Increase In Intestinal Permeability Research Articles

Association between serum zonulin level and severity of house dust mite allergic asthma

BackgroundIncreased intestinal permeability, either due to the exposure to antigens in asthmatic patients or due to a barrier defect, plays a critical role in susceptibility to environmental allergens. House dust mite allergy occurs more commonly than any other type of allergy among Egyptian asthmatic patients.AimTo assess the relation between serum zonulin level as a marker of increased intestinal permeability and the severity of house dust mite allergic asthma.MethodsA case–control study which included 48 patients with house dust mite allergic asthma and 48 healthy control subjects attending the Allergy and Immunology Unit, Microbiology and Immunology Department, Faculty of Medicine, Zagazig University.ResultsA statistically significant difference was detected between the two studied groups with respect to serum IgE and serum zonulin levels (p ˂ 0.001 and ˂ 0.001, respectively). The mean serum zonulin was equal to 258.3 ± 153.01 ng/ml in the asthmatic group and 80 ± 13 ng/ml in the control group. Serum zonulin level significantly increased with the increase of asthma severity (p ˂ 0.001). The cut off value of serum zonulin was ≥ 198 ng/ml, and the area under the curve was 0.76. It displayed sensitivity equal to 80% and specificity equal to 71.4%. Its negative predictive value was equal to 83.3%.ConclusionIntestinal barrier dysfunction contributes to the pathogenesis of allergic asthma. Serum zonulin level reflects an increase in intestinal permeability. Zonulin acts as prognostic factor of severity in asthma. Correction of the gut barrier defect may have a potential positive prognostic effect in asthma.

Supplementation of Kiwifruit Polyphenol Extract Attenuates High Fat Diet Induced Intestinal Barrier Damage and Inflammation via Reshaping Gut Microbiome.

Background: Impaired intestinal integrity and barrier function is associated with various diseases, including inflammatory bowel disease and metabolic syndrome. In recent years, plant-derived polyphenols have attracted much attention on regulating intestinal barrier function. Kiwifruit was recorded as a traditional Chinese medicine which can treat gastrointestinal diseases, but the mechanism was still unclear. In this study we investigated the effects of kiwifruit polyphenol extracts (KPE) on high fat diet induced intestinal permeability and its possible mechanism.Results: Dietary supplementation of KPE with 50 or 100 mg/kg bw could inhibit the increase of intestinal permeability caused by HFD and promote the expression of tight junction protein (Claudin-1, Occludin and ZO-1). From microbial diversity and RT-PCR, KPE administration reshaping gut microbiome, the relative abundance of Lactobacillus and Bifidobacterium were increased, and the relative abundance of Clostridium and Desulfovibrionaceae were decreased. The changes in microbe may influence intestinal inflammatory status. Then the expression of TLRs and cytokines were detected. KPE supplementation showed anti-inflammatory effect, the expression of IL-10 was increased and the expression of TLR-2, TLR-4, TNF-α and IL-1β were decreased. Correlation analysis indicated that the expression of tight junction protein was negative correlation with TLR-2, TLR-4, TNF-α and IL-1β expression, but positively correlated with Bacteroidete, Bifidobacterium and IL-10 expression; the expression of Bacteroidete, Lactobacillusand and Bifidobacterium were negative correlation with TLR4, TNF-α, and IL-1β expression.Conclusion: KPE treatment relieve the intestinal damage caused by HFD, which was related to the regulation of Bacteroidete, Lactobacillusand, and Bifidobacterium expression and inhibit intestinal inflammation. KPE could be a functional component for preventing gut damage and its related disease.

Acesulfame potassium induces dysbiosis and intestinal injury with enhanced lymphocyte migration to intestinal mucosa.

