Study Rationale: Recent research suggests that a protein in our cells involved in bacterial detection, called NOD2, may play a role in the development of Parkinson’s disease (PD) by triggering harmful brain inflammation. We will investigate if this happens when fragments of gut bacteria, which bind and activate NOD2, build up in the gut and leak into the bloodstream due to a weakened gut barrier. These bacterial fragments then pass into the brain and drive inflammation associated with PD development.
Hypothesis: Our hypothesis is that these bacterial fragments that activate NOD2 are highly abundant in the gut microbiota of persons with PD and when these fragments enter brain tissue, the consequent over-activation of the NOD2 receptor then results in brain inflammation linked to PD.
Study Design: To explore this idea, our first goal is to measure these fragments (cells “NOD2 ligands”) in the stool of people with PD and analyze their gut bacteria for the key enzymes that produce these potentially harmful fragments. Next, we’ll test whether we can measure these NOD2 ligands in stool and in blood, with the idea that if these ligands pass into the blood, they will be carried into the brain where the trigger pathological NOD2 activity. Finally, we’ll investigate whether using specific bacterial enzymes that break down these fragments can reduce their harmful effects.
Impact on Diagnosis/Treatment of Parkinson’s disease: Altogether, this work could help us better understand how gut bacteria contribute to PD, identify early warning signs of disease progression and point to new treatments that target the gut instead of the brain.
Next Steps for Development: Clinical application of this study is the potential to better diagnose and monitor PD, since we believe that NOD2 ligand bioavailability and the abundance of these specific enzymes can help with diagnosis and may reflect PD symptomology. Moreover, with therapeutics in mind, we could also foresee applications where we would give patients treatments that would lower the availability of NOD2 ligands in their gut and thereby reduce harmful inflammation in the brain associated with PD.