Objective: This study aims to investigate how gut microbiota composition influences trimethylamine N-oxide (TMAO) levels in PD patients and whether TMAO and gut microbiota composition correlates with disease severity, including motor and non-motor symptoms.

Background: Emerging evidence suggests that gut microbiota-derived metabolites like TMAO play a role in neurodegeneration and inflammation. While elevated TMAO is linked to cardiovascular and metabolic diseases, its impact on PD remains unclear. Given gut-brain axis dysfunction in PD, investigating the relationship between microbiota-derived TMAO and disease severity could provide new insights into disease pathogenesis and potential therapeutic strategies.

Method: This cross-sectional study involves PD patients and age-matched healthy controls. Biological samples (blood, feces, urine) were collected, and TMAO levels were quantified via spectrophotometry. Gut microbiota composition was analyzed using 16S rRNA sequencing, with taxonomic classification based on the SILVA database. Bioinformatics analysis assessed microbial diversity, relative abundance, and TMAO-associated functional pathways. Clinical data, including motor severity (MDS-UPDRS III) and non-motor symptoms, were correlated with TMAO levels. Statistical analyses included correlation tests and regression modeling.

Results: Preliminary findings (20 PD, 20 HC) indicate significant differences in gut microbiota composition, with increased TMAO-producing bacteria (Lachnospiraceae, Enterobacteriaceae) in PD patients. Plasma and urinary TMAO levelswere higher in PD (5.8 ± 1.4 µM, 12.6 ± 3.1 µM) compared to HCs (3.1 ± 0.9 µM, 6.8 ± 2.5 µM; p < 0.001). Microbiome analysis showed reduced alpha diversity (p = 0.004) and distinct beta diversity (p < 0.001). TMAO levels correlated with motor severity (MDS-UPDRS III: r = 0.45, p < 0.001), non-motor symptoms (NMSS: r = 0.40, p = 0.002). Regression analysis identified TMAO as an independent predictor of motor dysfunction (β = 0.36, p < 0.001). Functional analysis confirmed enrichment of TMAO biosynthesis pathways in PD.

Conclusion: These findings suggest that gut microbiota-derived TMAO may contribute to PD progression through neuroinflammatory and metabolic pathways. TMAO could serve as a potential biomarker for PD severity and offer novel therapeutic targets for modulating gut microbiota to mitigate disease progression.

References: Wallen, Z.D., Demirkan, A., Twa, G. et al. Metagenomics of Parkinson’s disease implicates the gut microbiome in multiple disease mechanisms. Nat Commun 13, 6958 (2022). https://doi.org/10.1038/s41467-022-34667-x
Sampson, T. R. et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 167, 1469–1480.e12 (2016).
Breen, D. P., Halliday, G. M. & Lang, A. E. Gut-brain axis and the spread of alpha-synuclein pathology: Vagal highway or dead end? Mov. Disord. 34, 307–316 (2019).Toh, T. S. et al. Gut microbiome in Parkinson’s disease: new insights from meta-analysis. Parkinsonism Relat. Disord. 94, 1–9 (2022).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/influence-of-gut-microbiota-derived-tmao-on-disease-severity-in-parkinsons-disease/