The artificial sweetener acesulfame potassium (ACK) is officially approved as safe for intake and has been used in processed foods. However, ACKs have been reported to induce metabolic syndrome, along with alteration of the gut microbiota in mice. In recent years, studies have suggested that this artificial sweetener promotes myeloperoxidase reactivity in Crohn's disease-like ileitis. We aimed to investigate the effect of ACK on the intestinal mucosa and gut microbiota of normal mice. Acesulfame potassium was administered to C57BL/6J mice (8weeks old) via free drinking. Intestinal damage was evaluated histologically, and messenger RNA (mRNA) levels of TNF-α, IFN-γ, IL1-β, MAdCAM-1, GLP1R, and GLP2R were determined with quantitative reverse transcription polymerase chain reaction (qRT-PCR). Immunohistochemistry was performed to examine the expression of MAdCAM-1 in the small intestine. The composition of gut microbiota was assessed using high-throughput sequencing. We performed intravital microscopic observation to examine if ACK altered lymphocyte migration to the intestinal microvessels. Acesulfame potassium increased the expression of proinflammatory cytokines, decreased the expression of GLP-1R and GLP-2R, and induced small intestinal injury with an increase in intestinal permeability, and ACK treatment induced microbial changes, but the transfer of feces alone from ACK mice did not reproduce intestinal damage in recipient mice. ACK treatment significantly increased the migration of lymphocytes to intestinal microvessels. Acesulfame potassium induces dysbiosis and intestinal injury with enhanced lymphocyte migration to intestinal mucosa. Massive use of non-caloric artificial sweeteners may not be as safe as we think.

Unique Gut Microbiome in HIV Patients on Antiretroviral Therapy (ART) Suggests Association with Chronic Inflammation.

ABSTRACTChronic inflammation is a hallmark of human immunodeficiency virus (HIV) infection and a risk factor for the development and progression of age-related comorbidities. Although HIV-associated gut dysbiosis has been suggested to be involved in sustained chronic inflammation, there remains a limited understanding of the association between gut dysbiosis and chronic inflammation during HIV infection. Here, we investigated compositional changes in the gut microbiome and its role in chronic inflammation in patients infected with HIV. We observed that the gut microbiomes of patients with low CD4 counts had reduced alpha diversity compared to those in uninfected controls. Following CD4 recovery, alpha diversity was restored, but intergroup dissimilarity of bacterial composition remained unchanged between patients and uninfected controls. Patients with HIV had higher abundance of the classes Negativicutes, Bacilli, and Coriobacteriia, as well as depletion of the class Clostridia. These relative abundances positively correlated with inflammatory cytokines and negatively correlated with anti-inflammatory cytokines. We found that gut dysbiosis accompanying HIV infection was characterized by a depletion of obligate anaerobic Clostridia and enrichment of facultative anaerobic bacteria, reflecting increased intestinal oxygen levels and intestinal permeability. Furthermore, it is likely that HIV-associated dysbiosis shifts the immunological balance toward inflammatory Th1 responses and encourages proinflammatory cytokine production. Our results suggest that gut dysbiosis contributes to sustaining chronic inflammation in patients with HIV infection despite effective antiretroviral therapy and that correcting gut dysbiosis will be effective in improving long-term outcomes in patients.IMPORTANCE Chronic inflammation is a hallmark of HIV infection and is associated with the development and progression of age-related comorbidities. Although the gastrointestinal tract is a major site of HIV replication and CD4+ T-cell depletion, the role of HIV-associated imbalance of gut microbiome in chronic inflammation is unclear. Here, we aimed to understand the causal relationship between abnormalities in the gut microbiome and chronic inflammation in patients with HIV. Our results suggest HIV-associated gut dysbiosis presents a more aerobic environment than that of healthy individuals, despite prolonged viral suppression. This dysbiosis likely results from a sustained increase in intestinal permeability, which supports sustained bacterial translocation in HIV patients, despite effective therapy. Additionally, we observed that several bacterial taxa enriched in HIV patients were associated with increased expression of inflammatory cytokines. Collectively, these results suggest that gut dysbiosis plays an important role in chronic inflammation in HIV patients.

Intestinal Barrier Dysfunction Exacerbates Neuroinflammation via the TLR4 Pathway in Mice With Heart Failure.

