Neuroprotection of Fasting Mimicking Diet on MPTP-Induced Parkinson's Disease Mice via Gut Microbiota and Metabolites

Abstract

Parkinson's disease (PD) is strongly associated with life style, especially dietary habits, which have gained attention as disease modifiers. Here, we report a fasting mimicking diet (FMD), fasting 3 days followed by 4 days of refeeding for three 1-week cycles, which accelerated the retention of motor function and attenuated the loss of dopaminergic neurons in the substantia nigra in 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-induced PD mice. Levels of brain-derived neurotrophic factor (BDNF), known to promote the survival of dopaminergic neurons, were increased in PD mice after FMD, suggesting an involvement of BDNF in FMD-mediated neuroprotection. Furthermore, FMD decreased the number of glial cells as well as the release of TNF-α and IL-1β in PD mice, showing that FMD also inhibited neuro-inflammation. 16S and 18S rRNA sequencing of fecal microbiota showed that FMD treatment modulated the shifts in gut microbiota composition, including higher abundance of Firmicutes, Tenericutes, and Opisthokonta and lower abundance of Proteobacteria at the phylum level in PD mice. Gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry revealed that FMD modulated the MPTP-induced lower propionic acid and isobutyric acid, and higher butyric acid and valeric acid and other metabolites. Transplantation of fecal microbiota, from normal mice with FMD treatment to antibiotic-pretreated PD mice increased dopamine levels in the recipient PD mice, suggesting that gut microbiota contributed to the neuroprotection of FMD for PD. These findings demonstrate that FMD can be a new means of preventing and treating PD through promoting a favorable gut microbiota composition and metabolites.

Fecal Microbiota Transplantation in Neurological Disorders

“…Healthy mice that received feces from PD mice had deteriorated motor function and decreased striatal neurotransmitters compared to controls. Zhou et al (2019) observed less motor function decline and loss of dopaminergic neurons in the substantia nigra in PD mice that received a fasting mimicking diet (FMD) compared to ad-libitum-fed PD mice. Furthermore, they observed a higher striatal dopamine and serotonin concentration in PD mice that had received feces from FMD-fed control mice compared to phosphate-buffered solution (PBS)-gavaged or ad-libitum microbiota-gavaged PD mice.…”

Characterization of the intestinal microbiota during Citrobacter rodentium infection in a mouse model of infection-triggered Parkinson’s disease

“…47 In a chemically induced mouse model of PD, a fecal microbiota transfer leading to increased propionic and isobutyric acid levels correlated with increased dopamine levels. 48 Conversely, a recent study from Sampson et al demonstrated that transferring a human PD-derived microbiota into a mouse alphasynuclein overexpression PD model resulted in increased butyric acid and propionic acid levels, followed by an increase in PD-like symptoms, and administration of a mix of SCFAs into germ-free mice recapitulated some of the observed effects. 30 SCFAs are highly implicated in intestinal barrier integrity and immunological responses.…”

The Role of Butyrate in Attenuating Pathobiont-Induced Hyperinflammation

“…Therefore, it is not surprising that fasting mimicking diets decrease dextran sulfate sodiuminduced inflammation and stimulate the commensal gut microbiota, leading to reduced IBD pathological changes in the intestines (113). Fasting mimicking diets are also able to reduce neuroinflammaton and to exert a protective effect (114). Fasting mimicking diets may increase butyrate, thereby exerting anti-inflammatory effects (114).…”