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Aim: In the present study, we investigated the involvement of NLRP3 inflammasome in the intestinal epithelial barrier (IEB) changes associated with obesity, and its role in the interplay between enteric glia and intestinal epithelial cells (IECs)., Methods: Wild-type C57BL/6J and NLRP3-KO ( -/- ) mice were fed with high-fat diet (HFD) or standard diet for 8 weeks. Colonic IEB integrity and inflammasome activation were assessed. Immunolocalization of colonic mucosal GFAP- and NLRP3-positive cells along with in vitro coculture experiments with enteric glial cells (EGCs) and IECs allowed to investigate the potential link between altered IEB, enteric gliosis, and NLRP3 activation., Results: HFD mice showed increased body weight, altered IEB integrity, increased GFAP-positive glial cells, and NLRP3 inflammasome hyperactivation. HFD-NLRP3 -/- mice showed a lower increase in body weight, an improvement in IEB integrity and an absence of enteric gliosis. Coculture experiments showed that palmitate and lipopolysaccharide contribute to IEB damage and promote enteric gliosis with consequent hyperactivation of enteric glial NLRP3/caspase-1/IL-1β signaling. Enteric glial-derived IL-1β release exacerbates the IEB alterations. Such an effect was abrogated upon incubation with anakinra (IL-1β receptor antagonist) and with conditioned medium derived from silenced-NLRP3 glial cells., Conclusion: HFD intake elicits mucosal enteric gliotic processes characterized by a hyperactivation of NLRP3/caspase-1/IL-1β signaling pathway, that contributes to further exacerbate the disruption of intestinal mucosal barrier integrity. However, we cannot rule out the contribution of NLRP3 inflammasome activation from other cells, such as immune cells, in IEB alterations associated with obesity. Overall, our results suggest that enteric glial NLRP3 inflammasome might represent an interesting molecular target for the development of novel pharmacological approaches aimed at managing the enteric inflammation and intestinal mucosal dysfunctions associated with obesity., (© 2024 The Author(s). Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

α-Synuclein (α-syn), a pathological hallmark of PD, is emerging as a bridging element at the crossroads between neuro/immune-inflammatory responses and neurodegeneration in PD. Several evidence show that pathological α-syn accumulates in neuronal and non-neuronal cells (i.e., neurons, microglia, macrophages, skin cells, and intestinal cells) in central and peripheral tissues since the prodromal phase of the disease, contributing to brain pathology. Indeed, pathological α-syn deposition can promote neurogenic/immune-inflammatory responses that contribute to systemic and central neuroinflammation associated with PD. After providing an overview of the structure and functions of physiological α-syn as well as its pathological forms, we review current studies about the role of neuronal and non-neuronal α-syn at the crossroads between neuroinflammation and neurodegeneration in PD. In addition, we provide an overview of the correlation between the accumulation of α-syn in central and peripheral tissues and PD, related symptoms, and neuroinflammation. Special attention was paid to discussing whether targeting α-syn can represent a suitable therapeutical approach for PD., (© 2024 The Author(s). Medicinal Research Reviews published by Wiley Periodicals LLC.)