AimsThe present study aimed to investigate alterations in neuroinflammation after heart failure (HF) and explore the potential mechanisms.MethodsMale wild-type (WT) and Toll-like receptor 4 (TLR4)-knockout (KO) mice were subjected to sham operation or ligation of the left anterior descending coronary artery to induce HF. 8 weeks later, cardiac functions were analyzed by echocardiography, and intestinal barrier functions were examined by measuring tight junction protein expression, intestinal permeability and plasma metabolite levels. Alterations in neuroinflammation in the brain were examined by measuring microglial activation, inflammatory cytokine levels and the proinflammatory signaling pathway. The intestinal barrier protector intestinal alkaline phosphatase (IAP) and intestinal homeostasis inhibitor L-phenylalanine (L-Phe) were used to examine the relationship between intestinal barrier dysfunction and neuroinflammation in mice with HF.ResultsEight weeks later, WT mice with HF displayed obvious increases in intestinal permeability and plasma lipopolysaccharide (LPS) levels, which were accompanied by elevated expression of TLR4 in the brain and enhanced neuroinflammation. Treatment with the intestinal barrier protector IAP significantly attenuated neuroinflammation after HF while effectively increasing plasma LPS levels. TLR4-KO mice showed significant improvements in HF-induced neuroinflammation, which was not markedly affected by intestinal barrier inhibitors or protectors.ConclusionHF could induce intestinal barrier dysfunction and increase gut-to-blood translocation of LPS, which could further promote neuroinflammation through the TLR4 pathway.

Bioactive Compounds in Food as a Current Therapeutic Approach to Maintain a Healthy Intestinal Epithelium.

The intestinal epithelium serves as an effective barrier against the external environment, hampering the passage of potentially harmful substances (such as pathogenic microbes) that could trigger an exacerbated host immune response. The integrity of this barrier is thus essential for the maintenance of proper intestinal homeostasis and efficient protective reactions against chemical and microbial challenges. The principal consequence of intestinal barrier defects is an increase in intestinal permeability, which leads to an increased influx of luminal stressors, such as pathogens, toxins, and allergens, which in turn trigger inflammation and immune response. The fine and fragile balance of intestinal homeostasis can be altered by multiple factors that regulate barrier function, many of which are poorly understood. This review will address the role of gut microbiota as well as food supplements (such as probiotics, prebiotics, and synbiotics) in modulating gut health and regulating intestinal barrier function. In particular, we will focus on three human pathologies: inflammatory bowel disease, irritable bowel syndrome, and food allergy.

Dynamics of changes in plasma fatty acid binding proteins and intestinal zonulin in patients with generalized intra-abdominal infection and abdominal sepsis depending on the severity of patients

Objective. Determine the levels of plasma intestinal fatty acid binding proteins levels in combination with zonulin in patients with generalized intra-abdominal infection and abdominal sepsis, and define the clinical usefulness them to assess the severity of patients.
 Materials ad methods. This study was based on an analysis of 59 patients of both sexes aged 18 to 70 years with generalized intra-abdominal infection (gIAI) and abdominal sepsis (AS).
 Results. According to the aims and objectives of the study the patients were divided into three groups: the 1st group - 26 patients with generalized peritonitis without sepsis according to the «Sepsis-3» criterion; the 2nd group - 24 patients with sepsis, and the 3rd group - 9 patients with septic shock. We found statistically significant higher levels of I-FABP in the all groups of patients (P = 0.000). The same tendency was observed in all periods of the study, and the most significant levels of I-FABP were by the tenth day after surgery in patients with septic shock: IQR 1567.3- 3876.1 (P = 0.000). Patients with abdominal sepsis did not have a statistically significant change in zonulin levels compared to patients with gIAI without sepsis (P = 0.560) and a similar trend was observed on the 3rd day after surgery (P = 0.135). Only by the 7th and 10th days after surgery changes in zonulin levels were significant in intra-abdominal infection patients without sepsis, with abdominal sepsis and septic shock (P = 0.000 and P = 0.004, respectively).
 Conclusions. Serum I-FABP levels were valuable and objectively early predictors of the severity of gastrointestinal injuries in gIAI. We also presented evidence of increased plasma zonulin levels in generalized intra-abdominal infection compared with the control group. Elevated zonulin levels were an additional indicator of the observed increase in intestinal permeability during gIAI, but zonulin was not an early biomarker of the severity of gastrointestinal damage like I-FABP.

