Gut dysfunction is commonly observed in Parkinson's disease (PD) and gastrointestinal symptoms have been reported to precede neurological motor symptoms. This issue led to hypothesize that intestine is a putative site of origin of PD pathology, with the subsequent spread toward the central nervous system (CNS), via gut-brain connections.
Many studies have been devoted to the comprehension of possible triggering conditions able to affect the enteric nervous system (ENS), located in the gut submucosal and myenteric plexi, causing the spread up of such neuropathological features to the CNS. Different studies pointed out to the role of intestinal inflammation and the related impaired mucosa permeability (leaky gut) as key factor in the generation of neuropathological features in the enteric neurons, like alpha synuclein (a-syn) mysfolding and Leucine-Rich-Repeated-Kinase-2 (LRRK-2) protein expression. In both humans and animal models, the disruption of the normal microbiota, by antibiotic overexposure, has been described as one of the most important leaky gut-referred conditions.
The present research aims at investigating the effect of leaky gut syndrome induced by administration of broad spectrum antibiotics (ampicillin, vancomycin, neomycin, and metronidazole) and an antifungal (amphotericin B) in mice, and to evaluate: (1) the immunological activation of the ENS/EGC following dysbiosis, and relative alpha-syn mysfolding and LRRK-2 increased protein expression in the gut submucosal/myenteric plexi; (2) if ENS-induced activation by dysbiosis is associated with an ascending neuropathological signaling to the CNS; (3) the pathway by which dysbiotic-activation of ENS alteration propagates from the periphery to the brain, and (4) to correlate these events with a parkinsonism- related neuropathology in mice.
