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. 2024;14(6):1129-1138.
doi: 10.3233/JPD-240244.

The Associations Among Gut Microbiota, Branched Chain Amino Acids, and Parkinson's Disease: Mendelian Randomization Study

Zhenzhen Yan  1 , Guohua Zhao  1   2
Affiliations

The Associations Among Gut Microbiota, Branched Chain Amino Acids, and Parkinson's Disease: Mendelian Randomization Study

Zhenzhen Yan et al. J Parkinsons Dis. 2024.

Abstract

Background: In experimental and observational studies, the characteristics of gut microbiota have been associated with Parkinson's disease (PD), among which metabolic pathways played an important role. However, the causality remained unclear.

Objective: Herein, we aimed to determine the potential impact of gut microbiota and gut microbiota-derived metabolites on PD risk using a Mendelian randomization (MR) approach.

Methods: We included as exposures gut microbial taxa abundance and gut-derived metabolites (branched chain amino acids [BCAAs]), with PD as the outcome. In addition, we explored whether BCAAs act as a mediating factor in the pathway from gut microbiota to PD.

Results: We found evidence of a causality of 15 microbial taxa and PD before and after sensitivity analyses, but not after multiple testing correction. There was significant association between BCAAs levels and the risk of PD, especially isoleucine (OR = 0.995, 95% CI 0.992-0.999, p = 0.004, pFDR = 0.012). In addition, the causality of gut microbiota and BCAAs was also explored that the increased g_Coprococcus abundance can result in the decrease in isoleucine level (OR = 1.046; 95% CI, 1.009-1.085; p = 0.016).

Conclusions: Our findings indicated suggestive association between gut microbiota and its metabolites and PD. Furthermore, higher BCAAs levels were associated with the decreased PD risk. This study may provide new targets for PD treatment, such as dietary BCAAs supplementation.

Keywords: Mendelian randomization; Parkinson’s disease; branched chain amino acids; gut microbiota.

Plain language summary

Dysbiosis of gut microbiota and its metabolites (branched chain amino acids, BCAAs) appears to be a related risk factor for Parkinson’s disease (PD). Thus far, studies mostly focused on cross-sectional observational studies of gut microbiota and its metabolites, but this Mendelian randomization analysis evaluated the potential impact of gut microbiota and gut microbiota derived metabolites (BCAAs) on PD risk. Gut microbiota and BCAAs as exposures and PD as outcome, it was found that there was no significant correlation between gut microbiota and PD, while increasing levels of BCAAs, especially isoleucine, increased the risk of PD. In addition, we also demonstrated that BCAAs could play a role in PD relying on the gut microbiota. For example, an increase in g-Coprococcus abundance can lead to a decrease in isoleucine levels in PD. Therefore, in the future, the PD risk may be reduced by maintaining the homeostasis of gut microbiota and its metabolites.

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Conflict of interest statement

The authors have no conflict of interest to report.

Figures

Fig. 1
Fig. 1
The overall design of MR analysis in the present study.
Fig. 2
Fig. 2
Leave-one-out sensitivity analysis for leucine (a), isoleucine (b) and valine (c) on PD. PD, Parkinson’s disease.
Fig. 3
Fig. 3
Scatter plot (a) and forest plot (b) of the causal effect of isoleucine on PD risk. PD, Parkinson’s disease.
Fig. 4
Fig. 4
The causal effect of isoleucine on g_Coprococcus. (a) Scatter plot, (b) Funnel plot and (c) Forest plot.
Fig. 5
Fig. 5
The schematic diagram of BCAAs function in PD. The pforA gene of gut microbiota upregulate the expression of PFOR that promotes the conversion of BCAAs into SCFAs. Then, SCFAs stimulate the release of GLP-1 from enteroendocrine L cells, which plays a neuroprotective role to improve motor deficits and dopaminergic neuron loss. BCAAs, branched chain amino acids; GLP-1, glucagon-like peptide 1; PFOR, pyruvate: ferriredoxin oxidoreductase; SCFAs, short chain fatty acids.
See this image and copyright information in PMC

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