Journal
NPJ PARKINSONS DISEASE
Volume 8, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41531-021-00263-x
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Funding
- Italian Ministry of University and Research (MIUR) [PROGGR09EC]
- BIO@SNS, Scuola Normale Superiore
- Department of Clinical and Experimental Medicine, University of Pisa
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This study reveals a series of events that occur early in Parkinson's disease, including bowel inflammation, impaired intestinal epithelial barrier, and dysbiosis. It also finds that early accumulation of intestinal alpha-synuclein compromises the intestinal barrier through the activation of inflammatory response and alters the intestinal microbiota, which may contribute to both bowel symptoms and central pathology.
Bowel inflammation, impaired intestinal epithelial barrier (IEB), and gut dysbiosis could represent early events in Parkinson's disease (PD). This study examined, in a descriptive manner, the correlation among enteric alpha-synuclein, bowel inflammation, impairments of IEB and alterations of enteric bacteria in a transgenic (Tg) model of PD before brain pathology. Human A53T alpha-synuclein Tg mice were sacrificed at 3, 6, and 9 months of age to evaluate concomitance of enteric inflammation, IEB impairments, and enteric bacterial metabolite alterations during the early phases of alpha-synucleinopathy. The molecular mechanisms underlying the interplay between alpha-synuclein, activation of immune/inflammatory responses and IEB alterations were investigated with in vitro experiments in cell cultures. Tg mice displayed an increase in colonic levels of IL-1 beta, TNF, caspase-1 activity and enteric glia activation since 3 months of age. Colonic TLR-2 and zonulin-1 expression were altered in Tg mice as compared with controls. Lipopolysaccharide levels were increased in Tg animals at 3 months, while fecal butyrate and propionate levels were decreased. Co-treatment with lipopolysaccharide and alpha-synuclein promoted IL-1 beta release in the supernatant of THP-1 cells. When applied to Caco-2 cells, the THP-1-derived supernatant decreased zonulin-1 and occludin expression. Such an effect was abrogated when THP-1 cells were incubated with WAD (caspase-1 inhibitor) or when Caco-2 were incubated with anakinra, while butyrate incubation did not prevent such decrease. Taken together, early enteric alpha-synuclein accumulation contributes to compromise IEB through the direct activation of canonical caspase-1-dependent inflammasome signaling. These changes could contribute both to bowel symptoms as well as central pathology.
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