Excretion Of 51Cr-EDTA Research Articles

Effect of liver transplantation on intestinal permeabilityand correlation with infection episodes.

BackgroundLiver cirrhosis has been known to be associated with increased intestinal permeability (IP); however, little is known about the modification of IP after liver transplantation (LT). The present study was aimed to assess IP after LT and evaluated its association with laboratory tests and clinical parameters, as well as with the development of infections.MethodsLT recipients were consecutively enrolled and compared with an equal number of patients with liver cirrhosis and healthy subjects. IP was assessed by urinary excretion of chromium-51 ethylenediaminetetraacetic acid (51Cr-EDTA).ResultsThe median 51Cr-EDTA excretion was found to be higher in 35 LT recipients as compared with that in the healthy controls [4.77% (2.79–6.03) vs. 2.07% (1.57–2.42), p<0.0001], and comparable to that in the cirrhotic patients [3.69% (2.34–6.57), p = 0.445]. 51Cr-EDTA excretion was not associated with clinical variables, the type of immunosuppressive therapy, donor-related factors, comorbidities and incidence of infections [infection/no infection: 4.97% (3.14–7.03) vs 4.62% (2.79–5.82), p = 0.938].ConclusionLT recipients show an increased IP, similar to that in patients with liver cirrhosis. However, it is not associated with a high risk of infections. Further investigations into the pathogenesis of this persistent impairment of the intestinal barrier are warranted.

Intestinal permeability, microbial translocation, changes in duodenal and fecal microbiota, and their associations with alcoholic liver disease progression in humans

ABSTRACT Background Animal data suggest a role of the gut-liver axis in progression of alcoholic liver disease (ALD), but human data are scarce especially for early disease stages. Methods We included patients with alcohol use disorder (AUD) who follow a rehabilitation program and matched healthy controls. We determined intestinal epithelial and vascular permeability (IP) (using urinary excretion of 51Cr-EDTA, fecal albumin content, and immunohistochemistry in distal duodenal biopsies), epithelial damage (histology, serum iFABP, and intestinal gene expression), and microbial translocation (Gram – and Gram + serum markers by ELISA). Duodenal mucosa-associated microbiota and fecal microbiota were analyzed by 16 S rRNA sequencing. ALD was staged by Fibroscan® (liver stiffness, controlled attenuation parameter) in combination with serum AST, ALT, and CK18-M65. Results Only a subset of AUD patients had increased 51Cr-EDTA and fecal albumin together with disrupted tight junctions and vasculature expression of plasmalemma Vesicle-Associated Protein-1. The so-defined increased intestinal permeability was not related to changes of the duodenal microbiota or alterations of the intestinal epithelium but associated with compositional changes of the fecal microbiota. Leaky gut alone did not explain increased microbial translocation in AUD patients. By contrast, duodenal dysbiosis with a dominance shift toward specific potential pathogenic bacteria genera (Streptococcus, Shuttleworthia, Rothia), increased IP and elevated markers of microbial translocation characterized AUD patients with progressive ALD (steato-hepatitis, steato-fibrosis). Conclusion Progressive ALD already at early disease stages is associated with duodenal mucosa-associated dysbiosis and elevated microbial translocation. Surprisingly, such modifications were not linked with increased IP. Rather, increased IP appears related to fecal microbiota dysbiosis.

Time-dependent effects on small intestinal transport by absorption-modifying excipients

