Biomarkers for Intestinal Permeability in Patients With Constipation

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

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).

Study Overview

• Status: Completed
• Conditions: Irritable Bowel Syndrome; Intestinal Diseases; Constipation
• Intervention / Treatment: Diagnostic test: Permeability measurement; Procedure: Esophagogastroduodenoscopy; Procedure: Flexible sigmoidoscopy

Detailed Description

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

• Study Type: Observational
• Enrollment (Actual): 39

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

• Sampling Method: Probability Sample

Study Population

IBS-Constipation patients and healthy volunteers

Description

Inclusion criteria:

1. 18 - 65 years old
2. IBS-C by Rome III criteria (for IBS-C participants)
3. No abdominal surgery (except appendectomy and cholecystectomy)

Exclusion criteria:

1. History of Inflammatory Bowel Disease (IBD) , microscopic colitis or celiac disease
2. Use of tobacco products within the past 6 months
3. Use of NSAIDs or aspirin within the past week
4. Use of oral corticosteroids within the previous 6 weeks
5. 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

6. Ingestion of any prescription, over the counter, or herbal medications which can affect gastrointestinal transit 7 days before study begins

   1. Any treatment specifically taken for IBS, including loperamide, cholestyramine, alosetron
   2. Drugs with a known pharmacological activity at 5-HT4, 5-HT2b or 5-HT3 receptors (e.g, tegaserod, ondansetron, tropisetron, granisetron, dolasetron, mirtazapine);
   3. All narcotics (e.g, codeine, morphine, and propoxyphene, either alone or in combination)
   4. Anti-cholinergic agents (e.g, dicyclomine, hyoscyamine, propantheline).
   5. Ultram

   6. 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);
   7. Antimuscarinics;
   8. Peppermint oil;
   9. Systemic antibiotics, rifaximin, metronidazole.
7. Bleeding disorders or medications that increase risk of bleeding from mucosal biopsies.
8. Score > 8 for anxiety or depression on Hospital anxiety and depression scale.
9. Pregnancy

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Healthy volunteers; 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; Saccharide excretion was compared between IBS-C and healthy volunteers; Other Names: Lactulose; 12C Mannitol; 13C Mannitol; Procedure: Esophagogastroduodenoscopy; Duodenal biopsies were collected from IBS-C and healthy volunteers; Procedure: Flexible sigmoidoscopy; Colonic biopsies were collected from IBS-C and healthy volunteers
IBS-C; 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; Saccharide excretion was compared between IBS-C and healthy volunteers; Other Names: Lactulose; 12C Mannitol; 13C Mannitol; Procedure: Esophagogastroduodenoscopy; Duodenal biopsies were collected from IBS-C and healthy volunteers; Procedure: Flexible sigmoidoscopy; Colonic biopsies were collected from IBS-C and healthy volunteers

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: Takeda Pharmaceuticals International, Inc.

Study record dates

Study Major Dates

• Study Start: September 1, 2014
• Primary Completion (Actual): December 8, 2016
• Study Completion (Actual): December 8, 2016

Study Registration Dates

• First Submitted: September 18, 2014
• First Submitted That Met QC Criteria: September 18, 2014
• First Posted (Estimate): September 23, 2014

Study Record Updates

• Last Update Posted (Actual): August 21, 2019
• Last Update Submitted That Met QC Criteria: August 19, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Signs and Symptoms, Digestive; Gastrointestinal Diseases; Colonic Diseases, Functional; Colonic Diseases; Irritable Bowel Syndrome; Constipation; Intestinal Diseases; Physiological Effects of Drugs; Gastrointestinal Agents; Natriuretic Agents; Diuretics, Osmotic; Diuretics; Lactulose; Mannitol
• Other Study ID Numbers: 14-002382

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No