Docosahexaenoic Acids / Q000008:administration & dosage / Q000097:blood; D005395:Fish Oils / Q000008:administration & dosage* / Q000097:blood; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010300:Parkinson Disease / Q000097:blood / Q000473:pathology*; D012402:Rotenone / Q000633:toxicity; D014529:Uridine / Q000008:administration & dosage* / Q000097:blood; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D005395:Fish Oils; D051844:alpha-Synuclein; D012402:Rotenone; D004281:Docosahexaenoic Acids; D014529:Uridine
keywords: Docosahexaenoic acid; GI dysfunction; Gut–brain and brain–gut axis; Rotenone Parkinson's model; Uridine