Fibroblast growth factor 21 ameliorates behavior deficits in Parkinson’s disease mouse model via modulating gut microbiota and metabolic homeostasis Original paper

What was studied?

This study investigated the therapeutic potential of fibroblast growth factor 21 (FGF21) in ameliorating behavioral deficits in a mouse model of Parkinson’s disease (PD), with a specific focus on its interactions with the gut microbiota and metabolic homeostasis along the microbiota–gut–brain axis. The researchers aimed to determine whether FGF21 administration could improve both motor and cognitive impairment in PD mice and whether these benefits were associated with modulations in the gut microbiome and metabolic profiles in both the brain and colon. Mice were rendered Parkinsonian using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and then treated with FGF21. Comprehensive behavioral testing, metabolic profiling using NMR spectroscopy, and 16S rRNA sequencing of colonic microbiota were performed to assess changes in neurobehavioral function, brain and colon metabolism, and gut microbial composition. The study’s focus keyphrase, “FGF21 modulates gut microbiota in Parkinson’s disease,” is central to the research, as the investigators explore how FGF21 orchestrates changes in the gut microbiome and links these to improvements in PD phenotypes.

Who was studied?

The subjects of this study were male C57BL/6 mice, aged at least 8 weeks and weighing between 20–26 grams, sourced from a professional laboratory animal supplier in Shanghai, China. The mice were randomized into three experimental groups: a control group receiving saline (CON), a group receiving MPTP injections to induce PD-like pathology (MPTP), and a group receiving both MPTP and FGF21 treatment (FGF21 + MPTP). Each group comprised 10 animals. After establishing the PD model, FGF21 was administered intraperitoneally for seven days in the FGF21 + MPTP group. Following treatment, behavioral tests (open field and Y maze), brain and colon tissue sampling, metabolic profiling, and gut microbiota sequencing were conducted. All animal protocols were approved by the local ethics committee, ensuring adherence to experimental standards.

Most important findings

The most significant findings highlight that FGF21 treatment markedly reversed both motor and cognitive deficits in MPTP-induced PD mice. FGF21 administration improved spontaneous locomotor activity, working memory, and bodyweight, and increased dopaminergic neuron survival in the substantia nigra as evidenced by tyrosine hydroxylase staining. At the metabolic level, NMR spectroscopy revealed that FGF21 restored region-specific metabolic homeostasis in the midbrain, striatum, and cortex. Key metabolic cycles affected included choline metabolism, the glutamate–glutamine–GABA cycle, and energy metabolism, all of which are critical for neuronal function.

Microbiome analysis demonstrated that PD mice exhibited gut dysbiosis characterized by decreased alpha diversity and an increased abundance of Bacteroidetes (notably Muribaculaceae and Bacteroidaceae) and reduced Firmicutes (including Ruminococcaceae and Lachnospiraceae). FGF21 treatment reversed these changes, restoring Firmicutes, Ruminococcaceae, and Lachnospiraceae abundance, and increasing overall microbial diversity. These families are key short-chain fatty acid (SCFA) producers, particularly butyrate, which is linked to neuroprotection. Linear discriminant analysis effect size (LEfSe) identified these taxa as signature microbial markers modulated by FGF21. Correlation analyses further established that specific microbial shifts were associated with restoration of colon metabolites—including choline, taurine, lactate, and 3-hydroxybutyrate—which are implicated in gut–brain signaling and neuroprotection.

Key implications

This study delivers compelling evidence that FGF21 not only alleviates behavioral and neurochemical deficits in a PD mouse model but does so through mechanisms involving modulation of the gut microbiota and the microbiota–gut–brain metabolic axis. The enrichment of butyrate-producing bacteria (Ruminococcaceae and Lachnospiraceae) and restoration of metabolic homeostasis in both brain and colon suggest a multifaceted therapeutic effect of FGF21, extending beyond direct neuroprotection to include the rebalancing of gut microbial communities and their metabolites. These findings support the integration of FGF21 and similar metabolic regulators into therapeutic strategies for PD, especially for ameliorating both motor and non-motor symptoms. Furthermore, the study provides robust microbiome signatures—such as increased Ruminococcaceae and Lachnospiraceae abundance—relevant for a microbiome signatures database, offering candidate biomarkers for future translational and clinical research.

Citation

Yang C, Wang W, Deng P, et al. Fibroblast growth factor 21 ameliorates behavior deficits in Parkinson’s disease mouse model via modulating gut microbiota and metabolic homeostasis. CNS Neurosci Ther. 2023;29:3815-3828. doi:10.1111/cns.14302