Gastrointestinal dysmotility in rodent models of Parkinson's disease.

Multiple studies describe prodromal, nonmotor dysfunctions that affect the quality of life of patients who subsequently develop Parkinson's disease (PD). These prodromal dysfunctions comprise a wide array of autonomic issues, including severe gastrointestinal (GI) motility disorders such as dysphagia, delayed gastric emptying, and chronic constipation. Indeed, strong evidence from studies in humans and animal models suggests that the GI tract and its neural, mainly vagal, connection to the central nervous system (CNS) could have a major role in the etiology of PD. In fact, misfolded α-synuclein aggregates that form Lewy bodies and neurites, i.e., the histological hallmarks of PD, are detected in the enteric nervous system (ENS) before clinical diagnosis of PD. The aim of the present review is to provide novel insights into the pathogenesis of GI dysmotility in PD, focusing our attention on functional, neurochemical, and molecular alterations in animal models.

Velusetrag rescues GI dysfunction, gut inflammation and dysbiosis in a mouse model of Parkinson's disease.

In patients with Parkinson's disease (PD), constipation is common, and it appears in a prodromal stage before the hallmark motor symptoms. The present study aimed to investigate whether Velusetrag, a selective 5­HT4 receptor agonist, may be a suitable candidate to improve intestinal motility in a mouse model of PD. Five months old PrP human A53T alpha-synuclein transgenic (Tg) mice, which display severe constipation along with decreased colonic cholinergic transmission already at 3 months, were treated daily with the drug for 4 weeks. Velusetrag treatment reduced constipation by significantly stimulating both the longitudinal and circular-driven contractions and improved inflammation by reducing the level of serum and colonic IL1ß and TNF-α and by decreasing the number of GFAP-positive glia cells in the colon of treated mice. No significant downregulation of the 5-HT4 receptor was observed but instead Velusetrag seemed to improve axonal degeneration in Tgs as shown by an increase in NF-H and VAChT staining. Ultimately, Velusetrag restored a well-balanced intestinal microbial composition comparable to non-Tg mice. Based on these promising data, we are confident that Velusetrag is potentially eligible for clinical studies to treat constipation in PD patients.

Are LRRK2 mysteries lurking in the gut?

Gut-brain axis and inflammation are two hot topics in Parkinson's disease (PD). In this setting, the leucine-rich repeat kinase 2 (LRRK2) gene, which encodes the eponym protein, has attracted much attention. LRRK2 is not only the gene most commonly associated with Parkinson's disease but also a susceptibility gene for Crohn's disease (CD), thereby suggesting that it may sit at the crossroads of gastrointestinal inflammation, Parkinson's, and Crohn's disease. In contrast to the accumulated data on LRRK2 in the central nervous system (CNS), research on LRRK2 in the digestive tract is still in its infancy, and the scope of the present review article is therefore to review existing studies on LRRK2 in the gastrointestinal tract in both physiological and pathological conditions. In light of current data on LRRK2 in the gastrointestinal tract, we discuss if LRRK2 could be or not regarded as a molecular link between gut inflammation, Parkinson's disease, and Crohn's disease, and we suggest directions for future research.

Use of Saccharomyces boulardii CNCM I-745 as therapeutic strategy for prevention of nonsteroidal anti-inflammatory drug-induced intestinal injury.

