LEAKY GUT: Intestinal Permeability in Obesity

Sponsor

Assistance Publique - Hôpitaux de Paris (Other)

Overall Status

Terminated

CT.gov ID

NCT02292121

Collaborator

Institute of Cardiometabolism and Nutrition, France (Other)

Enrollment

Location

Arms

24.7

Actual Duration (Months)

3.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

In rodents, obesity is associated with changes in tight junctions' structure in small intestine, which impacts intestinal permeability and results in metabolic complications. Few data exist in human. We hypothesized that intestinal permeability is altered in obese subjects in comparison to lean subjects, linked to metabolic and inflammatory status and that these alterations are modified after gastric bypass.

Condition or Disease	Intervention/Treatment	Phase
Obesity Metabolic Diseases Nutrition Disorders Body Weight	Procedure: Intestinal permeability Other: a solution of mannitol and lactitol	N/A

Detailed Description

The regulation of the permeability of the intestinal barrier is essential in the molecular traffic between the lumen and the internal environment. It affects the absorption of nutrients and tolerance or immunization against foodborne non-self antigens that penetrate the barrier. In rodents, increased endotoxemia has been proposed as an important player in low-grade inflammation accompanying the development of obesity and metabolic disorders. In humans, the intestinal barrier function is altered in inflammatory bowel diseases (IBD, Crohn's disease, ulcerative colitis and celiac disease). The term "leaky gut" is used to describe a porous intestine with hyper-permeability associated with acute or chronic inflammatory diseases such as "systemic inflammatory response syndrome (SIRS),"acute inflammatory bowel disease (IBD for "inflammatory bowel disease").

Deficiencies of the barrier are also observed in extra-intestinal diseases (type-1 diabetes, food allergies, and autoimmune diseases). Impairments in tight junctions may precede clinical signs and constitute a risk factor for developing diseases or secondarily be altered and cause an increased entry of undesirable bacterial or nutritional antigens. The state of the intercellular tight junctions of the intestine controls the diffusion of molecules between cells. A deficiency of the intestinal barrier function is often associated with structural changes in the tight junctions resulting from loss of localization of protein or expression of genes and / or cellular signals such as ZO-1, occludin or tricellulin.

There are few studies about the condition of the intestinal barrier in the context of human obesity.

The objectives of our study are to :

compare intestinal permeability in obese subjects with non obese subjects and after gastric bypass.
search links between intestinal permeability and 1) metabolic and inflammatory bioclinical parameters 2) dietary profiles 3) microbiota

Study Design

Study Type:

Interventional

Actual Enrollment :

80 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Diagnostic

Official Title:

Intestinal Permeability in Obesity of Intercellular Tight Junctions to Metabolic Complications

Actual Study Start Date :

Feb 24, 2014

Actual Primary Completion Date :

Mar 17, 2016

Actual Study Completion Date :

Mar 17, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: obese group 40 obese subjects undergoing gastric bypass explored at baseline and 30 explored post-surgery at 6 months	Procedure: Intestinal permeability 5h-intestinal permeability test 10-hour overnight fasting subject who first emptied his bladder drinks a solution of mannitol and lactitol. 2 hours after, the subject drinks 500mL of water in less than 30 minutes. All urine samples are collected during the 5h-test for measurement of lactitol and mannitol. Other: a solution of mannitol and lactitol
Active Comparator: non-obese control group (T1) 30 non-obese control subjects investigated for bio-clinical measures, IPT, zonulin, and LPS	Procedure: Intestinal permeability 5h-intestinal permeability test 10-hour overnight fasting subject who first emptied his bladder drinks a solution of mannitol and lactitol. 2 hours after, the subject drinks 500mL of water in less than 30 minutes. All urine samples are collected during the 5h-test for measurement of lactitol and mannitol. Other: a solution of mannitol and lactitol
No Intervention: non obese control group undergoing a surgery (T2) 40 non-obese candidates to a surgery that gives access to surgical jejunal samples to measure the expression of tight junctions proteins

Arm

Intervention/Treatment

Experimental: obese group

40 obese subjects undergoing gastric bypass explored at baseline and 30 explored post-surgery at 6 months

Procedure: Intestinal permeability

5h-intestinal permeability test 10-hour overnight fasting subject who first emptied his bladder drinks a solution of mannitol and lactitol. 2 hours after, the subject drinks 500mL of water in less than 30 minutes. All urine samples are collected during the 5h-test for measurement of lactitol and mannitol.