The relevance of the rat single-pass intestinal perfusion model for investigating in vivo time-dependent effects of absorption-modifying excipients (AMEs) is not fully established. Therefore, the dynamic effect and recovery of the intestinal mucosa was evaluated based on the lumen-to-blood flux (Jabs) of six model compounds, and the blood-to-lumen clearance of 51Cr-EDTA (CLCr), during and after 15- and 60-min mucosal exposure of the AMEs, sodium dodecyl sulfate (SDS) and chitosan, in separate experiments. The contribution of enteric neurons on the effect of SDS and chitosan was also evaluated by luminal coadministration of the nicotinic receptor antagonist, mecamylamine. The increases in Jabs and CLCr (maximum and total) during the perfusion experiments were dependent on exposure time (15 and 60 min), and the concentration of SDS, but not chitosan. The increases in Jabs and CLCr following the 15-min intestinal exposure of both SDS and chitosan were greater than those reported from an in vivo rat intraintestinal bolus model. However, the effect in the bolus model could be predicted from the increase of Jabs at the end of the 15-min exposure period, where a six-fold increase in Jabs was required for a corresponding effect in the in vivo bolus model. This illustrates that a rapid and robust effect of the AME is crucial to increase the in vivo intestinal absorption rate before the yet unabsorbed drug in lumen has been transported distally in the intestine. Further, the recovery of the intestinal mucosa was complete following 15-min exposures of SDS and chitosan, but it only recovered 50% after the 60-min intestinal exposures. Our study also showed that the luminal exposure of AMEs affected the absorptive model drug transport more than the excretion of 51Cr-EDTA, as Jabs for the drugs was more sensitive than CLCr at detecting dynamic mucosal AME effects, such as response rate and recovery. Finally, there appears to be no nicotinergic neural contribution to the absorption-enhancing effect of SDS and chitosan, as luminal administration of 0.1 mM mecamylamine had no effect.

A new model for estimating glomerular filtration rate in patients with cancer.

e14074 Background: The glomerular filtration rate (GFR) is essential for carboplatin chemotherapy dosing, however, the best method to estimate GFR in patients with cancer is unknown. We identify the most accurate and least biased method. Methods: Data on age, sex, height, weight, serum creatinine, and results for GFR from 51Cr-EDTA excretion measurements (51Cr-EDTA GFR) were obtained from Caucasian patients aged 18 years or older with histologically confirmed cancer diagnoses at the University of Cambridge Hospital NHS Trust, UK. We developed a new multivariable linear model for GFR using statistical regression analysis. 51Cr-EDTA GFR was compared to the estimated GFR (eGFR) from seven published and our new model using an internal validation data set and root-mean-squared-error (RMSE) and median residuals. A comparison of carboplatin dosing accuracy based on an absolute percentage error more than 20% (APE &gt; 20%) was undertaken. Results: Between August 2006 and January 2013 data from 2,471 patients were obtained. The new model improved the eGFR accuracy (RMSE 15.00ml/min (95% CI 14.12-16.00)) compared to all published models. Body surface area (BSA) adjusted CKD-EPI was the most accurate published models for eGFR (RMSE 16.30ml/min (95% CI 15.34-17.38)) for the internal validation set. Importantly, the new model reduced the fraction of patients with a carboplatin dose APE &gt; 20% to 14.17% in contrast to 18.62% for BSA adjusted CKD-EPI and 25.51% for the Cockcroft-Gault model. The results were externally validated. Conclusions: In a large data set, from patients with cancer, a new model improves eGFR and carboplatin dose calculations, when compared to BSA adjusted CKD-EPI, the model we identified as the best published model for determination of eGFR in patients with cancer.

Dietary calcium decreases but short-chain fructo-oligosaccharides increase colonic permeability in rats

An increased intestinal permeability is associated with several diseases. Nutrition can influence gut permeability. Previously, we showed that dietary Ca decreases whereas dietary short-chain fructo-oligosaccharides (scFOS) increase intestinal permeability in rats. However, it is unknown how and where in the gastrointestinal tract Ca and scFOS exert their effects. Rats were fed a Western low-Ca control diet, or a similar diet supplemented with either Ca or scFOS. Lactulose plus mannitol and Cr-EDTA were added to the diets to quantify small and total gastrointestinal permeability, respectively. Additionally, colonic tissue was mounted in Ussing chambers and exposed to faecal water of these rats. Dietary Ca immediately decreased urinary Cr-EDTA excretion by 24 % in Ca-fed rats compared with control rats. Dietary scFOS increased total Cr-EDTA permeability gradually with time, likely reflecting relatively slow gut microbiota adaptations, which finally resulted in a 30 % increase. The lactulose:mannitol ratio was 15 % higher for Ca-fed rats and 16 % lower for scFOS-fed rats compared with control rats. However, no dietary effect was present on individual urinary lactulose and mannitol excretion. The faecal waters did not influence colonic permeability in Ussing chambers. In conclusion, despite effects on the lactulose:mannitol ratio, individual lactulose values did not alter, indicating that diet did not influence small-intestinal permeability. Therefore, both nutrients affect permeability only in the colon: Ca decreases, while scFOS increase colonic permeability. As faecal water did not influence permeability in Ussing chambers, probably modulation of mucins and/or microbiota is important for the in vivo effects of dietary Ca and scFOS.

