Increase In Small Intestinal Permeability Research Articles

EP.WE.824Effect of bariatric surgery on gut permeability in humans: a systematic review

Abstract Aims Altered intestinal permeability (“leaky gut”) is associated with obesity. Several mechanisms have been suggested to explain the harmful sequalae that follow permeability change such as inflammation, alteration to the microbiome and onset of insulin resistance. Studies describe bariatric surgery as having varying effects on intestinal permeability. We aim to summarise and review the literature. Methods A systematic review was performed using MEDLINE, EMBASE, and Scopus to identify studies in humans that investigated permeability change after bariatric surgery. Results 5 studies were identified, all cohort. Heterogeneity precluded meta-analysis. All calculated permeability change following oral intake of different sugar solutions. Two studies described a reduction in gastroduodenal permeability post sleeve gastrectomy (SG), one from an increased baseline compared to lean controls. Two described an increase in small intestinal permeability after “malabsorptive” operations (biliopancreatic diversion and duodenal switch). Two found decreased small intestinal permeability at one month post Roux-en-Y gastric bypass and six months post SG. One including only SG had opposite findings of increased small intestinal permeability at 6 months. The only colonic change reported was increased permeability also 6 months post SG. Conclusion Research found both increased and decreased permeability of the small intestine. Two studies found reduced gastroduodenal permeability post operatively. Evidence regarding the effect of bariatric surgery on the permeability of the gastrointestinal tract and specifically the colon is limited and follow up, operation type and small numbers limit meaningful comparison. Further study into this crucial aspect of obesity both before and after surgery is needed.

New research sheds light on NSAID risks

individuals underwent a four-phase evaluation: ibuprofen before cycling, ibuprofen alone, cycling with no premedication, and a rest period. The treatment phase involved administration of two doses of ibuprofen 400 mg before cycling. Two measures of worsening GI integrity were found when the cyclists took ibuprofen before exercise compared with changes measured during the other three phases. The researchers detected an increase in small intestinal permeability and reduced gut barrier integrity. The small sample size limits application of the fi ndings; however, pharmacists should consider recommending something other than an NSAID before exercise, especially in patients at risk for GI problems.

Mechanism of Interleukin-1β Induced-Increase in Mouse Intestinal PermeabilityIn Vivo

Interleukin-1β (IL-1β) has been shown to play an essential role in mediating intestinal inflammation of Crohn's disease and other inflammatory conditions of the gut. Previous studies from our laboratory have shown that IL-1β causes an increase in intestinal tight-junction permeability in Caco-2 monolayers in vitro. However, the IL-1β effect on the intestinal epithelial barrier in vivo remains unclear. the major aims of this study were to examine the effect of IL-1β on mouse intestinal epithelial barrier in vivo and to delineate the mechanisms involved using an in vivo model system consisting of a recycling perfusion of mouse small intestine. Intraperitonial injection of IL-1β at varying doses (0-10 μg) caused a concentration-dependent increase in mouse intestinal permeability to the paracellular marker dextran (10 KD), and the maximal increase in dextran flux occurred at IL-1β dose of 5 μg. IL-1β treatment caused an increase in myosin light-chain kinase (MLCK) mRNA and protein expression in the small intestinal tissue starting at 24 h, which continued up to 72 h. Additionally, IL-1β did not cause an increase in intestinal permeability in MLCK-deficient mice (C57BL/6 MLCK(-/-)). MLCK inhibitor ML-7 (2 mg/kg body weight) also inhibited the IL-1β-induced increase in small intestinal permeability. The IL-1β-induced increase in mouse intestinal permeability was associated with an increase in NF-κB activation. The intestinal tissue-specific silencing of NF-κB p65 inhibited the IL-1β-induced increase in intestinal permeability and increase in MLCK expression. These data show for the first time that IL-1β causes an increase in mouse intestinal permeability in vivo. These data suggested that the mechanism of IL-1β-induced increase in mouse intestinal permeability in vivo involved NF-κB p65-induced activation of the mouse enterocyte MLCK gene.