BACKGROUND AND PURPOSE: Nonsteroidal anti-inflammatory drugs (NSAIDs) can be associated with severe adverse digestive effects. This study examined the protective effects of the probiotic Saccharomyces boulardii CNCM I-745 in a rat model of diclofenac-induced enteropathy. EXPERIMENTAL APPROACH: Enteropathy was induced in 40-week-old male rats by intragastric diclofenac (4 mg·kg-1 BID for 14 days). S. boulardii CNCM I-745 (3 g·kg-1 BID by oral gavage) was administered starting 14 days before (preventive protocol) or along with (curative protocol) diclofenac administration. Ileal damage, inflammation, barrier integrity, gut microbiota composition and toll-like receptors (TLRs)-nuclear factor κB (NF-κB) pathway were evaluated. KEY RESULTS: Diclofenac elicited intestinal damage, along with increments of myeloperoxidase, malondialdehyde, tumour necrosis factor and interleukin-1ß, overexpression of TLR2/4, myeloid differentiation primary response 88 (Myd88) and NF-κB p65, increased faecal calprotectin and butyrate levels, and decreased blood haemoglobin levels, occludin and butyrate transporter monocarboxylate transporter 1 (MCT1) expression. In addition, diclofenac provoked a shift of bacterial taxa in both faecal and ileal samples. Treatment with S. boulardii CNCM I-745, in both preventive and curative protocols, counteracted the majority of these deleterious changes. Only preventive administration of the probiotic counteracted NSAID-induced decreased expression of MCT1 and increase in faecal butyrate levels. Occludin expression, after probiotic treatment, did not significantly change. CONCLUSIONS AND IMPLICATIONS: Treatment with S. boulardii CNCM I-745 prevents diclofenac-induced enteropathy through anti-inflammatory and antioxidant activities. Such effects are likely to be related to increased tissue butyrate bioavailability, through an improvement of butyrate uptake by the enteric mucosa.

Adenosine signaling as target in cardiovascular pharmacology.

Increasing evidence demonstrated the relevance of adenosine system in the onset and development of cardiovascular diseases, such as hypertension, myocardial infarct, ischemia, hypertension, heart failure, and atherosclerosis. In this regard, intense research efforts are being focused on the characterization of the pathophysiological significance of adenosine, acting at its membrane receptors named A1, A2A, A2B, and A3 receptors, in cardiovascular diseases. The present review article provides an integrated and comprehensive overview about current clinical and pre-clinical evidence about the role of adenosine in the pathophysiology of cardiovascular diseases. Particular attention has been focused on current scientific evidence about the pharmacological ligands acting on adenosine pathway as useful tools to manage cardiovascular diseases.

Pharmacological modulation of P2X4 in inflammatory bowel diseases: the way towards novel therapeutics?

Inflammatory bowel diseases (IBDs) are a group of idiopathic, chronic, relapsing, inflammatory conditions, which include ulcerative colitis (UC) and Crohn's disease (CD). These disorders are characterised by intestinal symptoms associated with chronic inflammation of the intestinal mucosa, such as gut dysmotility and visceral pain. Currently, the pharmacological management of IBD patients is far from satisfactory in terms of efficacy and safety, thus spurring the interest of the scientific community to identify novel molecular targets for the management of these disorders. According to recent research, it appears that P2 purinergic receptors, which can regulate the host's response to inflammation, have been identified as potential targets for the treatment of IBDs. In particular, among P2 receptors, the P2X4 receptor subtype has recently captured the attention of the research community owing to its role in shaping immune/inflammatory responses. Based on this evidence, the present review has been conceived to provide a critical appraisal of the available knowledge about the role of P2X4R subtype in the pathophysiological mechanisms underlying IBDs, pointing out its potential as therapeutic target to develop innovative therapeutic strategies aimed at counteracting the inflammatory process, gut dysmotility and visceral hypersensitivity associated with these disorders.

Pathological Remodeling of the Gut Barrier as a Prodromal Event of High-Fat Diet-Induced Obesity.

Intestinal barrier alterations represent a primum movens in obesity and related intestinal dysfunctions. However, whether gut barrier remodeling represents prodromal events in obesity before weight gain, metabolic alterations, and systemic inflammation remains unclear. Herein, we examined morphologic changes in the gut barrier in a mouse model of high-fat diet (HFD) since the earliest phases of diet assumption. C57BL/6J mice were fed with standard diet (SD) or HFD for 1, 2, 4, or 8 weeks. Remodeling of intestinal epithelial barrier, inflammatory infiltrate, and collagen deposition in the colonic wall was assessed by histochemistry and immunofluorescence analysis. Obese mice displayed increased body and epididymal fat weight along with increased plasma resistin, IL-1ß, and IL-6 levels after 8 weeks of HFD. Starting from 1 week of HFD, mice displayed (1) a decreased claudin-1 expression in lining epithelial cells, (2) an altered mucus in goblet cells, (3) an increase in proliferating epithelial cells in colonic crypts, (4) eosinophil infiltration along with an increase in vascular P-selectin, and (5) deposition of collagen fibers. HFD intake is associated with morphologic changes in the large bowel at mucosal and submucosal levels. In particular, the main changes include alterations in the mucous layer and intestinal epithelial barrier integrity and activation of mucosal defense-enhanced fibrotic deposition. These changes represent early events occurring before the development of obesity condition that could contribute to compromising the intestinal mucosal barrier and functions, opening the way for systemic dissemination.

