AUTHOR=Jackson Aeja , Engen Phillip A. , Forsyth Christopher B. , Shaikh Maliha , Naqib Ankur , Wilber Sherry , Frausto Dulce M. , Raeisi Shohreh , Green Stefan J. , Bradaric Brinda Desai , Persons Amanda L. , Voigt Robin M. , Keshavarzian Ali 

TITLE=Intestinal Barrier Dysfunction in the Absence of Systemic Inflammation Fails to Exacerbate Motor Dysfunction and Brain Pathology in a Mouse Model of Parkinson's Disease

JOURNAL=Frontiers in Neurology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2022.882628

DOI=10.3389/fneur.2022.882628

ISSN=1664-2295

ABSTRACT=Introduction: Parkinson’s disease (PD) is the second most common neurodegenerative disease associated with aging. PD patients have systemic and neuroinflammation which is hypothesized to contribute to neurodegeneration. Recent studies highlight the importance of the gut-brain axis in PD pathogenesis and suggest that gut-derived inflammation can trigger and/or promote neuroinflammation and neurodegeneration in PD. However, it is not clear whether microbiota dysbiosis, intestinal barrier dysfunction, or intestinal inflammation (common features in PD patients) are primary drivers of disrupted gut-brain axis in PD that promote neuroinflammation and neurodegeneration.

Objective: To determine the role of microbiota dysbiosis, intestinal barrier dysfunction, and colonic inflammation in neuroinflammation and neurodegeneration in a genetic rodent model of PD (α-synuclein overexpressing (ASO) mice).

Methods: To distinguish the role of intestinal barrier dysfunction separate from inflammation, low dose (1%) dextran sodium sulfate (DSS) was administered in cycles for 52 days to ASO and control mice. The outcomes assessed included intestinal barrier integrity, intestinal inflammation, stool microbiome community, systemic inflammation, motor function, microglial activation, and dopaminergic neurons. 

Results: Low dose DSS treatment caused intestinal barrier dysfunction (sugar test, histological analysis), intestinal microbiota dysbiosis, mild intestinal inflammation (colon shortening, elevated MPO), but it did not increase systemic inflammation (serum cytokines). However, DSS did not exacerbate motor dysfunction, neuroinflammation (microglial activation), or dopaminergic neuron loss in ASO mice.

Conclusion: It appears that overt intestinal inflammation (high levels of stool calprotectin) and/or systemic inflammation may be required to promote the PD-like phenotype in ASO mice.