Exercise-Induced Splanchnic Hypoperfusion Results in Gut Dysfunction in Healthy Men

BackgroundSplanchnic hypoperfusion is common in various pathophysiological conditions and often considered to lead to gut dysfunction. While it is known that physiological situations such as physical exercise also result in splanchnic hypoperfusion, the consequences of flow redistribution at the expense of abdominal organs remained to be determined. This study focuses on the effects of splanchnic hypoperfusion on the gut, and the relationship between hypoperfusion, intestinal injury and permeability during physical exercise in healthy men.Methods and FindingsHealthy men cycled for 60 minutes at 70% of maximum workload capacity. Splanchnic hypoperfusion was assessed using gastric tonometry. Blood, sampled every 10 minutes, was analyzed for enterocyte damage parameters (intestinal fatty acid binding protein (I-FABP) and ileal bile acid binding protein (I-BABP)). Changes in intestinal permeability were assessed using sugar probes. Furthermore, liver and renal parameters were assessed. Splanchnic perfusion rapidly decreased during exercise, reflected by increased gapg-apCO2 from −0.85±0.15 to 0.85±0.42 kPa (p<0.001). Hypoperfusion increased plasma I-FABP (615±118 vs. 309±46 pg/ml, p<0.001) and I-BABP (14.30±2.20 vs. 5.06±1.27 ng/ml, p<0.001), and hypoperfusion correlated significantly with this small intestinal damage (rS = 0.59; p<0.001). Last of all, plasma analysis revealed an increase in small intestinal permeability after exercise (p<0.001), which correlated with intestinal injury (rS = 0.50; p<0.001). Liver parameters, but not renal parameters were elevated.ConclusionsExercise-induced splanchnic hypoperfusion results in quantifiable small intestinal injury. Importantly, the extent of intestinal injury correlates with transiently increased small intestinal permeability, indicating gut barrier dysfunction in healthy individuals. These physiological observations increase our knowledge of splanchnic hypoperfusion sequelae, and may help to understand and prevent these phenomena in patients.

Dietary fat and bile juice, but not obesity, are responsible for the increase in small intestinal permeability induced through the suppression of tight junction protein expression in LETO and OLETF rats

BackgroundAn increase in the intestinal permeability is considered to be associated with the inflammatory tone and development in the obesity and diabetes, however, the pathogenesis of the increase in the intestinal permeability is poorly understood. The present study was performed to determine the influence of obesity itself as well as dietary fat on the increase in intestinal permeability.MethodsAn obese rat strain, Otsuka Long Evans Tokushima Fatty (OLETF), and the lean counter strain, Long Evans Tokushima Otsuka (LETO), were fed standard or high fat diets for 16 weeks. Glucose tolerance, intestinal permeability, intestinal tight junction (TJ) proteins expression, plasma bile acids concentration were evaluated. In addition, the effects of rat bile juice and dietary fat, possible mediators of the increase in the intestinal permeability in the obesity, on TJ permeability were explored in human intestinal Caco-2 cells.ResultsThe OLETF rats showed higher glucose intolerance than did the LETO rats, which became more marked with the prolonged feeding of the high fat diet. Intestinal permeability in the OLETF rats evaluated by the urinary excretion of intestinal permeability markers (Cr-EDTA and phenolsulfonphthalein) was comparable to that in the LETO rats. Feeding the high fat diet increased intestinal permeability in both the OLETF and LETO rats, and the increases correlated with decreases in TJ proteins (claudin-1, claudin-3, occludin and junctional adhesion molecule-1) expression in the small, but not in the large intestine (cecum or colon). The plasma bile acids concentration was higher in rats fed the high fat diet. Exposure to bile juice and the fat emulsion increased TJ permeability with concomitant reductions in TJ protein expression (claudin-1, claudin-3, and junctional adhesion molecule-1) in the Caco-2 cell monolayers.ConclusionExcessive dietary fat and/or increased levels of luminal bile juice, but not genetic obesity, are responsible for the increase in small intestinal permeability resulting from the suppression of TJ protein expression.

Local effect of adenosine 5???-triphosphate on indomethacin-induced permeability changes in the human small intestine

Nonsteroidal anti-inflammatory drug (NSAID) use is associated with an elevated risk of gastrointestinal damage. As adenosine 5'-triphosphate (ATP) may play a protective role in the small intestine, our objective was to determine the local effect of ATP on small intestinal permeability changes induced by short-term challenge of the NSAID indomethacin in healthy humans. Mucosal permeability of the small intestine was assessed by the lactulose/rhamnose permeability test, that is, ingestion of a test drink containing 5 g lactulose and 0.5 g L-rhamnose followed by total urine collection for 5 h. Urinary excretion of lactulose and L-rhamnose was determined by fluorescent detection high-pressure liquid chromatography (HPLC). Basal small intestinal permeability was assessed as a control condition. As a model of increased small intestinal permeability, two doses of indomethacin were ingested before ingestion of the test drink (75 mg and 50 mg at 10 h and 1 h before the test drink, respectively). Concomitantly with indomethacin ingestion, placebo or 30 mg/kg ATP was administered through a naso-intestinal tube. Median urinary lactulose/rhamnose ratio (g/g) in the control condition was 0.023 (interquartile range: 0.013-0.041). Compared with the control condition, urinary lactulose/rhamnose ratio after ingestion of indomethacin and administration of placebo was significantly increased [0.042 (0.028-0.076); P<0.01]. In contrast, urinary lactulose/rhamnose ratio after indomethacin ingestion plus ATP administration [0.027 (0.020-0.046)] was significantly lower than the lactulose/rhamnose ratio in the placebo condition (P<0.01). Topical ATP administration into the small intestine during short-term challenge of the NSAID indomethacin attenuates the NSAID-induced increase in small intestinal permeability in healthy humans.