Health-seeking behaviour, views and preferences of adults with suspected increased intestinal permeability: A cross-sectional survey of Australian adults

BackgroundThe public health consequence of increased intestinal permeability (IP) is currently limited by the lack of patient-centred research. This study aims to describe the health-seeking behaviour of Australian adults with suspected IP. MethodsA cross-sectional survey of 589 Australian adults who have been diagnosed with IP or have suspected (undiagnosed) IP. ResultsThe majority (56.2%) of participants with suspected IP reported self-diagnosing their condition, with the majority (56.7%) of these participants preferring to be assessed using an accurate method by a general practitioner or naturopath. On average, Australian adults with suspected IP spent 11.1 (95% CI: 9.5, 12.8) years between first suspecting IP and receiving a formal diagnosis. Over the previous 12 months, participants spent an average of $699 on consultation fees, $2176 on dietary supplements for the treatment of IP, and an average of $287 on the assessment of IP. Furthermore, participants who find it difficult to live on their available household income spent significantly more (mean=$2963) on dietary supplements compared to participants who find it easy to live on their available household income ($1918) (p=0.015). ConclusionThe investigation of Australian adults with suspected IP found the majority of participants experienced a considerable length of time between first suspecting IP and receiving a diagnosis of IP. The out-of-pocket expenditure associated with the management of IP suggests a financial burden for people with suspected IP. The results of this study provide novel patient-centred considerations that can be used to inform a clinical practice guideline for the management of IP.

Leaky Gut: Effect of Dietary Fiber and Fats on Microbiome and Intestinal Barrier

Intestinal tract is the boundary that prevents harmful molecules from invading into the mucosal tissue, followed by systemic circulation. Intestinal permeability is an index for intestinal barrier integrity. Intestinal permeability has been shown to increase in various diseases—not only intestinal inflammatory diseases, but also systemic diseases, including diabetes, chronic kidney dysfunction, cancer, and cardiovascular diseases. Chronic increase of intestinal permeability is termed ‘leaky gut’ which is observed in the patients and animal models of these diseases. This state often correlates with the disease state. In addition, recent studies have revealed that gut microbiota affects intestinal and systemic heath conditions via their metabolite, especially short-chain fatty acids and lipopolysaccharides, which can trigger leaky gut. The etiology of leaky gut is still unknown; however, recent studies have uncovered exogenous factors that can modulate intestinal permeability. Nutrients are closely related to intestinal health and permeability that are actively investigated as a hot topic of scientific research. Here, we will review the effect of nutrients on intestinal permeability and microbiome for a better understanding of leaky gut and a possible mechanism of increase in intestinal permeability.

Effects of stocking density and dietary vitamin C on performance, meat quality, intestinal permeability, and stress indicators in broiler chickens.