Dietary Supplementation with the Probiotic SF68 Reinforces Intestinal Epithelial Barrier in Obese Mice by Improving Butyrate Bioavailability.

SCOPE: Modifications in intestinal microbiota and its metabolites, the short-chain fatty acids (SCFA) are main factors altering intestinal epithelial barrier integrity and eliciting the onset of a meta-inflammation observed in obesity. The present study is aimed at evaluating the efficacy of Enterococcus faecium (SF68) administration in counteracting the impairment of gut barrier and enteric inflammation in a model of diet-induced obesity, characterizing the molecular mechanisms underlying such beneficial effects. METHODS AND RESULTS: Male C57BL/6J mice, fed with standard diet (SD) or high-fat diet (HFD), are treated with SF68 (108  CFU day-1 ). After 8 weeks, plasma interleukin (IL)-1ß and lipopolysaccharide binding protein (LBP) are measured, analysis of fecal microbiota composition and butyrate content as well as intestinal malondialdehyde, myeloperoxidase, mucins, tight junction protein, and butyrate transporter expression are investigated. After 8 weeks, SF68 administration counteracts the body weight gain in HFD mice, reducing plasma IL-1ß and LBP. In parallel, SF68 treatment acts against the intestinal inflammation in HFD-fed animals and improves the intestinal barrier integrity and functionality in obese mice via the increase in tight junction protein and intestinal butyrate transporter (sodium-coupled monocarboxylate transporter 1 ) expression. CONCLUSIONS: Supplementation with SF68 reduces intestinal inflammation and reinforces the enteric epithelial barrier in obese mice, improving the transport and utilization of butyrate.

Enteric Glia and Brain Astroglia: Complex Communication in Health and Disease along the Gut-Brain Axis.

Several studies have provided interesting evidence about the role of the bidirectional communication between the gut and brain in the onset and development of several pathologic conditions, including inflammatory bowel diseases (IBDs), neurodegenerative diseases, and related comorbidities. Indeed, patients with IBD can experience neurologic disorders, including depression and cognitive impairment, besides typical intestinal symptoms. In parallel, patients with neurodegenerative disease, such as Parkinson disease and Alzheimer disease, are often characterized by the occurrence of functional gastrointestinal disorders. In this context, enteric glial cells and brain astrocytes are emerging as pivotal players in the initiation/maintenance of neuroinflammatory responses, which appear to contribute to the alterations of intestinal and neurologic functions observed in patients with IBD and neurodegenerative disorders. The present review was conceived to provide a comprehensive and critical overview of the available knowledge on the morphologic, molecular, and functional changes occurring in the enteric glia and brain astroglia in IBDs and neurologic disorders. In addition, our intent is to identify whether such alterations could represent a common denominator involved in the onset of comorbidities associated with the aforementioned disorders. This might help to identify putative targets useful to develop novel pharmacologic approaches for the therapeutic management of such disturbances.

Dietary Supplement, Containing the Dry Extract of Curcumin, Emblica and Cassia, Counteracts Intestinal Inflammation and Enteric Dysmotility Associated with Obesity.

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-1ß, 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.

LRRK2 expression in normal and pathologic human gut and in rodent enteric neural cell lines.

