Biomarkers for Intestinal Permeability in Patients With Constipation

Study Overview
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Brief Summary
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Our overall objective with this study is firstly to provide a comprehensive assessment of intestinal permeability, mucosal barrier function using existing biomarkers and secondly to explore novel biomarkers for measuring intestinal permeability in patients with constipation predominant Irritable Bowel Syndrome (IBS-C).

Detailed Description
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In order to determine the differences in permeability in IBS-C in comparison with healthy volunteers, the following will be determined: differences in in vivo small intestinal and colonic permeability, differences in small intestinal and colonic mucosal barrier function, differences in effects of fecal supernatants on barrier function of T84 monolayers, and differences in novel biomarkers for intestinal permeability

Official Title
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Biomarkers for Intestinal Permeability in Patients With Functional Lower Gastrointestinal Disorders Associated With Constipation.

Conditions
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Intestinal Diseases, Irritable Bowel Syndrome, Constipation

Intervention / Treatment
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* Diagnostic Test: Permeability measurement
* Procedure: Esophagogastroduodenoscopy
* Procedure: Flexible sigmoidoscopy


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: 18 - 65 years old IBS-C by Rome III criteria (for IBS-C participants) No abdominal surgery (except appendectomy and cholecystectomy) Exclusion criteria: History of Inflammatory Bowel Disease (IBD) , microscopic colitis or celiac disease Use of tobacco products within the past 6 months Use of NSAIDs or aspirin within the past week Use of oral corticosteroids within the previous 6 weeks Ingestion of artificial sweeteners such as Splenda (sucralose), Nutrasweet (aspartame), lactulose or mannitol 2 days before the study begins, e.g., foods to be avoided are sugarless gums or mints and diet soda Ingestion of any prescription, over the counter, or herbal medications which can affect gastrointestinal transit 7 days before study begins Any treatment specifically taken for IBS, including loperamide, cholestyramine, alosetron Drugs with a known pharmacological activity at 5-HT4, 5-HT2b or 5-HT3 receptors (e.g, tegaserod, ondansetron, tropisetron, granisetron, dolasetron, mirtazapine); All narcotics (e.g, codeine, morphine, and propoxyphene, either alone or in combination) Anti-cholinergic agents (e.g, dicyclomine, hyoscyamine, propantheline). Ultram GI preparations Anti-nausea agents (e.g, trimethobenzamide, promethazine, prochlorperazine, dimenhydrinate, hydroxyzine) Osmotic laxative agents (e.g, lactulose, sorbitol or PEG solutions as Miralax and Glycolax) Prokinetic agents (e.g, cisapride, metoclopramide, itopride, domperidone); Antimuscarinics; Peppermint oil; Systemic antibiotics, rifaximin, metronidazole. Bleeding disorders or medications that increase risk of bleeding from mucosal biopsies. Score > 8 for anxiety or depression on Hospital anxiety and depression scale. Pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Healthy volunteers<br>Permeability measurement: Ingestion of saccharides {mannitol (regular, 12C) 100 mg, lactulose 1 g and labelled (13C mannitol) 100 mg} in 250ml of water Esophagogastroduodenoscopy Flexible sigmoidoscopy | Diagnostic Test: Permeability measurement<br>* Saccharide excretion was compared between IBS-C and healthy volunteers<br>* Other names: Lactulose;Procedure: Esophagogastroduodenoscopy<br>* Duodenal biopsies were collected from IBS-C and healthy volunteers<br>Procedure: Flexible sigmoidoscopy<br>* Colonic biopsies were collected from IBS-C and healthy volunteers<br>|
| IBS-C<br>Permeability measurement: Ingestion of saccharides (mannitol (regular, 12C) 100 mg, lactulose 1 g and labelled (13C mannitol) 100 mg} in 250ml of water Esophagogastroduodenoscopy Flexible sigmoidoscopy | Diagnostic Test: Permeability measurement<br>* Saccharide excretion was compared between IBS-C and healthy volunteers<br>* Other names: Lactulose;Procedure: Esophagogastroduodenoscopy<br>* Duodenal biopsies were collected from IBS-C and healthy volunteers<br>Procedure: Flexible sigmoidoscopy<br>* Colonic biopsies were collected from IBS-C and healthy volunteers<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lactulose:C13 Mannitol Excretion Ratio 8-24hrs. | In vivo measurement of intestinal permeability using 13C mannitol & lactulose was used. High performance liquid chromatography-tandem mass spectrometry was used to measure concentrations calculated using the overall urine volume excreted in each interval. Concentrations of 13C adjusted for the % of 13C in 12C mannitol (4.98% of 12C mannitol excreted was subtracted from 13C mannitol values; determined by analyzing replicate samples of control urine). All lactulose or 13C mannitol concentrations 8-24hr post-ingestion were used to determine colonic permeability. Lactulose to 13C mannitol excretion ratios, as a measure of dose of saccharide administered, were calculated. | 8-24 hr post test-dose administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lactose:C13 Mannitol Excretion Ratio 0-2hours |  | 0-2 hr post-test dose administration | 
| Baseline Transmucosal Resistance (TMR) of Duodenal Mucosa |  | Baseline | 
| Cumulative FITC-Dextran (4kDa) Concentration Across Duodenal Mucosa | This is not a pharmacokinetic or pharmacodynamic measure. Hence only one time assessment is made 3 hours after FITC-Dextran (4kDa) administration. | 3 hours post FITC-Dextran (4kDa) administration | 
| Rate of FITC-Dextran (4kDa) Flux Across Duodenal Mucosa | This is not a pharmacokinetic or pharmacodynamic measure. Hence only one time assessment is made 3 hours after FITC-Dextran (4kDa) administration. | Over 3 hours post FITC-Dextran (4kDa) administration | 
| Baseline Transmucosal Resistance (TMR) of Colonic Mucosa |  | Baseline | 
| Cumulative FITC-Dextran (4kDa) Concentration Across Colonic Mucosa |  | 3 hours post FITC-Dextran (4kDa) administration | 
| Rate of FITC-Dextran (4kDa) Flux Across Colonic Mucosa |  | Over 3 hours post FITC-Dextran (4kDa) administration | 
| Cumulative E.Coli Bio- Particle K12 Concentration Across Duodenal Mucosa |  | 3 hours post E.coli Bio- Particle administration | 
| Rate of E.Coli Bio- Particle K12 Flux Across Duodenal Mucosa |  | Over 3 hours post E.coli Bio- Particle administration | 
| Cumulative E.Coli Bio- Particle K12 Concentration Across Colonic Mucosa |  | 3 hours post E.coli Bio- Particle administration | 
| Rate of E.Coli Bio- Particle K12 Flux Across Colonic Mucosa |  | Over 3 hours post E.coli Bio- Particle administration | 
| Duodenal Impedance |  | Baseline | 
| Mean Serum Endotoxin (Bacterial LPS) Levels |  | Fasting, one time measurement after 8 hours |