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

Abstract

IntroductionParkinson'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.ObjectiveTo 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].MethodsTo 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.ResultsLow 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.ConclusionDisruption of the intestinal barrier without overt intestinal inflammation is not associated with worsening of PD-like behavior and pathology in ASO mice.

Intragastric administration of low-dose rotenone post-colitis exacerbates damage to the nigrostriatal dopaminergic system in Parkinson’s disease: The pace accelerates even more

“…However, it is still to be determined if IBD patients are susceptible to developing PD because of a higher inflammatory milieu in the GI tract or if there are some other genetic or environmental factors along with GI inflammation that make them vulnerable to developing PD. Researchers have used transgenic (Tg) mice either overexpressing α-syn or susceptible genes that are dysregulated in PD to test the effect of DSS-induced colitis on α-syn accumulation and subsequent DAergic neurodegeneration 17,54 Moreover, it will be interesting to study the interaction of IBD with environmental toxins, such as exposure to pesticides, as the world is facing an unprecedented crisis of environmental health risks related to the excessive and unsafe use of pesticides. Consequently, it gives rise to a higher concentration of pesticide residue in the food chain, as evidenced by overall usage, especially in the food industry and agricultural sectors.…”

“…However, it is still to be determined if IBD patients are susceptible to developing PD because of a higher inflammatory milieu in the GI tract or if there are some other genetic or environmental factors along with GI inflammation that make them vulnerable to developing PD. Researchers have used transgenic (Tg) mice either overexpressing α-syn or susceptible genes that are dysregulated in PD to test the effect of DSS-induced colitis on α-syn accumulation and subsequent DAergic neurodegeneration 17,54…”

Experimental models of gut‐first Parkinson's disease: A systematic review

“…In addition to combining genetic overexpression of α-synuclein with gut delivery of environmental toxins 50,51 or PFFs, 90,94,97 gut inflammation can be used to accelerate parkinsonian pathology. [112][113][114][115] Pathogenesis in these models may not always involve ascending pathology and may require systemic inflammation 113 ; however, peripheral mechanisms are likely involved. 116 Microbial toxin models have shed light on potential microbiome-linked pathogenic mechanisms through studying isolated proteins or metabolites produced by microbes.…”

“…“Multi‐hit” models use a combination of pathogenic factors. In addition to combining genetic overexpression of α‐synuclein with gut delivery of environmental toxins 50,51 or PFFs, 90,94,97 gut inflammation can be used to accelerate parkinsonian pathology 112–115 . Pathogenesis in these models may not always involve ascending pathology and may require systemic inflammation 113 ; however, peripheral mechanisms are likely involved 116 .…”

The Interplay between Gut Microbiota and Parkinson’s Disease: Implications on Diagnosis and Treatment

“…Similar results were then replicated in 6-OHDA (hydroxydopamine)-treated rats (an animal model of PD), in which an increase in FITC-dextran permeability was observed as opposed to a decrease in transepithelial resistance, indicative of an impaired barrier functionality [ 140 ]. Of note, damage to the gut epithelial barrier alone without gut inflammation is not sufficient to explain disease severity and progression, as demonstrated in mice that overexpress human α -synuclein overexpressing (ASO mice) treated with dextran sodium sulfate, which is known to damage the mucosal epithelium [ 141 ]. These data demonstrate that a coordination of a series of complex, interconnected and related events is required to connect GI dysfunctions with PD symptoms.…”