Performance of 13C Mannitol for in Vivo Measurement of Small Intestinal Permeability

Study Overview
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Brief Summary
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The investigators' overall objective with this study is to determine performance characteristics of small intestine permeability measurement using 13C mannitol and 12C (regular) mannitol.

Detailed Description
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An impaired intestinal permeability is implicated in the pathophysiology of a number of disorders such as celiac disease, environmental enteropathy, inflammatory bowel disease, obesity, and HIV. Current measurements of intestinal permeability rely on urinary excretion of naturally available, orally ingested, non-absorbable sugars (e.g. lactulose, mannitol). However, dietary intake of these sugars limits interpretation from these assays. Subjects will have an esophagogastroduodenoscopy (EGD) with biopsies and provide a baseline urine sample. They will be asked to ingest 3 saccharides (12C mannitol 100 mg,13C mannitol 100 mg and lactulose 1 g) in 250 ml of water. Urine samples will be obtained every 30 min. in the Clinical Research and Trials Unit (CRTU) for 0-2 hours. Subjects will collect 2-8 hour sample in provided container. Another container will be provided to collect the 8-24 hour urine which will be returned the following morning. Subjects will undergo an Indomethacin challenge intervention. They will be instructed to take three 25 mg capsules 8 hours before their next visit (just before fasting). They will take 3 additional 25 mg capsules 30 min. before the repeat in vivo permeability testing. Repeat EGD with duodenal biopsies will be done. Long term follow-up will be done within 4-6 weeks of previous testing, where subjects will once again be asked to complete the in vivo permeability testing.

Official Title
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Performance of 13C Mannitol for in Vivo Measurement of Small Intestinal Permeability

Conditions
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Impaired Small Intestinal Permeability

Intervention / Treatment
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* Dietary Supplement: 12C mannitol
* Drug: Indomethacin
* Dietary Supplement: 13C mannitol
* Dietary Supplement: Lactulose


Participation Criteria
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Eligibility Criteria
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Healthy Volunteers Inclusion criteria: Age (yr) 18 to 65 No abdominal surgery (except appendectomy and cholecystectomy, others may be considered) Exclusion criteria: History of irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (Crohn's disease or ulcerative colitis), microscopic colitis or celiac disease. Use of tobacco products within the past 6 months (since nicotine may affect intestinal permeability) Use of nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin within seven days of first permeability test (as NSAIDs affect intestinal permeability) and second permeability test (except those administered for the study) Use of oral corticosteroids within the previous 6 weeks Ingestion of artificial sweeteners such as Splenda® (sucralose), NutraSweet® (aspartame), lactulose or mannitol within two (2) days of each permeability test and endoscopy procedure date, 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 within 7 days each permeability test and endoscopy procedure date. This includes drugs such as serotonin (5-HT) agents, narcotics, anticholinergics, anti-nausea medications, any medications for diarrhea or constipation. Antibiotics within 7 days each permeability test and endoscopy procedure date 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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All

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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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Healthy Volunteers<br>Subjects will receive a saccharide solution of 12C mannitol 100 mg, 13C mannitol 100 mg, and lactulose 1 g in 250ml of water at visits 2, 5, and 7 prior to permeability testing. The subjects will also receive Indomethacin capsules prior to visit 5. | Dietary Supplement: 12C mannitol<br>* 12C mannitol 100 mg<br>Drug: Indomethacin<br>* Subjects will receive six 25 mg capsules of Indomethacin (immediate release). The subjects will take 3 capsules 8 hours before the timing of visit 5 (before fasting), and 3 additional capsules 30 minutes before visit 5.<br>* Other names: Indocin;Dietary Supplement: 13C mannitol<br>* 13C mannitol 100 mg<br>Dietary Supplement: Lactulose<br>* lactulose 1 g<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Small intestine permeability as measured by change in cumulative excretion of mannitol 0-2 hours |  | baseline, approximately 2 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Colonic permeability as measured by change in mannitol excretion between 8 and 24 hours |  | 8 hours, approximately 24 hours | 
| Change in mannitol excretion at 24 hours |  | baseline, approximately 24 hours | 
| Change in lactulose-mannitol excretion assay at 2 hours | The ratio of urinary excretion of lactulose to mannitol was used to measure intestinal mucosal permeability, with higher ratios indicative of increased intestinal permeability. | baseline, approximately 2 hours | 
| Change in hour lactulose-mannitol excretion assay between 8 and 24 hours | The ratio of urinary excretion of lactulose to mannitol was used to measure intestinal mucosal permeability, with higher ratios indicative of increased intestinal permeability. | 8 hours, approximately 24 hours |