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

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

doi:10.3389/fneur.2022.882628

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

Front Neurol. 2022 May 18:13:882628. doi: 10.3389/fneur.2022.882628. eCollection 2022.

Authors

Aeja Jackson¹, Phillip A Engen¹, Christopher B Forsyth^{1

2

3}, Maliha Shaikh¹, Ankur Naqib¹, Sherry Wilber¹, Dulce M Frausto¹, Shohreh Raeisi¹, Stefan J Green^{2

4}, Brinda Desai Bradaric^{5

6}, Amanda L Persons^{6

7}, Robin M Voigt^{1

2

3}, Ali Keshavarzian^{1

2

3

8}

Affiliations

¹ Rush Medical College, Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, IL, United States.
² Department of Medicine, Rush University Medical Center, Chicago, IL, United States.
³ Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL, United States.
⁴ Genomics and Microbiome Core Facility, Rush University Medical Center, Chicago, IL, United States.
⁵ Bachelor of Science in Health Sciences Program, College of Health Sciences, Rush University Medical Center, Chicago, IL, United States.
⁶ Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, IL, United States.
⁷ Department of Physician Assistant Studies, Rush University Medical Center, Chicago, IL, United States.
⁸ Department of Physiology, Rush University Medical Center, Chicago, IL, United States.

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: Disruption of the intestinal barrier without overt intestinal inflammation is not associated with worsening of PD-like behavior and pathology in ASO mice.

Keywords: Parkinson's disease; dextran sodium sulfate (DSS); gut-brain axis; intestinal hyperpermeability; microbiome.