Background: No biomarkers are currently available to predict therapeutic response to ustekinumab (UST) in Crohn's disease (CD). The aim of this prospective study was to identify 1 or more cytokines able to predict mucosal healing in patients with CD treated with UST., Methods: We prospectively enrolled consecutive CD patients treated with UST. At weeks 0 (baseline), 24, and 48, a panel of serum cytokines was measured by a fluorescence assay. At the same time points, fecal calprotectin (FC) was assessed. A colonoscopy was performed at baseline and at week 48, where therapeutic outcome was evaluated in terms of mucosal healing., Results: Out of 44 patients enrolled, 22 (50%) achieved mucosal healing at the end of follow-up. Response was associated with higher interleukin (IL)-23 levels (P < .01). Fecal calprotectin levels decreased over time in responders but did not change in nonresponders (test for the interaction between time and mucosal healing, P < .001)., Conclusions: This pilot study showed that IL-23 and FC could be reliable biomarkers in predicting therapeutic outcome to UST therapy in CD. In particular, the correlation between baseline serum levels of IL-23 and mucosal healing at 48 weeks is particularly strong, paving the way for its use to drive therapeutic decisions., (© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Janus kinase inhibitors (JAKis) represent a fundamental therapeutic tool for the treatment of patients with immune-mediated inflammatory diseases. Although JAKis are often considered a homogeneous class of drugs whose members are thought to be largely interchangeable, there are significant differences in their efficacy and safety profiles. This narrative review analyzes the pharmacokinetic and pharmacodynamic differences among JAKIs, highlighting their clinical relevance based on the most recent available evidence. The article aims to provide rheumatologists, gastroenterologists and dermatologists with practical guidance for choosing the most appropriate JAKi for each patient, given the lack of evidence-based recommendations on this topic, to improve clinical outcomes. Due to its preferential action on JAK1, intestinal metabolization and proven absence of impact on male fertility, filgotinib may be characterized by an improved benefit/risk ratio compared with other less selective JAKis., Competing Interests: AA declares he received consulting/advisory board fees from AbbVie, Alfa-Sigma, Astra Zeneca, Biogen, Bristol-Myers Squibb, Celltrion, Eli-Lilly, Ferring, Galapagos, Gilead, Giuliani, Janssen, Lionhealth, MSD, Nestlé, Pfizer, Roche, Sanofi, Samsung Bioepis, Sandoz, Takeda, Tillots Pharma; speaker’s fees from AbbVie, AG Pharma, Biogen, Bristol-Myers Squibb, Celltrion, Eli-Lilly, Ferring, Galapagos, Janssen, Lionealth, MSD, Novartis, Pfizer, Roche, Samsung Bioepis, Sandoz, Takeda, Teva Pharmaceuticals; and research grants from MSD, Takeda, Pfizer, Biogen. MFa has acted as a consultant for: AbbVie, Celgene, Celltrion, Gilead, Pfizer, MSD, Bristol-Meyer, Takeda, Janssen-Cilag, Roche, Galapagos, Biogen; Sandoz, Eli-Lilly, Teva, Giuliani, he has received financial support for research from Janssen-Cilag, Pfizer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Antonioli, Armuzzi, Fantini and Fornai.)

Introduction: Visceral pain represents the most common digestive issue, frequently resulting from long-term inflammation, such as inflammatory bowel diseases. The lack of effective drugs prompted search of new therapeutic approaches. In this regard, gamma-aminobutyric acid (GABA) and Melissa officinalis (Mo) appear as excellent candidates as they were recognized to have several positive effects on the digestive system. The aim of this research was to evaluate the effects of a compound containing GABA and Mo (GABA-Mo 5:1) in inflammation-induced intestinal damage and visceral pain., Methods: Colitis was induced in rats by intrarectal 2,4-dinitrobenzenesulfonic acid (DNBS) administration. DNBS-treated animals received GABA-Mo (80 mg/kg BID), starting 3 days before DNBS administration, until 14 days after colitis induction (preventive protocol), or starting 7 days after DNBS until day 21 (curative protocol). Visceral pain was assessed by measuring the viscero-motor response (VMR) and the abdominal withdrawal reflex (AWR) to colorectal distension on day 7, 14 (both protocols) and 21 (curative protocol) after DNBS administration., Results: In the preventive protocol, GABA-Mo reduced AWR at day 14 but had no effect on VMR. In the spinal cord, treatment with GABA-Mo significantly prevented microglia reactivity (Iba-1 positive cells). In the colon, the supplement significantly decreased malondialdehyde (MDA, index of oxidative stress) and IL-1β levels and counteracted the decreased expression of claudin-1. Moreover, GABA-Mo normalized the increased levels of plasma lipopolysaccharide binding protein (LBP, index of altered intestinal permeability). In the curative protocol, GABA-Mo significantly counteracted visceral hypersensitivity persistence in DNBS-treated animals (day 14 and 21). In the spinal cord, GABA-Mo significantly reduced GFAP positive cell density (astrocytes). Histological evaluations highlighted a mild but significant effect of GABA-Mo in promoting healing from DNBS-induced colon damage. Colonic MDA and myeloperoxidase (index of leukocyte infiltration) levels were reduced, while the decreased colonic claudin-1 expression was normalized. In addition, the increased levels of plasma LBP were normalized by GABA-Mo administration., Discussion: In conclusion GABA-Mo, particularly in the curative protocol, was able to reduce visceral pain and intestinal inflammation, likely through a reinforcement of intestinal barrier integrity, thus representing a suitable approach for the management of abdominal pain, especially in the remission stages of colitis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Lucarini, Benvenuti, Di Salvo, D’Antongiovanni, Pellegrini, Valdiserra, Ciampi, Antonioli, Lambiase, Cancelli, Grosso, Di Cesare Mannelli, Bellini, Ghelardini and Fornai.)

