scholarly journals The Role of Intestinal Permeability in Gastrointestinal Disorders and Current Methods of Evaluation

2021 ◽  
Vol 8 ◽  
Author(s):  
Tim Vanuytsel ◽  
Jan Tack ◽  
Ricard Farre
Keyword(s):  
Intestinal Permeability ◽  
Barrier Function ◽  
Crucial Role ◽  
Intestinal Barrier Function ◽  
Current Evidence ◽  
Gastrointestinal Disorders ◽  
Fatty Acid Binding ◽  
Ussing Chambers

An increased intestinal permeability has been described in various gastrointestinal and non-gastrointestinal disorders. Nevertheless, the concept and definition of intestinal permeability is relatively broad and includes not only an altered paracellular route, regulated by tight junction proteins, but also the transcellular route involving membrane transporters and channels, and endocytic mechanisms. Paracellular intestinal permeability can be assessed in vivo by using different molecules (e.g., sugars, polyethylene glycols, 51Cr-EDTA) and ex vivo in Ussing chambers combining electrophysiology and probes of different molecular sizes. The latter is still the gold standard technique for assessing the epithelial barrier function, whereas in vivo techniques, including putative blood biomarkers such as intestinal fatty acid-binding protein and zonulin, are broadly used despite limitations. In the second part of the review, the current evidence of the role of impaired barrier function in the pathophysiology of selected gastrointestinal and liver diseases is discussed. Celiac disease is one of the conditions with the best evidence for impaired barrier function playing a crucial role with zonulin as its proposed regulator. Increased permeability is clearly present in inflammatory bowel disease, but the question of whether this is a primary event or a consequence of inflammation remains unsolved. The gut-liver axis with a crucial role in impaired intestinal barrier function is increasingly recognized in chronic alcoholic and metabolic liver disease. Finally, the current evidence does not support an important role for increased permeability in bile acid diarrhea.

scholarly journals Sauna dehydration as a new physiological challenge model for intestinal barrier function

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Maria Fernanda Roca Rubio ◽  
Ulrika Eriksson ◽  
Robert J. Brummer ◽  
Julia König
Keyword(s):  
Fatty Acid ◽  
Intestinal Permeability ◽  
Barrier Function ◽  
Fatty Acid Binding Protein ◽  
Binding Protein ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Fatty Acid Binding ◽  
Acid Binding Protein

AbstractThe intestinal barrier plays a crucial role in maintaining gut health, and an increased permeability has been linked to several intestinal and extra-intestinal disorders. There is an increasing demand for interventions aimed at strengthening this barrier and for in vivo challenge models to assess their efficiency. This study investigated the effect of sauna-induced dehydration on intestinal barrier function (clinicaltrials.gov: NCT03620825). Twenty healthy subjects underwent three conditions in random order: (1) Sauna dehydration (loss of 3% body weight), (2) non-steroidal anti-inflammatory drug (NSAID) intake, (3) negative control. Intestinal permeability was assessed by a multi-sugar urinary recovery test, while intestinal damage, bacterial translocation and cytokines were assessed by plasma markers. The sauna dehydration protocol resulted in an increase in gastroduodenal and small intestinal permeability. Presumably, this increase occurred without substantial damage to the enterocytes as plasma intestinal fatty acid-binding protein (I-FABP) and liver fatty acid-binding protein (L-FABP) were not affected. In addition, we observed significant increases in levels of lipopolysaccharide-binding protein (LBP), IL-6 and IL-8, while sCD14, IL-10, IFN-ɣ and TNF-α were not affected. These results suggest that sauna dehydration increased intestinal permeability and could be applied as a new physiological in vivo challenge model for intestinal barrier function.

scholarly journals Crosstalk between Inflammation and ROCK/MLCK Signaling Pathways in Gastrointestinal Disorders with Intestinal Hyperpermeability

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Lijun Du ◽  
John J. Kim ◽  
Jinhua Shen ◽  
Ning Dai
Keyword(s):  
Intestinal Permeability ◽  
Barrier Function ◽  
Coiled Coil ◽  
Intestinal Barrier ◽  
Mucosal Inflammation ◽  
Intestinal Barrier Function ◽  
Gastrointestinal Disorders ◽  
Irritable Bowel

