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

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.

Fig. 1

The overall design of MR analysis in the present study.

Fig. 2

Leave-one-out sensitivity analysis for leucine (a), isoleucine (b) and valine (c) on PD. PD, Parkinson’s disease.

Fig. 3

Scatter plot (a) and forest plot (b) of the causal effect of isoleucine on PD risk. PD, Parkinson’s disease.

Fig. 4

The causal effect of isoleucine on g_Coprococcus. (a) Scatter plot, (b) Funnel plot and (c) Forest plot.

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.