The gut-brain axis: is intestinal inflammation a silent driver of Parkinson's disease pathogenesis?

Abstract

The state of the intestinal environment can have profound effects on the activity of the central nervous system through the physiological contributions of the microbiota, regulation of intestinal barrier function, and altered activity of peripheral neurons. The common language employed for much of the gut-brain communication is the modulation of immune activity. Chronic proinflammatory immune activity is increasingly being recognized as a fundamental element of neurodegenerative disorders, and in Parkinson's disease, inflammation in the intestine appears particularly relevant in pathogenesis. We review the evidence that intestinal dysfunction is present in Parkinson's disease and that it may reflect the earliest manifestations of Parkinson's disease pathology, and we link these findings to dysregulated immune activity. Based on this, we present a model for Parkinson's disease pathogenesis in which the disorder originates in the intestine and progresses with inflammation as its underlying mechanism. More in-depth investigations into the physiological mechanisms underlying peripheral pre-motor symptoms in Parkinson's disease are expected to lead to the development of novel diagnostic and therapeutic measures that can slow or limit progression of the disease to more advanced stages involving debilitating motor and cognitive symptoms.

Fig. 1

Model of gut-originating, inflammation-driven PD pathogenesis. In a susceptible individual, inflammatory triggers (1) initiate immune responses in the gut that deleteriously impact the microbiota, increase intestinal permeability, and induce increased expression and aggregation of αSYN (2). Synucleinopathy may be transmitted from the gut to the brain via the vagus nerve (3b), and chronic intestinal inflammation and permeability promote systemic inflammation, which, among other things, can increase blood-brain barrier permeability (3a). Intestinal inflammation, systemic inflammation, and synuclein pathology in the brain all promote neuroinflammation (4) which drives the neurodegeneration that characterizes PD (5)