The objective of the current study was to investigate the effects of stocking density (SD) and dietary supplementation of vitamin C on growth performance, meat quality, intestinal permeability, and stress indicators in broiler chickens. The study was conducted using a completely randomized design with a 2 × 2 factorial arrangement consisting of 2 different SD and 2 supplemental levels of dietary vitamin C. A total of 1,368 Ross 308 broiler chickens of 21 days of age with similar body weights (BW) were randomly allotted to 1 of 4 treatments with 6 replicates each. Different numbers of birds per identical floor pen (2.0 m × 2.4 m) were used to create 2 different SD levels of low SD (9 birds/m2) and high SD (18 birds/m2). The basal diet was formulated with no supplemental vitamin C to meet or exceed nutrient recommendations of the Ross 308 manual. The other diet was prepared by supplementing 200 mg/kg vitamin C in the basal diet. The study lasted for 14 days. At the end of the study, 3 male birds per replicate were selected to analyze meat quality, intestinal permeability, and stress indicators such as blood heterophil:lymphocyte (H:L) and feather corticosterone (CORT) concentrations. Results indicated that there were no interactions between different SD and dietary supplementation of vitamin C for all measurements. For the main effects of SD, birds raised at high SD had less (p < 0.01) BW, BW gain, and feed intake with increasing stress responses including greater blood H:L and feather CORT concentrations (p < 0.01) than those raised at low SD. Transepithelial electrical resistance in the jejunal mucosa was decreased (p < 0.05) at high SD, indicating an increase in intestinal permeability. However, the main effects of dietary supplementation of 200 mg/kg vitamin C were insignificant for all measurements. In conclusion, high SD of broiler chickens impairs growth performance and intestinal barrier function with increasing stress responses. However, dietary supplementation of vitamin C may have little beneficial effects on broiler chickens raised at the high SD condition used in the present study.

Antimicrobial Peptides Human Beta-Defensin-2 and -3 Protect the Gut During Candida albicans Infections Enhancing the Intestinal Barrier Integrity: In Vitro Study.

The intestinal mucosa is composed of a monolayer of epithelial cells, which is highly polarized and firmly united to each other thanks to the presence of proteins complexes, called Tight junctions (TJs). Alteration of the mucus layer and TJs causes an increase in intestinal permeability, which can lead to a microbial translocation and systemic disorders. Candida albicans, in addition to its role of commensal, is an opportunistic pathogen responsible for disseminated candidiasis, especially in immunocompromised subjects where the dysbiosis leads to damage of the intestinal mucosal barrier . In this work, we used a line of intestinal epithelial cells able to stably express the genes that encodes human beta defensin-2 (HBD-2) and -3 (HBD-3) to monitor the invasion of C. albicans in vitro. Defensins are a group of antimicrobial peptides (AMPs) found in different living organisms, and are involved in the first line of defense in the innate immune response against pathogens. The results obtained show that the presence of antimicrobial peptides improves the expression of TJs and increases the Trans Epithelial Electrical Resistence value. In addition, the invasive ability of C. albicans in transfected cells is significantly reduced, as well as the expression levels of genes involved in the apoptotic pathway. Through the study of interaction between antimicrobial peptides and microbiota we will be able in the future to better understand the mechanisms by which they exert the host defense function against intestinal pathogens.

Melatonin-mediated MT2 attenuates colitis induced by dextran sodium sulfate via PI3K/AKT/Nrf2/SIRT1/RORα/NF-κB signaling pathways

BackgroundInflammatory bowel disease (IBD) is an inflammatory response relative chronic disease in the intestinal tract. Our previous study demonstrated melatonin exerts an improvement effect on stress related IBD. The present study was further performed to clarify the mechanism of melatonin in dextran sodium sulfate (DSS)-induced colitis in mice. MethodsWe successfully established a DSS-induced colitis mouse model and hydrogen peroxide (H2O2)-treated intestinal epithelial cells (IECs) with or without melatonin supplementation to explore the improvement of melatonin in the DSS-induced colitis. ResultsMelatonin supplementation normalized the colitis, oxidative stress, mitochondria dysfunction, apoptosis and inflammation response, including the increase of intestinal permeability, histological score and the level of IL-1β, TNF-α, iNOS, NLRP3, MDA, Bax, Caspase3, Cytochrome C and Caspase9, as well as the reduction of body weight, colon length, Card9, IFN-γ, IL-10, T-AOC, Calpain1, Mfn2, VDAC1, RORα and SIRT1 proteins in DSS-treated mice. However, the improvement effects of melatonin were blocked by MT2 antagonist 4P-PDOT, PI3K antagonist LY294002, AKT antagonist GSK690693 and Nrf2 antagonist ML385, while mimicked by P65 antagonist PDTC in H2O2-IECs. ConclusionMelatonin-mediated MT2 activated PI3K/AKT/Nrf2/RORα/SIRT1 pathway and suppressed NF-κB pathway, ultimately improved DSS-induced colitis, which provides evidence for melatonin as an efficient therapy against oxidative stress associated IBD.