The barrier function of the intestine is essential for maintaining the normal homeostasis of the gut and mucosal immune system. Abnormalities in intestinal barrier function expressed by increased intestinal permeability have long been observed in various gastrointestinal disorders such as Crohn’s disease (CD), ulcerative colitis (UC), celiac disease, and irritable bowel syndrome (IBS). Imbalance of metabolizing junction proteins and mucosal inflammation contributes to intestinal hyperpermeability. Emerging studies exploringin vitroandin vivomodel system demonstrate that Rho-associated coiled-coil containing protein kinase- (ROCK-) and myosin light chain kinase- (MLCK-) mediated pathways are involved in the regulation of intestinal permeability. With this perspective, we aim to summarize the current state of knowledge regarding the role of inflammation and ROCK-/MLCK-mediated pathways leading to intestinal hyperpermeability in gastrointestinal disorders. In the near future, it may be possible to specifically target these specific pathways to develop novel therapies for gastrointestinal disorders associated with increased gut permeability.

scholarly journals Mice lacking the Na+/H+ exchanger 2 have impaired recovery of intestinal barrier function

2008 ◽  
Vol 295 (4) ◽  
pp. G791-G797 ◽  
Author(s):  
Adam J. Moeser ◽  
Prashant K. Nighot ◽  
Kathleen A. Ryan ◽  
Janet E. Simpson ◽  
Lane L. Clarke ◽  
...  
Keyword(s):  
Tight Junctions ◽  
Barrier Function ◽  
Recovery Period ◽  
Intestinal Barrier ◽  
Serine Phosphorylation ◽  
Intestinal Barrier Function ◽  
Wild Type ◽  
Ussing Chambers

Ischemic injury induces breakdown of the intestinal barrier. Recent studies in porcine postischemic tissues indicate that inhibition of NHE2 results in enhanced recovery of barrier function in vitro via a process involving interepithelial tight junctions. To further study this process, recovery of barrier function was assessed in wild-type (NHE2+/+) and NHE2−/− mice in vivo and wild-type mice in vitro. Mice were subjected to complete mesenteric ischemia in vivo, after which barrier function was measured by blood-to-lumen mannitol clearance over a 3-h recovery period or measurement of transepithelial electrical resistance (TER) in Ussing chambers immediately following ischemia. Tissues were assessed for expression of select junctional proteins. Compared with NHE2+/+ mice, NHE2−/− mice had greater intestinal permeability during the postischemic recovery process. In contrast to prior porcine studies, pharmacological inhibition of NHE2 in postischemic tissues from wild-type mice also resulted in significant reductions in TER. Mucosa from NHE2−/− mice displayed a shift of occludin and claudin-1 expression to the Triton-X-soluble membrane fractions and showed disruption of occludin and claudin-1 localization patterns following injury. This was qualitatively and quantitatively recovered in NHE2+/+ mice compared with NHE2−/− mice by the end of the 3-h recovery period. Serine phosphorylation of occludin and claudin-1 was downregulated in NHE2−/− postischemia compared with wild-type mice. These data indicate an important role for NHE2 in recovery of barrier function in mice via a mechanism involving tight junctions.

scholarly journals Short intense psychological stress induced by skydiving does not impair intestinal barrier function

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0254280
Author(s):  
Maria Fernanda Roca Rubio ◽  
Ulrika Eriksson ◽  
Robert J. Brummer ◽  
Julia König
Keyword(s):  
Psychological Stress ◽  
Intestinal Permeability ◽  
Barrier Function ◽  
Healthy Subjects ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Fatty Acid Binding ◽  
Small Intestinal ◽  
Cortisol Levels ◽  
Psychological Stressor

Background and aim Psychological stress has been shown to increase intestinal permeability and is associated with the development of gastrointestinal disorders. This study aimed to investigate skydiving as an alternative model to analyse the effect of acute psychological stress on intestinal barrier function. Materials and methods Twenty healthy subjects participated in a tandem skydive followed by a negative control visit, of which 19 (9 females and 10 males, 25.9 ± 3.7 years) were included in the study. Intestinal permeability was assessed by a multi-sugar urinary recovery test. Sucrose recovery and lactulose/rhamnose ratio in 0-5h urine indicated gastroduodenal and small intestinal permeability, respectively, and sucralose/erythritol ratio in 5-24h urine indicated colonic permeability. Blood samples were taken to assess markers associated with barrier function. This study has been registered at ClinicalTrials.gov (NCT03644979) on August 23, 2018. Results Skydiving resulted in a significant increase in salivary cortisol levels directly after skydiving compared to the control visit. Cortisol levels were still increased two hours after landing, while cortisol levels before skydiving were not significantly different from the baseline at the control visit. Skydiving did not induce a significant increase in gastroduodenal, small intestinal or colonic permeability. There was also no significant increase in plasma intestinal and liver fatty acid-binding proteins, suggesting no damage to the enterocytes. Discussion These results show that the acute intense psychological stress induced by skydiving does not affect intestinal permeability in healthy subjects. Future models aiming to investigate the effect of stress on human intestinal barrier function should consider a more sustained exposure to the psychological stressor.

