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

AIMS: The effects of FGF21 on Parkinson's disease (PD) and its relationship with gut microbiota have not been elucidated. This study aimed to investigate whether FGF21 would attenuate behavioral impairment through microbiota–gut–brain metabolic axis in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) induced PD mice model. METHODS: Male C57BL/6 mice were rendomized into 3 groups: vehicle (CON); MPTP 30 mg/kg/day i.p. injection (MPTP); FGF21 1.5 mg/kg/d i.p. injection plus MPTP 30 mg/kg/day i.p. injection (FGF21 + MPTP). The behavioral features, metabolimics profiling, and 16 s rRNA sequencing were performed after FGF21 treatment for 7 days. RESULTS: MPTP‐induced PD mice showed motor and cognitive deficits accompanied by gut microbiota dysbiosis and brain‐region‐specific metabolic abnormalities. FGF21 treatment dramatically attenuated motor and cognitive dysfunction in PD mice. FGF21 produced a region‐specific alteration in the metabolic profile in the brain in ways indicative of greater ability in neurotransmitter metabolism and choline production. In addition, FGF21 also re‐structured the gut microbiota profile and increased the relative abundance of Clostridiales, Ruminococcaceae, and Lachnospiraceae, thereby rescuing the PD‐induced metabolic disorders in the colon. CONCLUSION: These findings indicate that FGF21 could affect behavior and brain metabolic homeostasis in ways that promote a favorable colonic microbiota composition and through effects on the microbiota–gut–brain metabolic axis.