Can the gut be the missing piece in uncovering PD pathogenesis?

It is now well established that Parkinson's disease (PD) is not only a movement disorder of the CNS but also a gastrointestinal disorder affecting the enteric nervous system (ENS). The gut-brain axis is a bidirectional communication between the brain and the gastrointestinal tract, which comprises besides the CNS and the ENS, the intestinal epithelial barrier, the intestinal microbiota and the enteroendocrine systems. In this review, we present the clinical and pathological evidence suggesting that the gut-brain axis is dysfunctional in PD by discussing the possible role of gut microbiota, inflammation and permeability in the development of the disease.

Chapelet G ，Leclair-Visonneau L ，Clairembault T ，Neunlist M ，Derkinderen P ... -  《-》

The Gut and Nonmotor Symptoms in Parkinson's Disease.

Gastrointestinal (GI) symptoms are one of the most common nonmotor symptoms (NMS) in patients with Parkinson's disease (PD) involving the whole GI tract (GIT) and being evident throughout the whole course of the disease. Furthermore, constipation serves as a risk factor for PD as well as an early prodromal NMS of PD. The gut as gateway to the environment with its enteric nervous system (ENS) plays a crucial role in the neurodegenerative process that leads to PD. Alpha-synucleinopathy as the pathological hallmark of PD could be found within the whole GIT in a rostrocaudal gradient interacting with the ENS, the gut microbiome, and enteric glial cells. Bidirectional interactions between the ENS and the central nervous system (CNS) via a brain-gut-enteric microbiota axis have been reported. As well as there is evidence out of animal, autopsy, and epidemiological studies that α-synuclein spreads via rostrocranial transmission by transsynaptic cell-to-cell transfer via the sympathetic and parasympathetic nervous system to the CNS causing the typical neuropathological changes of PD. Recognition of GI NMS as prodromal markers of PD as well as a better understanding of the brain-gut connection offers new insights in the pathophysiology of PD and might provide the opportunity of PD diagnosis before CNS involvement. Hereby the opportunity for development of neuroprotective and disease-modifying therapeutics, respectively, seem to be promising. This chapter covers the variety of GI NMS and its consequences in PD as well as the important role of the gut as part of the pathological process in PD.

Klingelhoefer L ，Reichmann H 《-》

Brain-gut-microbiota axis in Parkinson's disease.

Mulak A ，Bonaz B 《-》

The Gut-Brain Axis: Two Ways Signaling in Parkinson's Disease.

Parkinson's disease (PD) is a chronic, progressive and second most prevalent neurological disorder affecting the motor system. Cardinal motor impairment and α-synucleinopathy are the characteristic features of PD. Recently, it has been identified that the gut-brain axis is substantially regulated by the gut microbiome (GM) through an immunological, neuroendocrine, and neural mechanism. However, disturbance in the gut-microbiome-brain axis in PD might proceed to gastrointestinal manifestations intermittently leading to the motor system and the PD pathogenesis itself. The gut microbial toxins may induce the production of α-synuclein (α-syn) aggregates in the enteric nervous system (ENS), which may proliferate and propagate in a prion-like-manner through the vagus nerve to the central nervous system (CNS); supporting the hypothesis that, GM might play a pivotal role in PD pathogenesis. Overstimulated innate immune system due to intestinal bacterial overgrowth or gut dysbiosis and the enhanced intestinal permeability may persuade systemic inflammation, while the activation of enteric glial cells and enteric neurons may contribute to α-synucleinopathy. Gut microbiota can bear a significant impact on neurological outcomes such as learning, memory and cognition. In this review paper, we summarize how the alterations in gut microbiota and ENS inflammation are associated with PD pathogenesis. The evidence supporting the causative role played by gut-associated dysbiosis and microbial byproducts, in the onset of PD is also discussed. We have highlighted the landmark discoveries in the field of PD particularly focusing on the gut-brain axis. A better comprehension of the interaction between the gut-brain axis, gut microbiota, and PD can usher in novel therapeutic and diagnostic approaches.

Dogra N ，Mani RJ ，Katare DP 《-》

The Intestinal Barrier in Parkinson's Disease: Current State of Knowledge.

van IJzendoorn SCD ，Derkinderen P 《-》