A Low-Protein, High-Carbohydrate Diet Exerts a Neuroprotective Effect on Mice with 1‑Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Induced Parkinson’s Disease by Regulating the Microbiota-Metabolite–Brain Axis and Fibroblast Growth Factor 21

Parkinson’s disease (PD) is
closely linked to lifestyle
factors, particularly dietary patterns, which have attracted interest
as potential disease-modifying factors. Eating a low-protein, high-carbohydrate
(LPHC) diet is a promising dietary intervention against brain aging;
however, its protective effect on PD remains elusive. Here, we found
that an LPHC diet ameliorated 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine
(MPTP)-induced motor deficits, decreased dopaminergic neuronal death,
and increased the levels of striatal dopamine, serotonin, and their
metabolites in PD mice. Levels of fibroblast growth factor 21 (FGF-21),
a member of the fibroblast growth factor family, were elevated in
PD mice following LPHC treatment. Furthermore, the administration
of FGF-21 exerted a protective effect on MPTP-induced PC12 cells,
similar to the effect of an LPHC diet in MPTP-induced mice. Sequencing
of the 16S rDNA from fecal microbiota revealed that an LPHC diet normalized
the gut bacterial composition imbalance in PD mice, as evidenced by
the increased abundance of the genera Bifidobacterium, Ileibacterium, Turicibacter,
and Blautia and decreased abundance of Bilophila,
Alistipes, and Bacteroides. PICRUSt-predicted
fecal microbiome function revealed that an LPHC diet suppressed lipopolysaccharide
biosynthesis and the citrate cycle (TCA cycle), biosynthesis of ubiquinone
and other terpenoid-quinones, and oxidative phosphorylation pathways
caused by MPTP, and enhanced the biosynthesis of amino acids, carbohydrate
metabolism, and biosynthesis of other secondary metabolites. A nonmetabolomic
analysis of the serum and feces showed that an LPHC diet significantly
increased the levels of aromatic amino acids (AAAs), including tryptophan,
tyrosine, and phenylalanine. In addition, an LPHC diet elevated the
serum concentrations of bile acids (BAs), particularly tauroursodeoxycholic
acid (TUDCA) and taurine. Collectively, our current findings point
to the potential mechanism of administering an LPHC diet in attenuating
movement impairments in MPTP-induced PD mice, with AAAs, microbial
metabolites (TUDCA and taurine), and FGF-21 as key mediators along
the gut-microbiota–brain axis.