The Gut and Parkinson's Disease: Hype or Hope?

Abstract

In the last two decades it has become clear that Parkinson's disease (PD) is associated with a plethora of gastrointestinal symptoms originating from functional and structural changes in the gut and its associated neural structures. This is of particular interest not only because such symptoms have a major impact on the quality of life of PD patients, but also since accumulating evidence suggests that in at least a subgroup of patients, these disturbances precede the motor symptoms and diagnosis of PD by years and may thus give important insights into the origin and pathogenesis of the disease. In this mini-review we attempt to concisely summarize the current knowledge after two decades of research on the gut-brain axis in PD. We focus on alpha-synuclein pathology, biomarkers, and the gut microbiota and envision the development and impact of these research areas for the two decades to come.

Keywords: Alpha-synuclein; constipation; dysautonomia; gut-brain-axis; microbiota; prion.

Fig. 1.

The four most important issues that need to be addressed in the next 10 years regarding the gut in PD. (1) Alpha-synuclein deposits are observed in the ENS of PD patients (the microphotography shows phospho-alpha-synuclein immunostaining in the colonic myenteric plexus of a PD patient, scale bar 20μM). However, it remains to be determined if the alpha-synuclein aggregates in the ENS are biochemically similar to the ones found in the brain as this might be critical in our understanding of the role of the gut in PD pathogenesis. The picture shows lysates from colonic biopsies (left lane, ENS) and brain samples (right lane, CNS) from two PD patients that have been analyzed by western blot using C-20R total asyn antibody. Using this simple approach, no difference is observed between the ENS and the CNS and there is therefore a critical need to perform a comprehensive inventory of synuclein forms present in the ENS from PD patients using proteomic approaches. Molecular weight in kDa is indicated on the right. (2) Triggering of initial alpha-synuclein aggregation in enteric nerve terminals through extrinsic factors could be facilitated by intestinal hyperpermeability. It remains to be definitely demonstrated that intestinal permeability is increased in PD. (3) Results of immunohistochemistry-based studies on alpha-synuclein deposits in the ENS of PD patients have provided conflicting results. There is therefore a critical need to develop alternative techniques to detect alpha-synuclein aggregates in the gut. The inset illustrates a dot blot from gastrointestinal biopsy lysates of a control subject, stained with Syn-1 alpha-synuclein antibody. (4) Alterations of gut microbiota composition in PD have been shown in multiple cross-sectional studies from diverse populations. It will be crucial to determine the mechanisms that connect gut microbiota and PD in large multicenter studies of prodromal and de novo PD patients as well as animal models employing multiomics approaches. Eventually, the clinical diagnostic and therapeutic potential of the gut microbiota must be determined. The inset illustrates differently shaped bacteria and the molecular structures of the SCFAs butyrate, acetate and propionate. Drawings were modified from Servier Medical Art, licensed under a Creative Commons Attribution 3.0 Unported License.