Gastrointestinal tolerability of nimesulide, a selective cyclooxygenase-2 inhibitor, in experimental animals and man

These studies assessed the gastrointestinal tolerability and cyclooxygenase (COX) selectivity of nimesulide in animals and man. Nimesulide (15 and 30 mg/kg) had no significant 'topical' toxicity in animals as assessed by in vivo mitochondrial morphologcal studies and no increase in small intestinal permeability or inflammation in rats. Similarly, these doses did not affect mucosal prostaglandins significantly and there were no ulcers. At the very high does of 60 mg/kg, nimesulide had some 'topical' toxicity and lost some of its COX-2 selectivity, but this was not associated with inflammation or ulcers. Indomethacin (10 mg/kg, equivalent to 15 mg/kg of nimesulide) altered all of the above parameters and led to small bowel ulcers. This suggests that the gastrointestinal tolerability of nimesulide is not only due to its COX-2 selectivity, but that it is also due to its lack of 'topical' toxicity. Thirty six healthy subjects participated in a randomised, double-blind, double-dummy crossover study (14 day treatment with a washout) of the effect of nimesulide (100 mg bid) and naproxen (500 mg bid) on the gastroduodenal mucosa and small intestine (absorption-permeability and inflammation). An assessment was also made on their COX selectivity. Nimesulide caused significantly less gastric (p = 0.0001) and duodenal (p = 0.0086) damage than naproxen. Naproxen increased intestinal permeability significantly (p = 0.004) and caused intestinal inflammation while nimesulide (p > 0.40) did not. Nimesulide had no significant (p > 0.1) effect on COX-1 dependant platelet aggregation, reduced serum thromboxane B2 levels moderately by 24-34% (p 0.5). By comparison, naproxen had significantly (p < 0.0001) greater effects on these functions: abolished platelet aggregation to arachidonic acid, suppressed serum thromboxane B2 levels by 98% and gastric prostaglandin production by 76-82%. Nimesulide inhibited lipopolysaccharide-induced PGE2 formation in whole blood to a significantly (p < 0.01) greater extent than naproxen. ___TAGSTART___BR___TAGEND___This study shows that nimesulide has a preferential selectivity for COX-2 over COX-1 in vivo at full therapeutic doses. This selectivity is associated with minimal gastrointestinal damage in the short term.

Simultaneous administration of lactulose and 51Cr-ethylenediaminetetraacetic acid. A test to distinguish colonic from small-intestinal permeability change.

In normal adults intestinal permeation of ingested 51Cr-ethylenediaminetetraacetic acid (EDTA) is greater than that of lactulose. This difference is abolished in patients with ileostomies, suggesting that it results from colonic permeation of 51Cr-EDTA, which, unlike lactulose, resists bacterial degradation. To investigate the effect of an increase in colonic permeability on absorption of the two molecules, lactulose (5 g) and 51Cr-EDTA (50 microCi) were given orally in isosmolar solution to 11 patients with colitis, and their 24-h urinary excretion measured. By comparison the effect of an increase in small-intestinal permeability induced by ingestion of a hyperosmolar solution (4240 mosm/l) was measured in 10 healthy adults. Hyperosmolar stress increased the 24-h urinary excretion of 51Cr-EDTA above the normal mean + 2 standard deviations (3.31%) in all 10 healthy subjects, and in all of these excretion of lactulose was also increased (greater than 1.06%). In contrast, although seven colitics had a urinary excretion of 51Cr-EDTA above the normal mean + 2 SD, in only two of these patients was recovery of lactulose increased. This suggests that simultaneous administration of lactulose and 51Cr-EDTA may enable permeability changes affecting the colon alone to be distinguished from those involving the small intestine.