Objective: This work aims to investigate gut dysfunction and enteric neuropathy in several mouse models of PD to provide insight into enteric nervous system (ENS) involvement.

Background: Parkinson’s disease (PD) is a progressive neurological disorder associated with nerve damage and dysfunction in the brain and gut. Whilst animal models have been instrumental in understanding the pathogenesis and progression of PD in the brain, the nature of intestinal (enteric) nerve damage and gut dysfunction in PD progression remains unclear. Research into gut dysfunction using several methods and multiple rodent models has resulted in inconsistent findings. Disorders of transit or absorption could significantly impair bioavailability of potential therapeutic drugs for PD.

Method: MPTP-treated mice (n=6/group, aged 16 weeks), 6-OHDA-treated mice (n=5-7/group, aged 16 weeks) and A53T transgenic mice expressing mutant human α-synuclein (n=10-20/group, aged 28 weeks) were directly compared for gut dysfunction, sensorimotor deficits and enteric neuropathy. One week prior to euthanasia, gut deficits in mice were assessed via whole gut transit (WGTT), intrarectal bead expulsion, fecal pellet output (FPO) and fecal water content (FWC). Enteric neuropathy was assessed by immunohistochemistry.

Results: Both MPTP and A53T mice exhibited a significant reduction in FPO and changes in FWC and WGTT. These changes were correlated with a moderate to high level of neuronal loss in the ENS. Conversely, whilst 6-OHDA mice demonstrated a marked reduction in FWC compared to wild-type, there was no evidence of neuronal loss in the ENS.

Conclusion: Gut dysfunction is highly prevalent amongst PD sufferers, with 80-90% of patients experiencing some form of gut symptoms including dysphagia (swallowing difficulty), gastroparesis (slowed stomach emptying), chronic constipation and malabsorption. These gut symptoms often precede the onset of central motor deficits by decades and can severely impact the efficacy of oral medication in PD patients having detrimental effects on prognosis. Whilst all mouse models investigated exhibited some level of gut dysfunction, the extent of enteric neuropathy varied greatly across models. These findings provide information regarding the state of the gut in mouse models of PD, which may be pertinent to not only the progression of the disease but may also influence the oral bioavailability of therapeutic interventions for  PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/intestinal-nerve-damage-and-gut-dysfunction-in-mouse-models-of-parkinsons-disease/