The effect of oral glutamine on 5-fluorouracil/leucovorin-induced mucositis/stomatitis assessed by intestinal permeability test

Systemic chemotherapy may damage gastrointestinal epithelium. Mucositis is associated with increased intestinal permeability (IP). It is known that IP test with chromium 51-ethylene diaminetetra-acetate (51Cr-EDTA) is a useful tool to assess the mucositis. Oral glutamine supplements (OGS) may have a role in the prevention of chemotherapy-induced mucositis/stomatitis. The aim of this study was to characterize the relationship between the urinary excretion of 51Cr-EDTA and the severity of mucositis, and the effect of OGS on 5-fluorouracil/leucovorin (FU/LV)-induced mucositis/stomatitis. Fifty-one patients with advanced or metastatic cancer received FU/LV chemotherapy. The control group included 18 healthy volunteers. IP was assessed via the measurement of 51Cr-EDTA urinary excretion after oral challenge, on days 7 after the discontinuation of chemotherapy. Of the 51 patients, 22 patients received OGS (30 g/day) and 29 received only best supportive care (BSC). Glutamine supplementation continued for 15 days. It was initiated at least 3 days before the beginning of chemotherapy. Mucositis/stomatitis was graded according to version 3.0 of the Common Terminology Criteria for Adverse Events. In the chemotherapy group, the median (25 percentile, 75 percentile) IP test score was significantly higher than those of the control group [6.78% (4.63, 10.66) vs. 2.17% (1.38, 2.40), P<0.001]. The severity of stomatitis was significantly correlated with IP test scores (r=0.898, P<0.001). In the OGS group, the median IP test score was significantly lower than that of the BSC group [4.69% (3.10, 6.48) vs. 8.54% (6.48, 15.31), P<0.001]. A mucositis/stomatitis of grade 2-4 was observed in two patients of the OGS group (9%), and in 11 patients (38%) in the BSC group (P<0.001). The IP test may be a useful tool in the evaluation of mucositis/stomatitis. OGS may exert a protective effect on FU/LV-induced mucositis/stomatitis. Further studies, however, will be necessary to define the role of glutamine supplementation in FU/LV-induced mucositis/stomatitis.

Intestinal permeability in cirrhotic patients with and without ascites

Objective. It has been suggested that increased intestinal permeability plays a pathogenic role in bacterial infections, such as spontaneous bacterial peritonitis, in patients with liver cirrhosis. The aim of this study was to assess whether intestinal permeability is altered in cirrhotic patients with and without ascites. Material and methods. Intestinal permeability was assessed by a 51Cr-EDTA permeability test in 20 cirrhotic patients (10 with and 10 without ascites) along with 20 age- and gender-matched healthy controls. In six patients with ascites, the test was performed before and after therapeutic paracentesis. Results. The median (IQR) 24-h urinary excretion of 51Cr-EDTA was higher in patients with cirrhosis (1.94% (1.21–2.70%)) compared with that in controls (1.40% (1.09–1.99%); p<0.05). Patients with (2.05% (1.50–3.46%); p<0.05) but not those without ascites (1.94% (1.13–2.53%); p>0.1) had significantly higher excretion values compared with those of controls. Only one patient without ascites and a total of four patients with ascites had increased intestinal permeability (51Cr-EDTA excretion > 95% confidence than that of controls; p>0.1). Paracentesis did not affect urinary 51Cr-EDTA excretion significantly (1.69% (1.16–2.86%) versus 1.30% (1.08–1.79%) before and after, respectively; p>0.1). No significant correlation was found between clinical severity scores for liver disease and intestinal permeability. Conclusions. Only a small proportion of patients with liver cirrhosis have increased intestinal permeability and it is unlikely that this plays any major role in predisposing these patients to infections.