scholarly journals Matrix metalloproteinase 9-induced increase in intestinal epithelial tight junction permeability contributes to the severity of experimental DSS colitis

2015 ◽  
Vol 309 (12) ◽  
pp. G988-G997 ◽  
Author(s):  
Prashant Nighot ◽  
Rana Al-Sadi ◽  
Manmeet Rawat ◽  
Shuhong Guo ◽  
D. Martin Watterson ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Protein Expression ◽  
Barrier Function ◽  
Intestinal Inflammation ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Intestinal Epithelial ◽  
Dss Colitis

Recent studies have implicated a pathogenic role for matrix metalloproteinases 9 (MMP-9) in inflammatory bowel disease. Although loss of epithelial barrier function has been shown to be a key pathogenic factor for the development of intestinal inflammation, the role of MMP-9 in intestinal barrier function remains unclear. The aim of this study was to investigate the role of MMP-9 in intestinal barrier function and intestinal inflammation. Wild-type (WT) and MMP-9−/−mice were subjected to experimental dextran sodium sulfate (DSS) colitis by administration of 3% DSS in drinking water for 7 days. The mouse colonic permeability was measured in vivo by recycling perfusion of the entire colon using fluorescently labeled dextran. The DSS-induced increase in the colonic permeability was accompanied by an increase in intestinal epithelial cell MMP-9 expression in WT mice. The DSS-induced increase in intestinal permeability and the severity of DSS colitis was found to be attenuated in MMP-9−/−mice. The colonic protein expression of myosin light chain kinase (MLCK) and phospho-MLC was found to be significantly increased after DSS administration in WT mice but not in MMP-9−/−mice. The DSS-induced increase in colonic permeability and colonic inflammation was attenuated in MLCK−/−mice and MLCK inhibitor ML-7-treated WT mice. The DSS-induced increase in colonic surface epithelial cell MLCK mRNA was abolished in MMP-9−/−mice. Lastly, increased MMP-9 protein expression was detected within the colonic surface epithelial cells in ulcerative colitis cases. These data suggest a role of MMP-9 in modulation of colonic epithelial permeability and inflammation via MLCK.

scholarly journals Somatization in patients with predominant diarrhoea irritable bowel syndrome: the role of the intestinal barrier function and integrity

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Laura Prospero ◽  
Giuseppe Riezzo ◽  
Michele Linsalata ◽  
Antonella Orlando ◽  
Benedetta D’Attoma ◽  
...  
Keyword(s):  
Irritable Bowel Syndrome ◽  
Barrier Function ◽  
Rating Scale ◽  
Psychological Symptoms ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Fatty Acid Binding ◽  
Gastrointestinal Symptom Rating Scale ◽  
Gi Symptoms ◽  
Irritable Bowel

Abstract Background Irritable bowel syndrome (IBS) is characterised by gastrointestinal (GI) and psychological symptoms (e.g., depression, anxiety, and somatization). Depression and anxiety, but not somatization, have already been associated with altered intestinal barrier function, increased LPS, and dysbiosis. The study aimed to investigate the possible link between somatization and intestinal barrier in IBS with diarrhoea (IBS-D) patients. Methods Forty-seven IBS-D patients were classified as having low somatization (LS = 19) or high somatization (HS = 28) according to the Symptom Checklist-90-Revised (SCL-90-R), (cut-off score = 63). The IBS Severity Scoring System (IBS-SSS) and the Gastrointestinal Symptom Rating Scale (GSRS) questionnaires were administered to evaluate GI symptoms. The intestinal barrier function was studied by the lactulose/mannitol absorption test, faecal and serum zonulin, serum intestinal fatty-acid binding protein, and diamine oxidase. Inflammation was assessed by assaying serum Interleukins (IL-6, IL-8, IL-10), and tumour necrosis factor-α. Dysbiosis was assessed by the urinary concentrations of indole and skatole and serum lipopolysaccharide (LPS). All data were analysed using a non-parametric test. Results The GI symptoms profiles were significantly more severe, both as a single symptom and as clusters of IBS-SSS and GSRS, in HS than LS patients. This finding was associated with impaired small intestinal permeability and increased faecal zonulin levels. Besides, HS patients showed significantly higher IL-8 and lowered IL-10 concentrations than LS patients. Lastly, circulating LPS levels and the urinary concentrations of indole were higher in HS than LS ones, suggesting a more pronounced imbalance of the small intestine in the former patients. Conclusions IBS is a multifactorial disorder needing complete clinical, psychological, and biochemical evaluations. Trial registration: https://clinicaltrials.gov/ct2/show/NCT03423069.

