BackgroundGastrointestinal dysfunction can affect Parkinson’s disease (PD) patients long before the onset of motor symptoms. However, little is known about the relationship between gastrointestinal abnormalities and the development of PD. Contrary to other animal models, the human A53T alpha-synuclein (αS) transgenic mice, Line G2–3, develops αS-driven neurological and motor impairments after 9 months of age, displaying a long presymptomatic phase free of central nervous system (CNS) dysfunction.MethodsTo determine whether this line can be suitable to study constipation as it occurs in prodromal PD, gastrointestinal functionality was assessed in young mice through a multidisciplinary approach, based on behavioral and biochemical analysis combined with electrophysiological recordings of mouse intestinal preparations.ResultsWe found that the A53T αS mice display remarkable signs of gastrointestinal dysfunction that precede motor abnormalities and αS pathology in the CNS by at least 6 months. Young αS mice show a drastic delay in food transit along the gastrointestinal tract, of almost 2 h in 3 months old mice that increased to more than 3 h at 6 months. Such impairment was associated with abnormal formation of stools that resulted in less abundant but longer pellets excreted, suggesting a deficit in the intestinal peristalsis. In agreement with this, electrically evoked contractions of the colon, but not of the ileum, showed a reduced motor response in both longitudinal and circular muscle layers in αS mice already at 3 months of age, that was mainly due to an impaired cholinergic transmission of the underlying enteric nervous system. Interestingly, the presence of insoluble and aggregated αS was found in enteric neurons in both myenteric and submucosal plexi only in the colon of 3 months old αS mice, but not in the small intestine, and exacerbated with age, mimicking the increase in transit delay and the contraction deficit showed by behavioral and electrical recordings data.ConclusionsGastrointestinal dysfunction in A53T αS mice represents an early sign of αS-driven pathology without concomitant CNS involvement. We believe that this model can be very useful to study disease-modifying strategies that could extend the prodromal phase of PD and halt αS pathology from reaching the brain.Electronic supplementary materialThe online version of this article (10.1186/s40035-019-0146-z) contains supplementary material, which is available to authorized users.
Non-steroidal anti-inflammatory drugs (NSAIDs) can damage the small intestine, mainly through an involvement of enteric bacteria. This study examined the pathophysiology of NSAID-associated intestinal lesions in a rat model of diclofenac-enteropathy and evaluated the effect of rifaximin on small bowel damage. Enteropathy was induced in 40-week old male rats by intragastric diclofenac (4 mg/kg BID, 14 days). Rifaximin (delayed release formulation) was administered (50 mg/kg BID) 1 h before the NSAID. At the end of treatments, parameters dealing with ileal damage, inflammation, barrier integrity, microbiota composition, and TLR-NF-κB-inflammasome pathway were evaluated. In addition, the modulating effect of rifaximin on NLRP3 inflammasome was tested in an in vitro cell system. Diclofenac induced intestinal damage and inflammation, triggering an increase in tissue concentrations of tumor necrosis factor and interleukin-1β, higher expression of TLR-2 and TLR-4, MyD88, NF-κB and activation of caspase-1. In addition, the NSAID decreased ileal occludin expression and provoked a shift of bacterial phyla toward an increase in Proteobacteria and Bacteroidetes abundance. All these changes were counterbalanced by rifaximin co-administration. This drug was also capable of increasing the proportion of Lactobacilli, a genus depleted by the NSAID. In LPS-primed THP-1 cells stimulated by nigericin (a model to study the NLRP3 inflammasome), rifaximin reduced IL-1β production in a concentration-dependent fashion, this effect being associated with inhibition of the up-stream caspase-1 activation. In conclusion, diclofenac induced ileal mucosal lesions, driving inflammatory pathways and microbiota changes. In conclusion, rifaximin prevents diclofenac-induced enteropathy through both anti-bacterial and anti-inflammatory activities.