4. Probiotics, breastfeeding and atopic eczema

This article focuses on several aspects as follows; the relationship between permeability of the gastrointestinal tract and atopic eczema, probiotics and eczema, probiotics and the immune system in the gastrointestinal tract, breastfeeding and immunomodulation, and the relation between breastfeeding and the development of atopic eczema. It is concluded that there is evidence that some probiotic strains seem to be beneficial in the treatment of atopic eczema. GUT MUCOSAL BARRIER AND ATOPIC ECZEMA The gut mucosal barrier of patients with atopic eczema is impaired. In an in vitro study Majamaa & Isolauri (1) studied the absorption of horseradish peroxidase (HRP) through the gut mucosal barrier. Small intestinal biopsies were studied in Ussing chambers, measuring the absorption of both intact and degraded HRP. Compared with controls, absorption in patients with atopic eczema is increased. There are also several studies showing increased intestinal permeability in patients with bronchial asthma. Benard et al. (2) studied the urinary excretion of Cr EDTA, a recognized method of monitoring intestinal absorption, in asthmatics, in patients with chronic obstructive airways disease and in controls. There were significant differences between the asthmatics and the other two groups in respect of increased intestinal permeability. There was no significant difference in intestinal permeability between patients with allergic and non-allergic asthma, and the intestinal permeability was not correlated with the severity of asthma as measured by FEV1.

Hyperresponsiveness of the Mucosal Barrier in Crohnʼs Disease Is Not Tumor Necrosis Factor-Dependent

Crohn's disease (CD) is associated with gut barrier dysfunction. Besides the baseline barrier defect, a subgroup of patients also expresses an intestinal barrier hyperresponsiveness to nonsteroidal anti-inflammatory drugs. We studied whether reducing inflammation and restoring gut barrier dysfunction with anti-tumor necrosis factor (TNF) antibody treatment also antagonizes the permeability increase by oral nonsteroidal anti-inflammatory drug intake in patients with CD. Thirty-one healthy control subjects and 25 patients with active CD were studied. The 31 controls performed intestinal permeability testing for Cr-EDTA before (baseline) and after oral intake of indomethacin (50 + 75 mg). Twenty-five patients carried out a baseline and indomethacin-mediated permeability test before infliximab infusion. The patients repeated either the indomethacin test (12/25) or baseline and indomethacin tests (13/25), 1 month after this treatment. Intestinal permeability was studied by measurement of urinary excretion of Cr-EDTA after oral intake. Increased whole gut permeation before treatment (3.16%; interquartile range [IQR], 2.92-5.72) was restored to normal values (2.47%; IQR, 1.97-2.78) by anti-TNF treatment. Indomethacin increased whole gut permeability significantly more in patients with CD (before anti-TNF: 6.50%; IQR, 4.84-10.38; after anti-TNF: 5.50%; IQR, 3.97-10.09) compared with the healthy subjects (4.66%; IQR, 3.51-5.64). Eleven of 25 patients (44%) had an abnormal whole gut permeability response to indomethacin before anti-TNF, and 9 of them remained hyperresponsive after infusion, despite clinical remission. Although anti-TNF treatment suppresses inflammation and restores gut barrier function in patients with CD, it does not antagonize the barrier hyperresponsiveness to indomethacin. These data support the notion of an underlying intestinal mucosal barrier hyperresponsiveness in a subset of patients with CD, independent of inflammation.

Ursodeoxycholic Acid Ameliorates Experimental Ileitis Counteracting Intestinal Barrier Dysfunction and Oxidative Stress

The aim of this study was to evaluate the effect of ursodeoxycholic acid (UDCA) on intestinal permeability (IP) and reactive oxygen species (ROS) generation in indomethacin-induced enteropathy, a well-known experimental model of Crohn's disease. Seventy-eight male Wistar rats were randomly assigned to receive indomethacin, indomethacin + UDCA, or vehicles. Indomethacin induced a significant increase in the fraction of urinary excretion of 51Cr-EDTA following oral administration (7.9 +/- 1.3 vs 2.3 +/- 0.2%; P < 0.05) and lucigenin-amplified chemiluminescence in intestinal fragments ex vivo (10.1 +/- 1.9 vs 2.6 +/- 0.4 cpm x 10(3)/mg; P < 0.05) compared to controls. UDCA significantly reversed these effects (P < 0.05), without being incorporated in biliary bile acid composition (HPLC analysis). These findings support a local protective effect of UDCA in experimental ileitis by the modulation of intestinal barrier dysfunction and oxidative stress. In short, they provide insights into mechanisms of action of UDCA in intestinal inflammation and a new perspective on the treatment of Crohn's disease.