scholarly journals STAT3 Signalling via the IL-6ST/gp130 Cytokine Receptor Promotes Epithelial Integrity and Intestinal Barrier Function during DSS-Induced Colitis

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 187
Author(s):  
Lokman Pang ◽  
Jennifer Huynh ◽  
Mariah G. Alorro ◽  
Xia Li ◽  
Matthias Ernst ◽  
...  
Keyword(s):  
Barrier Function ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Intestinal Epithelial ◽  
Barrier Dysfunction ◽  
Epithelial Integrity ◽  
Barrier Integrity ◽  
Gp130 Receptor ◽  
Stat3 Signalling

The intestinal epithelium provides a barrier against commensal and pathogenic microorganisms. Barrier dysfunction promotes chronic inflammation, which can drive the pathogenesis of inflammatory bowel disease (IBD) and colorectal cancer (CRC). Although the Signal Transducer and Activator of Transcription-3 (STAT3) is overexpressed in both intestinal epithelial cells and immune cells in IBD patients, the role of the interleukin (IL)-6 family of cytokines through the shared IL-6ST/gp130 receptor and its associated STAT3 signalling in intestinal barrier integrity is unclear. We therefore investigated the role of STAT3 in retaining epithelial barrier integrity using dextran sulfate sodium (DSS)-induced colitis in two genetically modified mouse models, to either reduce STAT1/3 activation in response to IL-6 family cytokines with a truncated gp130∆STAT allele (GP130∆STAT/+), or by inducing short hairpin-mediated knockdown of Stat3 (shStat3). Here, we show that mice with reduced STAT3 activity are highly susceptible to DSS-induced colitis. Mechanistically, the IL-6/gp130/STAT3 signalling cascade orchestrates intestinal barrier function by modulating cytokine secretion and promoting epithelial integrity to maintain a defence against bacteria. Our study also identifies a crucial role of STAT3 in controlling intestinal permeability through tight junction proteins. Thus, therapeutically targeting the IL-6/gp130/STAT3 signalling axis to promote barrier function may serve as a treatment strategy for IBD patients.

scholarly journals The combined effect of food additive titanium dioxide and lipopolysaccharide on mouse intestinal barrier function after chronic exposure of titanium dioxide-contained feedstuffs

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Yongliang Zhang ◽  
Shumin Duan ◽  
Ying Liu ◽  
Yun Wang
Keyword(s):  
Titanium Dioxide ◽  
Intestinal Permeability ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
Antagonistic Effect ◽  
Food Additive ◽  
Combined Effect ◽  
Intestinal Barrier Function ◽  
Barrier Functions ◽  
Intestinal Villi

Abstract Objective Up to 44% of particulates of food-grade titanium dioxide (TiO2) are in nanoscale, while the effect and combined effect of which with other substances on intestinal barrier haven’t been fully understood yet. This study is aimed to study the effect of two kinds of TiO2 nanoparticles (TiO2 NPs and TiO2 MPs) on intestinal barrier functions, to reveal the combined effect of TiO2 NPs and Lipopolysaccharide (LPS) on intestinal barrier. Methods Male ICR mice were randomly divided into 18 groups (3 feed types * 3 exposure length * 2 LPS dosage) and were fed with normal or TiO2-mixed feed (containing 1% (mass fraction, w/w) TiO2 NPs or TiO2 MPs) for 1, 3, 6 months, followed by a single oral administration of 0 or 10 mg/(kg body weight) LPS. Four hours later, the transportation of TiO2, the intestinal barrier functions and the inflammatory response were evaluated. Results Both TiO2 notably increased the intestinal villi height / crypt depth ratios after 1 and 3 months of exposure, and increased the expression of ileal tight junction proteins (ZO-1 and occludin) after 1 month of exposure. After 6 months of exposure, TiO2 NPs led to reduced feed consumption, TiO2 MPs caused spare microvilli in small intestine and elevated Ti content in the blood cells. The intestinal permeability didn’t change in both TiO2 exposed groups. After LPS administration, we observed altered intestinal villi height / crypt depth ratios, lowered intestinal permeability (DAO) and upregulated expression of ileal ZO-1 in both (TiO2 +LPS) exposed groups. There are no significant changes of ileal or serum cytokines except for a higher serum TNF-α level in LPS treated group. The antagonistic effect was found between TiO2 NPs and LPS, but there are complicated interactions between TiO2 MPs and LPS. Conclusion Long-term intake of food additive TiO2 could alter the intestinal epithelial structure without influencing intestinal barrier function. Co-exposure of TiO2 and LPS would enhance intestinal barrier function without causing notable inflammatory responses, and there is antagonistic effect between TiO2 NPs and LPS. All the minor effects observed might associate with the gentle exposure method where TiO2 being ingested with feed.

