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:

Our proposed studies aim to systematically characterize and confirm the processes by which bacterial TMAO can drive PD pathology and disease progression at the gut-brain axis. For these studies, we will us a combination of animal models to assess if elevated TMAO can exacerbate motor and non-motor symptoms features relevant to human PD. The results from studies will provide new insights and clear evidence for TMAO as a possible driver of disease progression at the gut-brain axis in PD.

Impact on Diagnosis/Treatment of Parkinson’s disease:

Elevated levels of TMAO have already been reported in PD patients and some studies suggest that higher circulating TMAO levels are associated with worsening PD symptoms and outcomes. However, how this occurs remains to be defined. Our studies will explore three potential mechanisms by which TMAO can contribute to the onset and progression of PD based on our initial supporting evidence.

Next Steps for Development:

If our studies in PD models with this project confirm the mechanisms involved as we expect, these results will then provide the basis for developing new treatment strategies aimed at reducing TMAO-mediated pathology in PD to slow or halt disease progression.

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