Leucine-rich repeat kinase 2 (LRRK2) gene, which is the gene most commonly associated with Parkinson's disease (PD), is also a susceptibility gene for Crohn's disease, thereby suggesting that LRRK2 may sit at the crossroads of gastrointestinal inflammation, Parkinson's, and Crohn's disease. LRRK2 protein has been studied intensely in both CNS neurons and in immune cells, but there are only few studies on LRRK2 in the enteric nervous system (ENS). LRRK2 is present in ENS ganglia and the existing studies on LRRK2 expression in colonic biopsies from PD subjects have yielded conflicting results. Herein, we propose to extend these findings by studying in more details LRRK2 expression in the ENS. LRRK2 expression was evaluated in full thickness segments of colon of 16 Lewy body, 12 non-Lewy body disorders cases, and 3 non-neurodegenerative controls and in various enteric neural cell lines. We showed that, in addition to enteric neurons, LRRK2 is constitutively expressed in enteric glial cells in both fetal and adult tissues. LRRK2 immunofluorescence intensity in the myenteric ganglia was not different between Lewy body and non-Lewy body disorders. Additionally, we identified the cAMP pathway as a key signaling pathway involved in the regulation of LRRK2 expression and phosphorylation in the enteric glial cells. Our study is the first detailed characterization of LRRK2 in the ENS and the first to show that enteric glial cells express LRRK2. Our findings provide a basis to unravel the functions of LRRK2 in the ENS and to further investigate the pathological changes in enteric synucleinopathies.

The intestinal barrier in disorders of the central nervous system.

The intestinal barrier, which primarily consists of a mucus layer, an epithelial barrier, and a gut vascular barrier, has a crucial role in health and disease by facilitating nutrient absorption and preventing the entry of pathogens. The intestinal barrier is in close contact with gut microbiota on its luminal side and with enteric neurons and glial cells on its tissue side. Mounting evidence now suggests that the intestinal barrier is compromised not only in digestive disorders, but also in disorders of the central nervous system (CNS), such as Parkinson's disease, autism spectrum disorder, depression, multiple sclerosis, and Alzheimer's disease. After providing an overview of the structure and functions of the intestinal barrier, we review existing preclinical and clinical studies supporting the notion that intestinal barrier dysfunction is present in neurological, neurodevelopmental, and psychiatric disorders. On the basis of this evidence, we discuss the mechanisms that possibly link gut barrier dysfunction and CNS disorders and the potential impact that evaluating enteric barriers in brain disorders could have on clinical practice, in terms of novel diagnostic and therapeutic strategies, in the near future.

Intestinal histomorphological and molecular alterations in patients with Parkinson's disease.

BACKGROUND AND PURPOSE: Changes 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. METHODS: Nineteen PD patients and nineteen asymptomatic subjects were enrolled. Blood lipopolysaccharide binding protein (LBP, marker of altered intestinal permeability) and interleukin-1ß (IL-1ß) levels, as well as stool IL-1ß 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. RESULTS: Faecal microbiota analysis revealed a significant difference in the α-diversity in PD patients compared to controls, while no differences were found in the ß-diversity. Compared to controls, PD patients showed significant chenags in plasma LBP levels, as well as faecal TNF and IL-1ß 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. CONCLUSIONS: Parkinson'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.

Role of cyclooxygenase pathways in bowel fibrotic remodelling in a murine model of experimental colitis.

OBJECTIVE: Gut fibrosis occurs under chronic inflammation. This study examined the effects of different cyclooxygenase (COX) inhibitors on fibrosis in the inflamed colon. METHODS: Colitis was induced by 2,4-dinitrobenzenesulfonic acid (DNBS) in albino male Sprague-Dawley rats. After 6, 12 and 18 days, macroscopic and microscopic damage, collagen and elastic fibre content were examined. At day 6, pro-fibrotic factors (collagen I and III, hydroxyproline, fibronectin, matrix metalloproteinase-2 and -9), transforming growth factor-beta (TGF-ß) signalling [TGF-ß, Ras homolog gene family member A (RhoA), phosphorylated small mother against decapentaplegic (pSMAD)-2 and -6] and peristalsis were assessed, and the effects of indomethacin, SC-560 or celecoxib were tested. KEY FINDINGS: Six days after DNBS administration, significant histopathological signs of fibrotic remodelling were observed in rats. At day 6, pro-fibrotic factors were up-regulated and colonic peristalsis was altered. COX inhibitors reversed the histochemical, molecular and functional changes in the fibrotic colon. COX inhibition reduced TGF-ß expression, SMAD2 phosphorylation and RhoA, and increased SMAD6 expression. CONCLUSIONS: Colonic fibrosis is associated with altered bowel motility and induction of profibrotic factors driven by TGF-ß signalling. COX-1 and COX-2 inhibition counteracts this fibrotic remodelling by the modulation of TGF-ß/SMAD signalling, mainly via SMAD6 induction and reduction in SMAD2 phosphorylation.

