– LeakyPark

The intestinal epithelial barrier (IEB), which primarily consists of epithelial cells stitched together with connecting proteins called tight junctions plays a critical role in health and disease. It acts as a selectively permeable barrier regulating the absorption of nutrients, electrolytes and water, while maintaining an effective defense against foreign antigens and enteric microbiota. A compromised IEB function has unequivocally been associated with inflammatory conditions in the gut. More recently a compromised IEB has also been described in Parkinson’s disease (PD) further reinforcing the observation supporting that PD is gut-brain axis disorder and fueling the hypothesis that gut-derived factors may participate in its development and/or progression. However, the existing studies on the IEB in PD are still preliminary and it remains to be determined if the IEB is altered in premotor and early-stage PD and if gut permeability is associated with a more severe disease progression.
Our working hypothesis is that gut hyperpermeability occurs early in the evolution of PD and that it is associated with a more severe disease progression. To test this hypothesis, we propose to perform a comprehensive analysis of the IEB both functionally and structurally in subjects with idiopathic REM sleep behavior disorder (iRBD, an early manifestation of PD, which may antedate the onset of prototypical motor symptoms by years), early-stage/mid-stage PD and controls and to correlate these biological data with clinical parameters at baseline and after a 3-year follow-up. Additional experiments will be carried out in two complementary animal models of PD, one genetic (mice transgenic for A53T human alpha-synuclein) and one toxic (mice gavaged with rotenone). Both animal models develop gastrointestinal dysfunction together with IEB disruption prior to motor symptoms and central neurodegeneration. The role of the IEB in the progression of motor symptoms and CNS neuropathology will be evaluated following its disruption or reinforcement by pharmacological means.
To achieve these objectives, we set up an international collaboration between 4 research teams: Pascal Derkinderen’s group, TENS, France (F); Silvia Cerri’s group, Mondino Foundation, Italy (I); François Cossais lab, Kiel University, Germany (D) and Kristína Kulcsárová’s group, P. J. Safarik University, Slovakia (SK). Three groups (F, G and SK) have complementary expertise on the gastrointestinal tract in PD including among others detection of pathological alpha-synuclein and analysis of enteric inflammation; in addition, all these groups have cohorts of iRBD and PD subjects with a longitudinal comprehensive clinical characterization together with a unique collection of paraffin embedded and frozen intestinal biopsies. Cerri’s group (I) brings its experience in the characterization of enteric neuropathy and barrier dysfunction in animal models of PD. The permeability and morphology of the IEB will be analyzed in colonic biopsies from two different cohorts of iRBD and PD subjects (F, D/SK) using the gold standard method for the evaluation of permeability (Ussing chambers, F) and cutting-edge approaches such as spatial transcriptomics (D). This study will help us determine whether gut hyperpermeability occurs (or not) in early-stage PD and if it is related with disease progression. Due to the strong interconnection between enteric and central nervous systems, a leaky intestinal barrier may allow factors from the gut lumen to affect neurons both in the intestine and in the brain. Conversely, restoration of IEB physiological properties may represent a novel disease-modifying approach in PD, as already proposed in other gastrointestinal disorders. In addition, the assessment of IEB permeability might be used as a disease biomarker either for early detection or management of disease progression and/or for a better disease classification.