Objective: To define changes in gut microbiota composition and metabolism to enable identification of novel therapeutic targets and strategies for disease modification.

Background: Multiple cohort studies indicate that gut microbiota composition is significantly altered in people with Parkinson’s disease (PD). However, the functional and pathological significance of gut dysbiosis in PD remains poorly understood. Gastrointestinal dysfunction is a common complaint in PD patients, often preceding clinical diagnosis and typically accompanied by increased gut mucosal permeability.

Method: In this study, we evaluated the changes in circulating gut microbiota metabolites in PD patient biofluids and used high-resolution functional metagenomics to determine changes in microbial composition and pathways compared to an age-matched healthy cohort. We also performed global and targeted metabolomics in PD patient biofluids including blood and urine.

Results: e found changes in multiple microbial metabolites in our PD cohort, including Trimethylamine (TMA), a brain-permeable metabolite of bacterial-origin with a positive association with the rate of PD progression and cognitive decline. We also found changes in polyamines, amino acid metabolism and some bile acids. TMA and its metabolites were also altered in both PD patient blood and urine in a cohort of healthy (n=44) and PD (n=46) individuals. We also uncovered elevated levels of neurotoxic Formaldehyde (FA), in our PD patient cohort. Our high-resolution functional metagenomics studies demonstrate for the first time that TMA-generating bacteria, as well as bacterial enzymatic pathways responsible for its generation to be increased in PD patients. This included elevated Clostridium species Our mechanistic studies also revealed that circulating TMAO can accelerate synuclein aggregation and immune activation in microglia and PBMCs. We also uncovered a trend towards loss of beneficial bacteria which produce anti-inflammatory metabolites, such as butyrate, in PD patients

Conclusion: Taken together, our results provide novel mechanistic insights into how gut dysbiosis and altered microbial metabolism can drive disease progression in PD

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MDS Abstracts - https://www.mdsabstracts.org/abstract/altered-gut-microbiota-composition-and-metabolism-in-parkinsons-disease/