The effect of oral glutamine supplement (OGS) on fluorouracil (5-FU) induced intestinal mucosal damage (IMD) assessed by intestinal permeability (IP) test

8050 Background: Systemic chemotherapy may damage gastrointestinal epithelium. IMD and mucositis are one of the most common side effect of chemotherapy. However, there is not a tool for direct measurement of IMD. IMD is associated with increased IP. It is known that IP test with chromium-ethylenediaminetetraacetic acid (51Cr-EDTA) is a useful tool to assess the IMD. Glutamine is the energy source for gastrointestinal epithelium. OGS may have a role in the prevention of chemotherapy induced IMD and mucositis. The aims of this study were to evaluate the relationship between the urinary excretion of 51Cr-EDTA and the severity of IMD and mucositis, and the effect of OGS on 5-FU induced IMD and mucositis. Methods: Fifty one patients with advanced cancer received 5-FU based chemotherapy. Eighteen healthy volunteers were in the control group. IP was assessed by measurement of the urinary excretion of 51Cr-EDTA after oral challenge, on days 6–12 after chemotherapy. Among fifty one patients, twenty two patients received OGS (30 g/day) and twenty nine only best supportive care (BSC). OGS was continued for 15 days. It was started at least three days before chemotherapy. mucositis was graded according to the National Cancer Institute common toxicity criteria. Results: In the chemotherapy group, the mean value of IP test was significantly higher than in the control group (8.68±6.55% vs 1.99±0.53%, respectively, p<0.001). The severity of oral mucositis was correlated with the value of IP test ( p<0.001, r= 0.792). In the OGS group, the mean value of IP test was significantly lower than in the BSC group (5.44±3.42% vs 11.26±7.24%, respectively, p=0.001). In the OGS group, grade II-IV of mucositis was observed in the six patients(10%), and in the eleven patients (38%) in the BSC group. (p<0.001). Conclusions: The IP test may be a useful tool for assessing IMD and mucositis. OGS may have a protective effect on 5-FU based chemotherapy induced IMD and mucositis. Further studies are needed to define the role of OGS in chemotherapy induced IMD and mucositis. No significant financial relationships to disclose.

In vivo Influence of Nicotine on Human Basal and NSAID-induced Gut Barrier Function

Background: Smoking reduces the non-steroidal anti-inflammatory drug (NSAID)-induced small intestinal permeability increase in healthy people. It also affects inflammatory bowel disease that is associated with a disturbed gut barrier function. To assess the role of nicotine on barrier function, its influence on basal and NSAID-induced intestinal permeability was studied in healthy volunteers. Methods: Thirty-one healthy non-smoker subjects performed permeability tests with 51Cr-EDTA and sugar markers (sucrose, lactulose, mannitol, sucralose) before and during 2 weeks of nicotine patch application, and with and without indomethacin intake, respectively. Since smoking has been described as affecting motility, transit measurements were also done with the sodium[13C]-octanoate and lactose- [13C]-ureïde breath tests before and during nicotine exposure. Correlations between permeability markers were checked and the influence of gastrointestinal transit was assessed. Results: Nicotine did not affect barrier function in vivo, nor gastric emptying, small-bowel transit time or orocaecal transit. 51Cr-EDTA and lactulose correlated in basal 0–6 h permeability testing (r= 0.529, P < 0.0001), as did 6–24 h excretion of 51Cr-EDTA and sucralose (r= 0.474, P < 0.001); 97% and 90% of the subjects had a permeability increase after indomethacin intake for 0–6 h and 6–24 h excretion of Cr-EDTA, respectively. This population proportion is 63% for lactulose/mannitol and 83% for sucralose. Conclusions: Short-term exposure to nicotine does not alter normal basal or NSAID-induced gut barrier function or transit. 51Cr-EDTA and the respective sugar markers correlate well in in vivo permeability testing in healthy humans. The radioactive test detects more NSAID-induced permeability increase than does the lactulose/mannitol ratio permeability test.

Anti-tumor necrosis factor treatment restores the gut barrier in Crohn's disease.

