Validating the functional role of the pathogenic microbiome metabolite Trimethylamine (TMA) at the gut-brain axis in Parkinson's disease

Validating the functional role of the pathogenic microbiome metabolite Trimethylamine (TMA) at the gut-brain axis in Parkinson’s disease

Study Rationale:

Gut dysfunction and microbiome dysbiosis have been linked to the onset and progression of PD pathology. However, the mechanisms by which an altered gut microbial population can initiate or contribute to disease progression remains poorly defined. We recently uncovered that the microbial pathways for synthesis of Trimethylamine (TMA) are specifically elevated in PD patients. Our own studies in Australian PD patients and other published reports have shown that TMAO is elevated in PD patient bloods and biofluids. Further, some studies suggest that elevated TMAO could in PD patients can indicate faster disease progression and worsened outcomes. Our project aims to define the precise mechanisms by which TMAO can drive disease progression in PD.

Hypothesis:

We propose that elevated levels of circulating TMAO can initiate and/or contribute to PD pathology and progression by worsening alpha synuclein pathology, inflammasome activation and 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.