Glomerular hyperfiltration in morbid obesity: Role of the inflammasome signalling.

AIM: Obesity is associated with glomerular hyperfiltration which may precede the development of overt renal damage. Few studies evaluated the link between inflammasome signalling and hyperfiltration. The aim is to evaluate the relationship between IL1-ß/Caspase-1, insulin sensitivity and hyperfiltration in subjects with severe obesity, before and after weight loss. METHODS: Forty-six patients with BMI > 35 kg/m2 , without type-2-diabetes or hypertension, were evaluated at baseline and 6 months after bariatric surgery with oral glucose tollerance test, bioimpedance analysis and blood tests. The eGFR was calculated according to EPIcr-cys formula and insulin sensitivity by Oral Glucose Insulin Sensitivity. IL-1ß/Caspase-1 were measured with the ELISA-kit. HF was defined as eGFR ≥ 140 ml/min (non-indexed for BSA). RESULTS: Sixteen subjects at baseline had hyperfiltration, with a higher insulin resistance, BMI, lean mass and plasma levels of IL-1ß/Caspase-1. After surgery, there was a reduction in BMI and improvement in insulin resistance in all patients. However, in 8 of 16 patients hyperfiltration persisted and IL-1ß/Caspase-1 levels did not decrease (3.22 ± 0.79 vs. 3.13 ± 1.03 and 23.7 ± 12.1 vs. 20.6 ± 9.1, pre vs. post, pg/ml), while cytokines normalized in all the other patients in parallel with the eGFR. In a logistic regression model, correcting for the main covariates, lean mass and IL-1ß before surgery (p = .01 and p = .03, respectively), were the only predictors of hyperfiltration. CONCLUSION: Weight loss is effective in reducing hyperfiltration in most, but not all patients. Hyperfiltration remains unchanged in subjects who do not have a reduction in IL-1ß/Caspase-1, suggesting a pathogenetic role of the inflammasome signalling in the early stages of nephropathy.

Anti-inflammatory Effects of Novel P2X4 Receptor Antagonists, NC-2600 and NP-1815-PX, in a Murine Model of Colitis.

The pharmacological blockade of P2X4 receptors has shown potential benefits in the management of several immune/inflammatory diseases. However, data regarding the involvement of P2X4 receptors in the pathophysiological mechanisms of action in intestinal inflammation are not well defined. We aimed to evaluate the anti-inflammatory effects of two novel and selective P2X4 receptor antagonists, NC-2600 and NP-1815-PX, and characterize the molecular mechanisms of their action in a murine model of 2,4-dinitrobenzene sulfonic acid (DNBS)-induced colitis. These two drugs and dexamethasone (DEX) were administered orally for 6 days, immediately after the manifestation of DNBS. The body weight decrease, resulting from colitis, was attenuated by NC-2600 and NP-1815-PX, but not DEX. However, all three drugs attenuated the increase in spleen weight and ameliorated macroscopic and microscopic colonic tissue damage. Furthermore, all three compounds decreased tissue IL-1ß levels and caspase-1 expression and activity. Colonic tissue increase of tumor necrosis factor was downregulated by DEX, while both NC-2600 and NP-1815-PX were ineffective. The reduction of occludin associated with colitis was ameliorated by NC-2600 and NP-1815-PX, but not DEX. In THP-1 cells, lipopolysaccharide and ATP upregulated IL-1ß release and NLRP3, caspase-1, caspase-5, and caspase-8 activity, but not of caspase-4. These changes were prevented by NC-2600 and NP-1815-PX treatment. For the first time, the above findings show that the selective inhibition of P2X4 receptors represents a viable approach to manage bowel inflammation via the inhibition of NLRP3 inflammasome signaling pathways.

The administration of Enterococcus faecium SF68 counteracts compositional shifts in the gut microbiota of diet-induced obese mice.

