PD-GUT · Parkinson's disease: does it all start with gut inflammation?

Burgeoning evidence shows that Parkinson's disease (PD) involves the gut before affecting the brain, leading to the fascinating hypothesis that the gut might be the site of disease initiation. Remarkably, the gut origin of PD is still poorly understood. Multiple triggers could serve as a first insult: infections, dysbiosis, and inflammatory bowel diseases (IBDs). All these conditions ultimately converge on intestinal inflammation. Thus, an intriguing hypothesis is that PD is a systemic illness that originates from an inflammatory insult in the gut. This hypothesis is based on the observation that genetic traits relevant for both sporadic and familial PD also modulate immune responses to enteric pathogens and confer risk to IBDs. To dissect shared mechanisms among these seemingly unrelated diseases, I envision a multi- and interdisciplinary project with a unique integration of competences in neuroscience, immunology, and microbiology. Moving beyond the state of the art, I will combine patient stem cell-derived organoid, organ-on-a-chip, and single-cell sequencing approaches to decode the role of intestinal inflammation in PD and to identify new mediators of immune cell contributions to neurodegeneration. Specifically, I will i) mechanistically dissect cell type-specific host immune responses to intestinal pathogens and their link to PD; ii) establish complex human pluripotent stem cell-derived intestinal organoids to investigate intestinal inflammation; and ii) implement patient multiorganoid platforms to identify key players in the communication between the inflamed gut and the brain. Unveiling the critical steps that initiate PD may lead to a conceptual leap forward in our understanding of how the gut affects the brain in both health and disease. The novel methodologies that will be developed will also lay the foundations for future interventions aimed at targeting intestinal inflammation in enteric and neurological diseases.