The present study was designed to examine the role of enteric glial cells (EGCs) in colonic neuromuscular dysfunctions in a mouse model of high‐fat diet (HFD)‐induced obesity. C57BL/6J mice were fed with HFD or standard diet (SD) for 1, 2, or 8 weeks. Colonic interleukin (IL)‐1β, IL‐6, and malondialdehyde (MDA) levels were measured. Expression of occludin in colonic tissues was examined by western blot. Substance P (SP), S100β, GFAP, and phosphorylated mitogen‐activated protein kinase 1 (pERK) were assessed in whole mount specimens of colonic plexus by immunohistochemistry. Colonic tachykininergic contractions, elicited by electrical stimulation or exogenous SP, were recorded in the presence or absence of fluorocitrate (FC). To mimic exposure to HFD, cultured EGCs were incubated with palmitate (PA) and/or lipopolysaccharide (LPS). SP and IL‐1β levels were assayed in the culture medium by ELISA. HFD mice displayed an increase in colonic IL‐1β and MDA, and a reduction of occludin at week 2. These changes occurred to a greater extent at week 8. In vitro electrically evoked tachykininergic contractions were enhanced in HFD mice after 2 or 8 weeks, and they were blunted by FC. Colonic IL‐6 levels as well as substance P and S100β density in myenteric ganglia of HFD mice were increased at week 8, but not at week 1 or 2. In cultured EGCs, co‐incubation with palmitate plus LPS led to a significant increase in both SP and IL‐1β release. HFD‐induced obesity is characterized by a hyperactivation of EGCs and is involved in the development of enteric motor disorders through an increase in tachykininergic activity and release of pro‐inflammatory mediators.
Increasing evidence suggests that intestinal dysfunctions may represent early events in Alzheimer’s disease and contribute to brain pathology. This study examined the relationship between onset of cognitive impairment and colonic dysfunctions in a spontaneous AD model before the full development of brain pathology. SAMP8 mice underwent Morris water maze and assessment of faecal output at four, six and eight months of age. In vitro colonic motility was examined. Faecal and colonic Aβ, tau proteins, α-synuclein and IL-1β were assessed by ELISA. Colonic citrate synthase activity was assessed by spectrophotometry. Colonic NLRP3, caspase-1 and ASC expression were evaluated by Western blotting. Colonic eosinophil density and claudin-1 expression were evaluated by immunohistochemistry. The effect of Aβ on NLRP3 signalling and mitochondrial function was tested in cultured cells. Cognitive impairment and decreased faecal output occurred in SAMP8 mice from six months. When compared with SAMR1, SAMP8 animals displayed: (1) impaired in vitro colonic contractions; (2) increased enteric AD-related proteins, IL-1β, active-caspase-1 expression and eosinophil density; and (3) decreased citrate synthase activity and claudin-1 expression. In THP-1 cells, Aβ promoted IL-1β release, which was abrogated upon incubation with caspase-1 inhibitor or in ASC-/- cells. Aβ decreased mitochondrial function in THP-1 cells. In SAMP8, enteric AD-related proteins deposition, inflammation and impaired colonic excitatory neurotransmission, occurring before the full brain pathology development, could contribute to bowel dysmotility and represent prodromal events in AD.
Adenosine A receptors (AR) regulate several enteric functions. However, their implication in the pathophysiology of intestinal dysmotility associated with high-fat diet (HFD)-induced obesity has not been elucidated. We investigated the expression of AR in mouse colon and their role in the mechanisms underlying the development of enteric dysmotility associated with obesity. Wild-type C57BL/6J mice were fed with HFD (60% kcal from fat) or normocaloric diet (NCD; 18% kcal from fat) for 8 weeks. Colonic AR localization was examined by immunofluorescence. The role of AR in the control of colonic motility was examined in functional experiments on longitudinal muscle preparations (LMPs). In NCD mice, AR were predominantly located in myenteric neurons; in HFD animals, their expression increased throughout the neuromuscular layer. Functionally, the AR antagonist MRS1754 enhanced electrically induced NK-mediated tachykininergic contractions in LMPs from HFD mice, while it was less effective in tissues from NCD mice. The A receptor agonist BAY 60-6583 decreased colonic tachykininergic contractions in LMPs, with higher efficacy in preparations from obese mice. Both AR ligands did not affect contractions elicited by exogenous substance P. Obesity is related with a condition of colonic inflammation, leading to an increase of AR expression. AR, modulating the activity of excitatory tachykininergic nerves, participate to the enteric dysmotility associated with obesity.
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