Microorganisms with probiotic properties are eliciting an increasing interest as coadjuvants in the prevention and treatment of obesity through modulation of the gut microbiota. In this study, a probiotic formulation based on Enterococcus faecium SF68 was administered to mice fed with a high-fat diet (HFD) to evaluate its efficacy in reducing body mass gain and in modulating the intestinal bacterial composition. Both stool and ileum samples were collected from untreated and treated mice and absolute abundances of specific taxa constituting the gut microbial consortium were evaluated. SF68 administration significantly reduced the HFD-induced weight gain. In these animals, the microbial gut composition shifted toward an enrichment in microbes positively correlated with mucus thickness, lower inflammation, lower glycemia levels, and SCFA production (i.e., Bifidobacterium, Akkermansia, and Faecalibacterium), as well as a depletion in bacterial phyla having a key role in obesity (i.e., Firmicutes, Proteobacteria). Our results demonstrate the efficacy of E. faecium SF68 in adjusting the composition of the dysbiotic microbiota of HFD-fed animals, thus ameliorating clinical conditions and exerting anti-obesity effects.

From the intestinal mucosal barrier to the enteric neuromuscular compartment: an integrated overview on the morphological changes in Parkinson's disease.

Gastrointestinal dysfunctions represent the most common non-motor symptoms in Parkinson's disease (PD). Of note, changes in gut microbiota, impairments of intestinal epithelial barrier (IEB), bowel inflammation and neuroplastic rearrangements of the enteric nervous system (ENS) could be involved in the pathophysiology of the intestinal disturbances in PD. In this context, although several review articles have pooled together evidence on the alterations of enteric bacteria-neuro-immune network in PD, a revision of the literature on the specific morphological changes occurring in the intestinal mucosal barrier, the ENS and enteric muscular layers in PD, is lacking. The present review provides a complete appraisal of the available knowledge on the morphological alterations of intestinal mucosal barrier, with particular focus on IEB, ENS and enteric muscular layers in PD. In particular, our intent was to critically discuss whether, based on evidence from translational studies and pre-clinical models, morphological changes in the intestinal barrier and enteric neuromuscular compartment contribute to the pathophysiology of intestinal dysfunctions occurring in PD.

Palmitoylethanolamide Counteracts Enteric Inflammation and Bowel Motor Dysfunctions in a Mouse Model of Alzheimer's Disease.

Palmitoylethanolamide (PEA), an endogenous lipid mediator, is emerging as a promising pharmacological agent in multiple neurodegenerative disorders for its anti-inflammatory and neuroprotective properties. However, its effects on enteric inflammation and colonic dysmotility associated with Alzheimer's disease (AD) are lacking. This study was designed to investigate the beneficial effect of PEA administration in counteracting the enteric inflammation and relieving the bowel motor dysfunctions in an AD mouse model, SAMP8 mice. In addition, the ability of PEA in modulating the activation of enteric glial cells (EGCs), pivotally involved in the pathophysiology of bowel dysfunctions associated with inflammatory conditions, has also been examined. SAMP8 mice at 4 months of age were treated orally with PEA (5 mg/kg/day) for 2 months. SAMR1 animals were employed as controls. At the end of treatment, parameters dealing with colonic motility, inflammation, barrier integrity and AD protein accumulation were evaluated. The effect of PEA on EGCs was tested in cultured cells treated with lipopolysaccharide (LPS) plus ß-amyloid 1-42 (Aß). SAMP8 treated with PEA displayed: 1) an improvement of in vitro colonic motor activity, citrate synthase activity and intestinal epithelial barrier integrity and 2) a decrease in colonic Aß and α-synuclein (α-syn) accumulation, S100-ß expression as well as enteric IL-1ß and circulating LPS levels, as compared with untreated SAMP8 mice. In EGCs, treatment with PEA counteracted the increment of S100-ß, TLR-4, NF-κB p65 and IL-1ß release induced by LPS and Aß. These results suggest that PEA, under a condition of cognitive decline, prevents the enteric glial hyperactivation, reduces AD protein accumulation and counteracts the onset and progression of colonic inflammatory condition, as well as relieves intestinal motor dysfunctions and improves the intestinal epithelial barrier integrity. Therefore, PEA represents a viable approach for the management of the enteric inflammation and motor contractile abnormalities associated with AD.