AB0073 INTESTINAL PERMEABILITY IN SPONDYLOARTHRITIS: A SYSTEMATIC REVIEW OF THE LITERATURE

Background:Growing evidence argue for a role of the gut in the pathophysiology of various chronic rheumatic diseases such as spondyloarthritis (SpA). This so-called “gut-joint axis” involves dysbiosis, bacterial translocation, intestinal inflammation and increase in intestinal permeability. Recent data from clinical and basic research suggested that the integrity of the intestinal barrier might be a key determinant in translating autoimmunity to inflammation, making intestinal permeability a potential marker or a target for future therapies.Objectives:To analyse the available data on intestinal permeability in SpA patients and the effects of drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) on intestinal permeability.Methods:A systematic review was conducted. Without date restriction, the following databases were searched through September 1, 2020: Medline, Embase and Cochrane. Studies with patients with SpA assessing the intestinal permeability were selected. Some of the included studies have assessed the effect of NSAIDs on intestinal permeability.Results:A total of 12 studies were included in the final analysis. The 12 studies involved a total of 268 SpA patients, including 240 ankylosing spondylitis (AS). Among the studies included, four studies used the lactulose/mannitol test, four studies used the 51Cr-ethylenediaminetetraacetic test and two studies used the polyethylene glycols test. Nine of the 12 studies reported increased intestinal permeability regardless on the method used for intestinal permeability evaluation. Four studies evaluated the link between disease activity, assessed by CRP and ESR levels, and intestinal permeability and showed no correlation between increased intestinal permeability and markers of disease activity in AS patients. As regards the effects of NSAIDs on intestinal permeability, data are controversial. Two studies, including one evaluating indomethacin, did not show any influence of NSAIDs in AS patients, one study showed an increase in intestinal permeability under NSAIDs in only 60% of the patients, another study reported increased intestinal permeability. When comparing the effect of NSAIDs in patients with AS to healthy subjects, one study reported a comparable NSAIDs-induced increase in intestinal permeability in both groups.Conclusion:The results of our review suggest that increased intestinal permeability is present in SpA patients even in the absence of NSAIDs use and regardless of the method used to assess intestinal permeability. The effects of NSAIDs on intestinal permeability in SpA patients is more controversial and further studies are needed to clarify them.Disclosure of Interests:None declared

The american lifestyle induced obesity syndrome (ALIOS) diet induces an increase in intestinal permeability and exacerbates inflammation in female and male mice via the TLR4 signalling pathway

The american lifestyle induced obesity syndrome (ALIOS) diet induces an increase in intestinal permeability and exacerbates inflammation in female and male mice via the TLR4 signalling pathway

The Impact of Alcohol in Inflammatory Bowel Diseases.

Several environmental factors have been implicated in the pathogenesis of inflammatory bowel diseases (IBD); however, the evidence for alcohol is sparse, as is its implications on disease activity and overall management. Here, we examine the available evidence for the effect of alcohol on IBD, including its association with the development of IBD, role in exacerbations, and potential medication interactions. Several mechanisms have been demonstrated to mediate the effects of ethanol in the gastrointestinal tract. Alcohol has been shown to alter the gut microbiome, disrupt intestinal barrier, and increase intestinal permeability, directly and indirectly promoting immune activation. Conversely, specific alcoholic beverages, notably red wine, may have anti-inflammatory properties capable of assisting in disease control and affecting disease monitoring. Nonetheless, most alcohol-mediated effects seem to facilitate intestinal inflammation and consequently impact disease onset, recurrence, and symptom control. Furthermore, alcohol use interferes with the metabolism of several medications leading to increased side effect profiles or even loss of effect. Notably, mesalamine, azathioprine, methotrexate, and biologic medications can all be affected by concomitant alcohol intake via a variety of mechanisms.

