Study Rationale: Imbalances in the bacteria that inhabit the gut have been linked to the onset and progression of Parkinson’s disease (PD). However, the mechanisms by which an altered microbiome can initiate or contribute to disease progression remain poorly defined. We recently discovered that people with PD have elevated levels of trimethylamine, a metabolite produced by intestinal microbes. The liver converts this molecule to trimethylamine N-oxide (TMAO), a chemical that we have found exacerbates alpha-synuclein aggregation, reduces GBA1 activity in the brain and triggers activation of the NLRP3 inflammasome — all mechanisms known to contribute to PD pathology and progression.
Hypothesis: We propose that elevation of circulating TMAO can initiate or contribute to PD pathology and progression by enhancing alpha-synuclein aggregation, boosting inflammasome activation and reducing GBA1 activity at the gut-brain axis.
Study Design: We aim to systematically characterize and confirm the pathological mechanisms by which TMAO can drive PD pathology and progression at the gut-brain axis. For these studies, we will use different preclinical models to assess whether treatment with TMAO produces synuclein pathology, inflammasome activation and GBA1 dysfunction, leading to exacerbation of motor and non-motor symptoms relevant to PD. The results will provide new insights and crucial evidence for TMAO as a potential driver of disease progression at the gut-brain axis.
Impact on Diagnosis/Treatment of Parkinson’s disease: The results of this study will enhance our understanding of the mechanisms that lead to PD and should facilitate the development of new treatment strategies targeting TMAO-mediated pathological processes in PD.
Next Steps for Development: Our studies will provide insights into the ways that changes in intestinal microbiota can trigger PD pathology by altering the gut-brain axis. These results will provide the basis for developing new treatment strategies aimed at reducing TMAO-mediated pathology in PD to slow or halt disease progression.