Other: a solution of mannitol and lactitol

Active Comparator: non-obese control group (T1)

30 non-obese control subjects investigated for bio-clinical measures, IPT, zonulin, and LPS

Procedure: Intestinal permeability

Other: a solution of mannitol and lactitol

No Intervention: non obese control group undergoing a surgery (T2)

40 non-obese candidates to a surgery that gives access to surgical jejunal samples to measure the expression of tight junctions proteins

Outcome Measures

Primary Outcome Measures

urinary lactitol / mannitol ratio by an intestinal permeability test (IPT) [before gastric bypass and 6 months after]
Measures of urinary lactitol / mannitol ratio by an intestinal permeability test (IPT) in obese patients before gastric bypass and 6 months after

Secondary Outcome Measures

fasting zonulin serum concentrations [before gastric bypass and 6 months after]
Measures of fasting zonulin serum concentrations in obese patients before gastric bypass and 6 months after
LPS serum concentrations [before gastric bypass and 6 months after]
Measures of LPS serum concentrations in obese patients before gastric bypass and 6 months after
urinary lactitol / mannitol ratio by an intestinal permeability test (IPT) [inclusion and after one month]
Measures of urinary lactitol / mannitol ratio by an intestinal permeability test (IPT) in non-obese control subjects, performed twice with a one-month interval.
surgical samples during surgery (sub-cutaneous and visceral adipose tissue) [intraoperative]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion criteria :

Control subjects T1:

Registered for social security
Signed consent form
male or female subject between 18 and 65 years old
Fasting plasma triglycerides < 1.5 g/l (< 1.7 mmol/l)
Fasting plasma total cholesterol < 2.5 g/l (< 6 mmol/l)
fasting glycaemia < 5,5 mmol/l
BMI <25kg/m² & >18 kg/m²
Mean systolic blood pressure <140 mmHg and mean diastolic blood pressure < 90 mmHg.

Control subjects T2

Registered for social security
Signed consent form
male or female subject between 18 and 70 years old
IMC<25kg/m² et >18 kg/m²
candidate to surgery giving access to jejunal samples

Obese subjects OB:

Registered for social security
Signed consent form
male or female subject between 18 and 65 years old
Candidate to bariatric surgery (bypass) with massive (IBMI >= 40 kg/m²) or severe obesity (BMI between 35 & 40 kg/m²) with at least one obesity-related comorbidity and with a stable weight (+/-5kg) for the last 3 months, after approval by a multidisciplinary team

Exclusion criteria :

Control subjects T1:

Subject with a history of vascular symptomatic disease in the last 6 months before selection.
Subject receiving a treatment that can affect measured parameters
Pregnancy
Subject with acute or chronic disease that can affect measured parameters or to life-threatening. Including but not limited :
Diabetic subjects
Subject with kidney disease: nephrotic syndrome, chronic renal failure
Subject having a gastrointestinal disorder or disease limiting intestinal absorption (celiac disease), bariatric surgery.
Active inflammatory disease or a history of IBD
Subject in a situation that, according to the investigator's opinion could interfere with an optimal participation to the study or constitute a particular risk to the subject
Subject in an exclusion period after participating in another clinical trial
Adult person subject to legal protection or unable to consent.
Persons deprived of their liberty by judicial or administrative decision

Control subjects T2

Subject with a history of symptomatic vascular disease (myocardial infarction, angina syndrome threat, surgical or endovascular surgery, stroke, lower limb arteritis symptomatic) of less than 6 months
Subject with any acute or chronic disease which may influence the results of the study or to life-threatening. Including but not limiting:
diabetic patients
Subject with kidney disease: nephrotic syndrome, chronic renal failure and / or serum creatinine> 1.7 times the upper limit of the reference value
Adult person subject to legal protection or unable to consent.
Persons deprived of their liberty by judicial or administrative decision

Obese subjects candidates for surgery:

Subject receiving treatment systemically or topically, which may interfere with the evaluation of the parameters studied (NSAIDs, antibiotics in the previous month)
Any disease or psychosocial context making prolonged regular monitoring impossible, which also represents a contraindication for bariatric surgery.
Adult person subject to legal protection or unable to consent.
Persons deprived of their liberty by judicial or administrative decision