Food antigens exacerbate intestinal damage and inflammation following the disruption of the mucosal barrier

Food antigens are closely related to progression of inflammatory bowel disease; however, details of how they induce intestinal immune responses and causes intestinal inflammation is not yet clear. The present study aimed to examine the effects of oral collagen on the intestinal mucosa, and elucidate the mechanism of food antigen-induced enteritis. Here, we provide evidence that Aspirin (a mucosal-damaging agent) and type II collagen (CII; a food antigen) acted synergistically to disrupt the intestinal mucosal barrier, and increase intestinal permeability, which resulted in a large amount of CII entered into the lamina propria, where it interacted with the intestinal immune system, promoted intestinal inflammation, and shaped innate and adaptive immune reactions into Th1-dominant. The underlying mechanism of the CII-induced intestinal inflammation may associate with higher levels of Th1, TLR2 and TLR4, and lower levels of Th2 in the intestine of Aspirin + CII treated rats.The study indicate that compromised integrity of the intestinal barrier appears to be a prerequisite for CII-induced intestinal inflammation. The synergistic effect of food antigens and mucosal barrier injury is an important cause of intestinal inflammation. This new understanding the role of food antigen on intestinal inflammation will provide us with a new strategy for treatment and prevention of intestinal inflammation.

Early Th2 response to Plasmodium yoelii infection is associated with intestinal mastocytosis, bacteremia and elevated intestinal permeability.

Abstract The presence of bacteria in the blood or bacteremia is complication of malaria that occurs across a broad range of ages and clinical manifestations and is associated with increased morbidity and mortality, but the factors that predispose patients to developing this “leaky gut” phenotype are poorly understood. Enteric bacteria are thought to translocate from the intestinal lumen into circulation via damaged tight and adherens junctions. Mast cell (MC) activation in both humans and mice is known to disrupt epithelial junction integrity and increase intestinal permeability. Increases in intestinal MCs have been noted in both mouse and primate models of malaria. Activated MCs are potent sources of Th2 cytokines, histamine, and other factors that can influence both the innate and adaptive immune response. To better understand the temporal patterns of both the circulating and intestinal immune response to non-lethal infection, we infected C57BL/6J mice with Plasmodium yoelii yoelii 17XNL and analyzed circulating white blood cell counts, bacteria levels, cytokines, intestinal permeability to dextran and ileal MC numbers 1, 2, 4, 6, 8 and 10 days post infection. We observed an early elevation (day 4) in Th2 cytokines interleukin (IL)-4, IL-6 and IL-10. Interestingly, we also observed an early elevation in basophils and eosinophils, granulocytes associated with allergic inflammation. These findings coincided with the first appearance of MCs in the ileum and preceded the development of bacteremia (day 6) and elevations in intestinal permeability to dextran (day 8), suggesting the early Th2 response to infection is a potential driver of mastocytosis and increased permeability.

Obstrucción intestinal secundaria a hernia intercostal transdiafragmática

The presence of digestive symptoms associated with irritable bowel syndrome (IBS) in patients with inflammatory bowel disease (IBD) in remission is a topic of growing interest. Although there is heterogeneity in clinical studies regarding the use of IBD remission criteria and the diagnosis of IBS, the available data indicate that the IBD-IBS overlap would affect up to one third of patients in remission, and they agree on the finding of a negative impact on the mental health and quality of life of the individuals who suffer from it. The pathophysiological bases that would explain this potential overlap are not completely clear. However, an alteration in the brain-gut axis associated with an increase in intestinal permeability, neuroimmune activation and dysbiosis would be common to both conditions. The hypothesis of a new clinical condition or syndrome - "Irritable Inflammatory Bowel Disease" or "Post-inflammatory IBS" - is the subject of intense investigation. The clinical approach is based on certifying the remission of IBD activity and ruling out other non-inflammatory causes of potentially treatable persistent functional digestive symptoms. In the case of symptoms associated with IBS, in the absence of sufficient evidence, comprehensive and personalised management of the clinical picture (dietary, pharmacological and psychotherapeutic measures) should be carried out, similar to a genuine IBS.

