AbstractsBowel 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 α-synuclein, bowel inflammation, impairments of IEB and alterations of enteric bacteria in a transgenic (Tg) model of PD before brain pathology. Human A53T α-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 α-synucleinopathy. The molecular mechanisms underlying the interplay between α-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-1β, 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 α-synuclein promoted IL-1β 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 YVAD (caspase-1 inhibitor) or when Caco-2 were incubated with anakinra, while butyrate incubation did not prevent such decrease. Taken together, early enteric α-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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Background and purposeChanges in gut microbiota composition, enteric inflammation, impairments of the intestinal epithelial barrier and neuroplastic changes in the enteric nervous system have been reported in Parkinson's disease (PD) patients and could contribute to the onset of both neurological and gastrointestinal symptoms. However, their mutual interplay has rarely been investigated. This study evaluated, in an integrated manner, changes in faecal microbiota composition, morphofunctional alterations of colonic mucosal barrier and changes of inflammatory markers in blood and stools of PD patients.MethodsNineteen PD patients and nineteen asymptomatic subjects were enrolled. Blood lipopolysaccharide binding protein (LBP, marker of altered intestinal permeability) and interleukin‐1β (IL‐1β) levels, as well as stool IL‐1β and tumour necrosis factor (TNF) levels, were evaluated. Gut microbiota analysis was performed. Epithelial mucins, collagen fibres, claudin‐1 and S100‐positive glial cells as markers of an impairment of the intestinal barrier, mucosal remodelling and enteric glial activation were evaluated on colonic mucosal specimens collected during colonoscopy.ResultsFaecal microbiota analysis revealed a significant difference in the α‐diversity in PD patients compared to controls, while no differences were found in the β‐diversity. Compared to controls, PD patients showed significant chenags in plasma LBP levels, as well as faecal TNF and IL‐1β levels. The histological analysis showed a decrease in epithelial neutral mucins and claudin‐1 expression and an increased expression of acidic mucins, collagen fibres and S100‐positive glial cells.ConclusionsParkinson's disease patients are characterized by enteric inflammation and increased intestinal epithelial barrier permeability, as well as colonic mucosal barrier remodelling, associated with changes in gut microbiota composition.

Intestinal epithelial barrier (IEB) impairment and enteric inflammation are involved in the onset of obesity and gut-related dysmotility. Dietary supplementation with natural plant extracts represents a useful strategy for the management of body weight gain and systemic inflammation associated with obesity. Here, we evaluate the efficacy of a food supplement containing the dry extract of Curcumin, Emblica and Cassia in counteracting enteric inflammation and motor abnormalities in a mouse model of obesity, induced by a high-fat diet (HFD). Male C57BL/6 mice, fed with standard diet (SD) or HFD, were treated with a natural mixture (Curcumin, Emblica and Cassia). After 8 weeks, body weight, BMI, liver and spleen weight, along with metabolic parameters and colonic motor activity were evaluated. Additionally, plasma LBP, fecal calprotectin, colonic levels of MPO and IL-1β, as well as the expression of occludin, TLR-4, MYD88 and NF-κB were investigated. Plant-based food supplement administration (1) counteracted the increase in body weight, BMI and metabolic parameters, along with a reduction in spleen and liver weight; (2) showed strengthening effects on the IEB integrity; and (3) reduced enteric inflammation and oxidative stress, as well as ameliorated the colonic contractile dysfunctions. Natural mixture administration reduced intestinal inflammation and counteracted the intestinal motor dysfunction associated with obesity.

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