Nowadays, the pharmacological management of visceral hypersensitivity associated with colitis is ineffective. In this context, targeting purinergic P2X4 receptor (P2X4R), which can modulate visceral pain transmission, could represent a promising therapeutic strategy. Herein, we tested the pain-relieving effect of two novel and selective P2X4R antagonists (NC-2600 and NP-1815-PX) in a murine model of DNBS-induced colitis and investigated the mechanisms underlying their effect. Tested drugs and dexamethasone (DEX) were administered orally, two days after colitis induction. Treatment with tested drugs and DEX improved tissue inflammatory parameters (body weight, spleen weight, macroscopic damage, TNF and IL-1β levels) in DNBS-rats. In addition, NC-2600 and NP-1815-PX attenuated visceral pain better than DEX and prevented the reduction of occludin expression. In in vitro studies, treatment of CaCo2 cells with supernatant from THP-1 cells, previously treated with LPS plus ATP, reduced the expression of tight junctions protein. By contrast, CaCo2 cells treated with supernatant from THP-1 cells, previously incubated with tested drugs, counteracted the reduction of tight junctions due to the inhibition of P2X4R/NLRP3/IL-1β axis. In conclusion, these results suggest that the direct and selective inhibition of P2X4R represents a viable approach for the management of visceral pain associated with colitis via NLRP3/IL-1β axis inhibition.

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., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Parkinson's disease (PD) is a common and slow-progressing neurodegenerative disorder characterized by motor and non-motor symptoms, including gastrointestinal (GI) dysfunctions. Over the last years, the microbiota-gut-brain (MGB) axis is emerging as a bacterial-neuro-immune ascending pathway that contributes to the progression of PD. Indeed, PD patients are characterized by changes in gut microbiota composition, alterations of intestinal epithelial barrier (IEB) and enteric neurogenic/inflammatory responses that, besides determining intestinal disturbances, contribute to brain pathology. In this context, despite the causal relationship between gut dysbiosis, impaired MGB axis and PD remains to be elucidated, emerging evidence shows that MGB axis modulation can represent a suitable therapeutical strategy for the treatment of PD. This review provides an overview of the available knowledge about the beneficial effects of gut-directed therapies, including dietary interventions, prebiotics, probiotics, synbiotics and fecal microbiota transplantation (FMT), in both PD patients and animal models. In this context, particular attention has been devoted to the mechanisms by which the modulation of MGB axis could halt or slow down PD pathology and, most importantly, how these approaches can be included in the clinical practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Benvenuti, Di Salvo, Bellini, Seguella, Rettura, Esposito, Antonioli, Ceravolo, Bernardini, Pellegrini and Fornai.)

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-1β, 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., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

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-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., 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 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., 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., (© 2022 European Academy of Neurology.)

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-1β, 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., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

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.

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 A 1 , A 2A , A 2B , and A 3 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., Competing Interests: Declaration of competing interest Luca Antonioli, Matteo Fornai, Carolina Pellegrini, Pal Pacher declare no conflict of interest. George Hasko owns stock in Purine Pharmaceuticals, Inc. This study was funded by NIH (R01HL158519-GH, R01GM066189-GH, R01DK113790-GH)., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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 (10 8  CFU day -1 ). After 8 weeks, plasma interleukin (IL)-1β 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-1β 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., (© 2023 The Authors. Molecular Nutrition & Food Research published by Wiley-VCH GmbH.)

Feline panleukopenia is a highly contagious and often fatal disease in cats. The virus, known as feline panleukopenia virus (FPV), primarily affects kittens and unvaccinated cats. It is transmitted through contact with infected cats or their bodily fluids, as well as contaminated objects and environments. The diagnosis of FPV infection can be confirmed through a combination of clinical signs, blood tests, and fecal testing. Prevention through vaccination is recommended for all cats. This case report describes an outbreak of feline panleukopenia in a group of unvaccinated domestic cats that resulted in acute mortality. The lesions were evaluated using histopathology, and the specific viral strain was characterized using molecular techniques. The clinical course of the outbreak was peracute, with a hemorrhagic pattern and 100% of lethality. The observed clinical-pathological pattern was unusual; nevertheless, molecular studies did not highlight peculiar genomic features of the parvovirus isolate. The outbreak affected 3 out of 12 cats in a very short time. However, the prompt application of biosecurity measures and vaccination resulted in an effective interruption of virus spread. In conclusion, we could assume that the virus found the ideal conditions to infect and replicate at high titers, resulting in a particularly aggressive outbreak.

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.

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-β) signalling [TGF-β, 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-β 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-β signalling. COX-1 and COX-2 inhibition counteracts this fibrotic remodelling by the modulation of TGF-β/SMAD signalling, mainly via SMAD6 induction and reduction in SMAD2 phosphorylation., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)