Matrix Metalloproteinase-9 (MMP-9) induced disruption of intestinal epithelial tight junction barrier is mediated by NF-κB activation.

BackgroundMatrix Metalloproteinase-9 (MMP-9) has been shown to play a key role in mediating inflammation and tissue damage in inflammatory bowel disease (IBD). In patients with IBD, the intestinal tight junction (TJ) barrier is compromised as characterized by an increase in intestinal permeability. MMP-9 is elevated in intestinal tissue, serum and stool of patients with IBD. Previous studies from our laboratory showed that MMP-9 causes an increase in intestinal epithelial TJ permeability and that the MMP-9 induced increase in intestinal permeability is an important pathogenic factor contributing to the development of intestinal inflammation in IBD. However, the intracellular mechanisms that mediate the MMP-9 modulation of intestinal barrier function remain unclear.AimsThe main aim of this study was to further elucidate the molecular mechanisms involved in MMP-9 induced increase in intestinal epithelial TJ permeability using Caco-2 monolayers as an in-vitro model system.ResultsMMP-9 induced increase in Caco-2 TJ permeability was associated with activation and cytoplasmic-to-nuclear translocation of NF-κB p65. Knocking-down NF-κB p65 by siRNA transfection prevented the MMP-9 induced expression of the NF-κB target gene IL-8, myosin light chain kinase (MLCK) protein expression, and subsequently prevented the increase in Caco-2 TJ permeability. In addition, the effect of MMP-9 on Caco-2 intestinal epithelial TJ barrier function was not mediated by apoptosis or necrosis.ConclusionOur data show that the MMP-9 induced disruption of Caco-2 intestinal epithelial TJ barrier function is regulated by NF-κB pathway activation of MLCK.

Tetrandrine attenuates intestinal epithelial barrier defects caused by colitis through promoting the expression of Occludin via the AhR-miR-429 pathway.

The elevated intestinal permeability due to mucosal barrier defects is not only secondary to inflammatory bowel disease but also precedes enteritis. Tetrandrine, a bisbenzyl isoquinoline alkaloid isolated from the dried roots of Stephamis tetlandra S. Moor, was previously demonstrated to ameliorate colitis induced by dextran sulfate sodium (DSS) in mice. Here, we investigate whether and how tetrandrine protects against the disruption of the intestinal epithelial barrier under colitis condition. The data show that oral administration of tetrandrine significantly counteracted the increase of intestinal permeability in DSS-treated mice, enhanced the mRNA and protein expression of Occludin and Claudin1 in the colon, but hardly affected the expression of ZO-1 and Mucin2. In vitro, tetrandrine treatment rescued the decrease of monolayer transmembrane resistance and the increase of epithelial cell permeability induced by TNF-α, upregulated the expression of Occludin, and downregulated the expression of Claudin1 but did not affect the expression of ZO-1. The siRNA of Occludin largely weakened the protective effect of tetrandrine on the epithelial barrier function in Caco-2 cells. MiR-429 mimic obviously counteracted the upregulation of tetrandrine on the expression of Occludin and the amelioration on epithelial barrier defects, in contrast, miR-429 inhibitor showed the opposite effects. The antagonist (CH223191) and siAhR of aryl hydrocarbon receptor (AhR) nearly completely diminished the effects of tetrandrine, including inhibition of the miR429 expression, the upregulation of Occludin expression, and amelioration of intestinal epithelial barrier defects in Caco-2 cells. In colitis mice, CH223191 significantly weakened the protective effect of tetrandrine on colitis and intestinal mucosal barrier and diminished the downregulation on miR-429 expression and the promotion on Occludin expression in the colon. In summary, tetrandrine can attenuate the intestinal epithelial barrier defects in colitis through promoting Occludin expression via the AhR/miR-429 pathway, and it might be used to treat colitis as a barrier protector.