A primary defect of the tight junctions and, hence, increased intestinal epithelial permeability has been proposed as a basic pathogenic event in Crohn's disease. Challenge of the mucosal immune system by the commensal gut flora would then result in chronic inflammation. Alternatively, increased permeability could be the result of inflammation. Our aim was to study intestinal permeability in refractory Crohn's disease before and after treatment with monoclonal chimeric antibodies directed against tumor necrosis factor (TNF) to investigate whether the abnormal permeability persists after control of inflammation. Twenty-three patients with active Crohn's disease were evaluated before and 4 wk after a single infusion of 5 mg/kg infliximab. Intestinal permeability was studied by measurement of urinary excretion of 51Cr-EDTA after oral intake. The increased permeation of 51Cr-EDTA through the small intestine (1.63% interquartile range [IQR] 1.06-2.07) and the overall permeation (3.27% IQR 2.40-4.38) before therapy decreased significantly after infliximab infusion to values (1.04% IQR 0.74-1.54 and 2.42% IQR 2.03-2.80, respectively) in the range of those found in normal volunteers (1.12% IQR 0.85-1.58 and 2.28% IQR 1.88-2.86, respectively). Inhibiting the proinflammatory cytokine tumor necrosis factor dramatically reduces gut inflammation and largely restores the gut barrier in Crohn's disease. Our data confirm the central role of TNF in gut barrier modulation in inflammatory conditions in vivo.

Anti-tumor necrosis factor treatment restores the gut barrier in Crohn’s disease

OBJECTIVES: A primary defect of the tight junctions and, hence, increased intestinal epithelial permeability has been proposed as a basic pathogenic event in Crohn’s disease. Challenge of the mucosal immune system by the commensal gut flora would then result in chronic inflammation. Alternatively, increased permeability could be the result of inflammation. Our aim was to study intestinal permeability in refractory Crohn’s disease before and after treatment with monoclonal chimeric antibodies directed against tumor necrosis factor (TNF) to investigate whether the abnormal permeability persists after control of inflammation. METHODS: Twenty-three patients with active Crohn’s disease were evaluated before and 4 wk after a single infusion of 5 mg/kg infliximab. Intestinal permeability was studied by measurement of urinary excretion of 51Cr-EDTA after oral intake. RESULTS: The increased permeation of 51Cr-EDTA through the small intestine (1.63% interquartile range [IQR] 1.06–2.07) and the overall permeation (3.27% IQR 2.40–4.38) before therapy decreased significantly after infliximab infusion to values (1.04% IQR 0.74–1.54 and 2.42% IQR 2.03–2.80, respectively) in the range of those found in normal volunteers (1.12% IQR 0.85–1.58 and 2.28% IQR 1.88–2.86, respectively). CONCLUSION: Inhibiting the proinflammatory cytokine tumor necrosis factor dramatically reduces gut inflammation and largely restores the gut barrier in Crohn’s disease. Our data confirm the central role of TNF in gut barrier modulation in inflammatory conditions in vivo.

Oral bovine serum concentrate improves cryptosporidial enteritis in calves.

Cryptosporidium parvum produces a prolonged watery diarrhea unresponsive to conventional antimicrobials. Because of reported efficacy of antibody-based immunotherapy, we studied the effect of inexpensive, commercially available oral bovine serum concentrate (BSC) in experimental cryptosporidiosis. Twenty-four calves were treated with 57 g/d BSC (n = 12) or soy protein (n = 12) added to their standard whey protein-based milk replacer (227 g/2 L twice daily). Of the 24, 9 were also treated with L-glutamine (GLN), 8 g/L (50 mM) in the milk (5 calves in the BSC group and 4 in the soy group). Animals were inoculated with 10(8) cryptosporidium oocysts per os on d 8 of life and received oral rehydration on d 12-14. Eight uninfected controls were treated with BSC or soy protein. Fecal and urine volume and urinary Cr-EDTA excretion were measured. Animals were killed on d 18 of life. Cryptosporidiosis induced severe watery diarrhea lasting >9 d and produced a 25% increase in intestinal permeability, a 33% decrease in villous surface area, and a 40% reduction in mucosal lactase specific activity. Glutamine treatment had no effect on the diarrhea or any of the intestinal tests; and therefore pooled data were used to compare the 12 calves treated with BSC with the 12 treated with soy. In animals receiving BSC, peak diarrheal volume and intestinal permeability were reduced 33%, fewer oocysts were shed, intestinal crypts were significantly deeper, and villous surface area returned to normal by 9 d after infection (all p <or= 0.05). BSC should be studied as a treatment for human cryptosporidiosis.