scholarly journals Markers of Intestinal Permeability Are Rapidly Improved by Alcohol Withdrawal in Patients with Alcohol-Related Liver Disease

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1659
Author(s):  
Finn Jung ◽  
Katharina Burger ◽  
Raphaela Staltner ◽  
Annette Brandt ◽  
Sebastian Mueller ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Damage ◽  
Alcohol Withdrawal ◽  
Barrier Function ◽  
Binding Protein ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Fatty Acid Binding ◽  
Liver Health ◽  
Related Liver Disease

Changes in intestinal microbiome and barrier function are critical in the development of alcohol-related liver disease (ALD). Here, we determined the effects of a one-week alcohol withdrawal on parameters of intestinal barrier function in heavy drinkers with ALD in comparison to healthy non-drinkers (controls). In serum samples of 17 controls (m = 10/f = 7) and 37 age-matched ALD patients (m = 26/f = 11) undergoing a one-week alcohol withdrawal, markers of liver health and intestinal barrier function were assessed. Liver damage, e.g., fibrosis and hepatic steatosis, were assessed using FibroScan. Before alcohol withdrawal, markers of liver damage, lipopolysaccharide binding protein (LBP) and overall TLR4/TLR2 ligands in serum were significantly higher in ALD patients than in controls, whereas intestinal fatty acid binding protein (I-FABP) and zonulin protein concentrations in serum were lower. All parameters, with the exception of LBP, were significantly improved after alcohol withdrawal; however, not to the level of controls. Our data suggest that one-week of abstinence improves markers of intestinal barrier function and liver health in ALD patients.

scholarly journals The DNA Sensor AIM2 Protects against Streptozotocin-Induced Type 1 Diabetes by Regulating Intestinal Homeostasis via the IL-18 Pathway

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 959 ◽  
Author(s):  
Jefferson Antônio Leite ◽  
Gabriela Pessenda ◽  
Isabel C. Guerra-Gomes ◽  
Alynne Karen Mendonça de Santana ◽  
Camila André Pereira ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Gut Microbiota ◽  
Bacterial Translocation ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Dna Sensor ◽  
Proinflammatory Response

Pattern recognition receptors (PRRs), such as Nod2, Nlrp3, Tlr2, Trl4, and Tlr9, are directly involved in type 1 diabetes (T1D) susceptibility. However, the role of the cytosolic DNA sensor, AIM2, in T1D pathogenesis is still unknown. Here, we demonstrate that C57BL/6 mice lacking AIM2 (AIM2−/−) are prone to streptozotocin (STZ)-induced T1D, compared to WT C57BL/6 mice. The AIM2−/− mice phenotype is associated with a greater proinflammatory response in pancreatic tissues, alterations in gut microbiota and bacterial translocation to pancreatic lymph nodes (PLNs). These alterations are related to an increased intestinal permeability mediated by tight-junction disruption. Notably, AIM2−/− mice treated with broad-spectrum antibiotics (ABX) are protected from STZ-induced T1D and display a lower pancreatic proinflammatory response. Mechanistically, the AIM2 inflammasome is activated in vivo, leading to an IL-18 release in the ileum at 15 days after an STZ injection. IL-18 favors RegIIIγ production, thus mitigating gut microbiota alterations and reinforcing the intestinal barrier function. Together, our findings show a regulatory role of AIM2, mediated by IL-18, in shaping gut microbiota and reducing bacterial translocation and proinflammatory response against insulin-producing β cells, which ultimately results in protection against T1D onset in an STZ-induced diabetes model.

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