Intestinal alterations of mucosal barrier integrity, motility and enteric nerve in cynomolgus monkey model of Parkinson's disease

The most prevalent non-motor symptoms in individuals with Parkinson's disease (PD) such as constipation and bloating that significantly impact patients' quality of life. However, the pathophysiological mechanisms underlying these symptoms remain unclear. PD model with typical and stable symptoms was induced by individualized dosing of MPTP with Kurlan score increased to 10 or above and remained steady for three months or more. TH-positive neurons in the injured substantia nigra (SN) of the brain of PD monkeys showed up to 83.95 % reduction. Histopathological examination indicated severe damage to both enteric nerve and TH neurons, along with significant disruption of mucosal structure, intestinal barrier integrity and motility in PD monkeys across all four intestinal segments, including the duodenum, ileum, transverse colon, and rectum. The association between dopaminergic neuronal deficits in SN and these above mentioned intestinal disorders, that might be attributed to the abnormal regulation of gastrointestinal function due to the breakdown of the integrity of the nigrostriatal dopaminergic nervous system. Therefore, the abnormal alterations found in gut of PD monkeys and its triggered possible secondary pathophysiological cascade reactions might be a potential mechanism underlying the presence of constipation and other intestinal symptoms observed in PD patients. These findings in this study provide a valuable scientific basis for investigating the pathogenesis of gastrointestinal symptoms in PD patients and potential therapeutic approaches. (The graphical abstract is by Figdraw).