(51)CrEDTA colonic permeability and therapy response in patients with ulcerative colitis.

Orally administered (51)Cr-labelled ethylenediaminetetraacetic acid ((51)CrEDTA) has been used to evaluate intestinal permeability in inflammatory bowel disease, especially Crohn's disease. However, information about colonic permeability in ulcerative colitis (UC) is relatively scarce. The aim of this study was to investigate the urinary excretion of orally administered (51)CrEDTA, its relation to disease activity and its response to medical therapy in patients with UC. Forty-three patients with UC and 19 controls were examined. Disease activity was evaluated by endoscopy. In 19 patients with active UC, the (51)CrEDTA permeability test was repeated after medical therapy. (51)CrEDTA (95 microCi; 26 MBq) was given orally after an overnight fast and urine was collected over a 24 h period. The first urine samples were taken 5 h and the second 24 h after the oral administration of (51)CrEDTA. Urine samples were counted in a gamma counter. In controls, the median 5 h and 24 h excretions were 0.10% and 0.93%, respectively. Patients with UC showed significantly increased urine (51)CrEDTA excretion at both time intervals (5 h: 2.41%, P<0.0002; 24 h: 6.72%, P<0.0001). There was also a significant correlation between intestinal permeability and disease activity (5 h: r=0.45, P=0.0025; 24 h: r=0.51 P=0.0006). After medical therapy, (51)CrEDTA urinary excretion was significantly decreased (pre-treatment UC: 7.87%; post-treatment UC: 2.50%; P<0.0002). Briefly, the (51)CrEDTA test reflected colonic permeability in UC and might be useful as an indicator of disease severity. Moreover, this study suggested that, in patients with UC, medical therapy not only leads to the recovery of acute inflammation but also restores mucosal barrier integrity and function.

Is an Increased Intestinal Permeability a Valid Predictor of Relapse in Crohn Disease?

Background: An increased intestinal permeability (IP) may be a pathogenetic factor in Crohn disease (CD). Increases in IP could be an indicator of subclinical disease and precede clinical relapses. We examined whether an increased IP is a valid predictor of relapse in CD. Methods: 27 patients with CD in remission (CDAI <150) and 22 healthy controls ingested 3.7 MBq of 51Cr-EDTA, 20 kBq of 14Cmannitol and 5 g of unlabelled mannitol in 100 ml of distilled water. The percent urine excretion (24 h) of labelled markers was determined. Patients were followed for 1 year or until relapse, defined as CDAI > 150 and > 50 from baseline. Results: Median (25th-75th percentiles). The excretion of 51Cr-EDTA was 1.55% (1.13%-2.53%) for patients and 1.20% (1.11%-1.44%) for controls (P = 0.04). Three of 9 patients with a raised, and 6 of 18 patients with a normal, 51Cr-EDTA excretion relapsed (P = 1.00; Fisher's exact test). Thus, the specificity and sensitivity of the 51Cr-EDTA test as a predictor of relapse was 33% and 33%, respectively. The 51Cr-EDTA/14C-mannitol index was 0.060 (0.037-0.093) for patients and 0.045 (0.038-0.054) for controls (P = 0.06). Four of 12 patients with a raised, and 5 of 15 patients with a normal, index relapsed (P = 1.00; Fisher's exact test). Thus, the specificity and sensitivity of the index test as a predictor of relapse was 33% and 44%, respectively. For controls and patients in remission, who were tested twice, variability of and fluctuations in both the 51Cr-EDTA excretion and the index were greatest for patients. Conclusions: This study supports previous findings of an increased IP in patients with CD. Although fluctuations in the permeation of markers were pronounced in CD, neither the excretion of 51Cr-EDTA nor the 51Cr-EDTA/14C-mannitol index test were valid predictors of relapse in CD.

