Project Portugal 2030

Summary

This project aims to prove the ability of bacterial mediators such as microbial extracellular vesicles (EVs) and SCFAs to significantly influence the immune system via the small intestinal axis, revert gut inflammation and arrest PD. We will conduct preclinical studies in a well characterized gut disbiotic mice model (gmPD-mice) developed in our group (Annex 1). In our view, chronic gut dysbiosis impacts the mucosa-associated microbiome, alters resident immune cell responses, and favors a local pro-inflammatory milieu that disrupts intestinal barrier integrity allowing bacterial-effectors translocation into intestinal cells, namely enteric neurons. Systemic low-grade inflammation will sensitize the BBB that will contribute to neuroinflammation. Additionally, enteric neurons will communicate with SN dopaminergic neurons through the vagus nerve in a way that neuronal innate immunity is activated to signal microglial cells and induce neuroinflammation. Our main goal is to validate new promising anti-inflammatory candidates of bacterial origin and to show that, by averting gut and systemic inflammation, we will prevent the progression of the pathology to the CNS in “gut-first” PD cases. We argue that chronic sub-clinical gut dysbiosis resulting from aberrant microbial colonization could trigger PD by activation of intestinal cell pro-inflammatory responses, which prime peripheral Th1 responses that negatively affect the permeability of the epithelial layer. Peripheral low-grade inflammation (gut and blood) will facilitate neuroinflammation and ultimately the PD neurodegenerative process. We anticipate that the positive effects of butyrate and EVs from probiotic bacteria on inflammation will elicit a cascade of events that will reshape the microbial communities in the gut, leading to reversal of dysbiosis and amelioration of the pro-inflammatory status likely occurring in the PD gut, which will also be reflected in the brain. We expect that bacterial derived anti-inflammatory mediators will 1) target immune and epithelial intestinal cells; 2) modulate gut inflammation and revert dysbiotic processes improving intestinal barrier; 3) modulate immune blood cells, neurons and microgial cells, decreasing peripheral and brain inflammation and 4) potentiate brain metabolism. These combined modulatory actions will avoid the neurodegenerative process and motor behavior alterations. The specific scientific aims are: 1) To validate ileum mucosa-associated microbiome, gut inflammation and enteric aSyn aggregation as PD prodromal biomarkers 2) To prove that bacterial-derived anti-inflammatory mediators avert motor behavior alterations and SNpc and DMV TH+ cell loss in microbiota-transplanted mice (gut-first gmPD mice). 3) To determine the influence of anti-inflammatory mediators in gut inflammation and barrier integrity. 4) To identify intestinal immune pathways modulated by bacterial-derived anti-inflammatory mediators. 5) To tackle the effect of SCFAs and probiotic EVs on systemic inflammation. 6) To evaluate the effects of this new anti-inflammatory strategy on BBB leakage, mitochondrial fragmentation and microglia activation. 7) To understand how neuronal immune control is related to the production/aggregation of aSyn.