Format

Send to

Choose Destination
Neurobiol Dis. 2018 Dec 20. pii: S0969-9961(18)30768-X. doi: 10.1016/j.nbd.2018.12.012. [Epub ahead of print]

Chronic stress-induced gut dysfunction exacerbates Parkinson's disease phenotype and pathology in a rotenone-induced mouse model of Parkinson's disease.

Author information

1
Department of Neurobiology, The University of Chicago, Chicago, IL, USA; Department of Internal Medicine, Division of Digestive Diseases, Rush University Medical Center, Chicago, IL, USA.
2
Department of Internal Medicine, Division of Digestive Diseases, Rush University Medical Center, Chicago, IL, USA.
3
Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL, USA.
4
Department of Neurology, Rush University Medical Center, Chicago, IL, USA.
5
Department of Neurology, University of Wisconsin School of Public Health, Madison, WI, USA.
6
Department of Internal Medicine, Division of Digestive Diseases, Rush University Medical Center, Chicago, IL, USA; Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands. Electronic address: Ali_Keshavarzian@rush.edu.

Abstract

Recent evidence provides support for involvement of the microbiota-gut-brain axis in Parkinson's disease (PD) pathogenesis. We propose that a pro-inflammatory intestinal milieu, due to intestinal hyper-permeability and/or microbial dysbiosis, initiates or exacerbates PD pathogenesis. One factor that can cause intestinal hyper-permeability and dysbiosis is chronic stress which has been shown to accelerate neuronal degeneration and motor deficits in Parkinsonism rodent models. We hypothesized that stress-induced 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 test this hypothesis, mice received unpredictable restraint stress (RS) for 12 weeks, and during the last six weeks mice also received a daily administration of low-dose rotenone (10 mg/kg/day) orally. The initial six weeks of RS caused significantly higher urinary cortisol, intestinal hyperpermeability, and decreased abundance of putative "anti-inflammatory" bacteria (Lactobacillus) compared to non-stressed mice. 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 increased α-synuclein (α-syn) protein levels in the colon compared to controls. Restraint stress exacerbated these rotenone-induced changes. Specifically, RS potentiated rotenone-induced effects in the colon including: (1) intestinal hyper-permeability, (2) disruption of tight junction proteins (ZO-1, Occludin, Claudin1), (3) oxidative stress (N-tyrosine), (4) inflammation in glial cells (GFAP + enteric glia cells), (5) α-syn, (6) increased relative abundance of fecal Akkermansia (mucin-degrading Gram-negative bacteria), and (7) 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 dystrophic/phagocytic microglia as well as (FJ-C+) dying cells in the substantia nigra (SN), (2) increased lipopolysaccharide (LPS) reactivity in the SN, and (3) reduced dopamine (DA) and DA metabolites (DOPAC, HVA) in the striatum compared to control mice. Our findings support a model in which chronic stress-induced, gut-derived, pro-inflammatory milieu exacerbates the PD phenotype via a dysfunctional microbiota-gut-brain axis.

KEYWORDS:

Intestinal barrier; Intestinal hyper-permeability; Microbiome dysbiosis; Microbiota-gut-brain axis; Neurodegenerative disease; Parkinson's disease; Peripheral inflammation; Rodent behavior

PMID:
30579705
DOI:
10.1016/j.nbd.2018.12.012

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center