Chronic Stress-induced Gut Dysfunction Exacerbates Parkinson's Disease Phenotype via the Gut-Brain Axis in a Rotenone-induced Parkinson's Disease Rodent Model.

Recent evidence provides support for an involvement of the microbiota-gut-brain axis in Parkinson's disease (PD) pathogenesis. We propose that an intestinal pro-inflammatory milieu, due to leaky gut and/or microbial dysbiosis, could initiate or exacerbate PD pathogenesis. Chronic stress is one factor that may be contributing to the leaky gut and microbiota changes. The studies showing chronic stress accelerated neural degeneration and motor deficits in Parkinsonism rodent models focused mainly on the hypothalamic-pituitary axis. The role of the stress-induced dysfunctional gut-brain axis in neurodegeneration remains unknown. We hypothesized that intestinal barrier dysfunction and microbial dysbiosis lead to a pro-inflammatory milieu that exacerbates the PD phenotype in the low-dose oral rotenone PD mice model. To induce intestinal barrier dysfunction, mice received unpredictable restraint stress (RS) for total 12 weeks, in which during the last six weeks mice also received a daily administration of low-dose rotenone (10mg/kg/day) orally. The initial six weeks of RS resulted in significantly higher urinary cortisol, intestinal hyperpermeability, and decreased abundance of anti-inflammatory bacteria (Lactobacillus) compared to their non-stressed counterparts. Rotenone alone (i.e., without RS) disrupted the colonic expression of the tight junction protein ZO-1, increased oxidative stress (N-tyrosine), increased myenteric plexus enteric glial cell GFAP expression and higher a-synuclein expression in the colon compared to controls. Restraint stress exacerbated these rotenone-induced changes. Specifically, RS potentiated rotenone-induced effects in the intestine: 1) leaky gut, 2) disruption of colonic tight junction proteins (ZO-1, Occludin, Claudin1), 3) oxidative stress (N-tyrosine), 4) neuroinflammation (GFAP + enteric glia cells), 5) a-synuclein expression in the colon, 6) increased relative abundance of Akkermansia (mucin degrading Gram-negative bacteria), and 7) promoted endotoxemia. In addition, RS promoted a number of rotenone-induced effects in the brain including: 1) reduced number of resting microglia and a higher number of dying cells (FJ-C+) in the substantia nigra (SN), 2) increased lipopolysaccharide (LPS) reactivity in the SN, and 3) reduced dopamine and dopamine metabolites (DOPAC, HVA) in the striatum. Our findings support a model in which chronic stress-induced, gut-derived, pro-inflammatory gut milieu exacerbates the PD phenotype via a dysfunctional microbiota-gut-brain axis.