Relationship between Intestinal Permeability and Calprotectin Concentration in Gut Lavage Fluid

Calprotectin is released from neutrophils and monocytes, and increased calprotectin levels in stool may serve as a marker of intestinal inflammation. Intestinal permeability is increased in inflammatory bowel diseases, especially in Crohn disease. We studied the relationship between intestinal permeability and calprotectin concentration in intestinal lavage fluid in patients with known or suspected inflammatory bowel disease (IBD). Thirty-eight patients were examined; 17 had Crohn disease; 3, ulcerative colitis; and 18, irritable bowel syndrome. Intestinal lavage was performed by means of a nasojejunal tube positioned by gastroduodenoscopy. By means of a peristaltic pump 2 l isotonic polyethylene glycol solution (MW, 3350) containing 50 microCi 51Cr-labelled ethylenediaminetetraacetic acid (EDTA) were administered through the tube over a period of 40 min. The first clear fluid passed per rectum was collected and analysed for calprotectin levels with an enzyme-linked immunosorbent assay method. Urine was collected for 5 h and analysed for gamma radioactivity. 51Cr-EDTA excretion in urine was expressed as percentage of dose administered (that is, intestinal permeability). Both intestinal permeability and calprotectin concentration were significantly higher in patients with IBD than in patients with functional conditions. In Crohn disease the values depended on disease activity but not on whether the disease was located in the small or in the large bowel. There was a highly significant correlation between calprotectin concentration in gut lavage fluid and intestinal permeability (r=0.79, P<0.0001). The significant correlation between calprotectin concentration in gut lavage fluid and intestinal permeability supports the view that increased intestinal permeability in IBD might, at least in part, be a consequence of increased transepithelial migration of neutrophils.

Effect of glutamine on the intestinal permeability changes induced by indomethacin in humans.

Long-term non-steroidal anti-inflammatory drug (NSAID) intake may induce increased intestinal permeability, eventually resulting in enteropathy. Because increased permeability might be related to cell damage resulting from energy depletion, it was hypothesized that glutamine--the major energy source of the intestinal mucosal cell--might prevent permeability changes. The 6-h urinary excretion of 51Cr-EDTA after an oral load of 51Cr-EDTA was used in this study as a measure for intestinal permeability. Healthy volunteers underwent a series of permeability tests: (i) basal test; (ii) test following NSAID (indomethacin); (iii) test following NSAID in combination with glutamine and/or misoprostol. The NSAID induced increased permeability in all volunteers. Pre-treatment with glutamine (3x7 g daily, 1 week before NSAID-dosing) did not prevent the NSAID-induced increase in permeability. Multiple doses of glutamine close in time to NSAID-dosing resulted in significantly lower permeability compared to the NSAID without glutamine. Co-administration of misoprostol with the multiple-dose scheme of glutamine resulted in a further reduction in the NSAID-induced increase in permeability. Glutamine decreases the permeability changes caused by NSAID-dosing when it is administered close in time, and misoprostol has a synergistic effect.

In vivo butyrate metabolism and colonic permeability in extensive ulcerative colitis

Background & Aims: Impaired short-chain fatty acid metabolism by the colonocyte has been suggested as a pathogenic factor in ulcerative colitis (UC). The aim of this study was to measure in vivo butyrate metabolism in UC and to correlate butyrate oxidation with colonic permeability. Methods: Butyrate oxidation was measured by means of a 14CO 2-breath test after rectal instillation of 14C-butyrate. 51Cr-ethylenediaminetetraacetic acid (EDTA) was added to the enema, and the urinary % dose excretion of 51Cr-EDTA after 6 hours was a measure for permeability. Results: Patients with active extensive UC showed a significantly lower butyrate oxidation and increased colonic permeability in comparison to healthy controls. Butyrate oxidation correlated significantly negative with clinical activity. Oxidation of butyrate was not decreased in most patients with inactive extensive UC. In 3 patients with inactive disease and decreased oxidation, a relapse occurred within a few weeks after the test, whereas all patients with normal oxidation maintained their remission for at least 3 months. A significantly negative correlation existed between butyrate oxidation and colonic permeability. Conclusions: Patients with active extensive UC have a decreased colonic butyrate oxidation. However, the fact that remission is associated with normal oxidation suggests that UC mucosa is not intrinsically altered in butyrate oxidation, making this unlikely to be a primary defect in UC. GASTROENTEROLOGY 1998;115:584-590