Intestinal Permeability in Obesity (LEAKY GUT)

Intestinal Permeability in Obesity of Intercellular Tight Junctions to Metabolic Complications

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.

Study Overview

• Status: Terminated
• Conditions: Metabolic Diseases; Obesity; Nutrition Disorders; Body Weight
• Intervention / Treatment: Procedure: Intestinal permeability; Other: a solution of mannitol and lactitol

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 Type: Interventional
• Enrollment (Actual): 80
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Paris, France, 75013
    • Groupe Hospitalier Pitie-Salpetriere

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria :

- Control subjects T1:

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

Control subjects T2

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

Obese subjects OB:

1. Registered for social security
2. Signed consent form
3. male or female subject between 18 and 65 years old
4. 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:

1. Subject with a history of vascular symptomatic disease in the last 6 months before selection.
2. Subject receiving a treatment that can affect measured parameters
3. Pregnancy

4. Subject with acute or chronic disease that can affect measured parameters or to life-threatening. Including but not limited :

   1. Diabetic subjects
   2. Subject with kidney disease: nephrotic syndrome, chronic renal failure
   3. Subject having a gastrointestinal disorder or disease limiting intestinal absorption (celiac disease), bariatric surgery.
   4. Active inflammatory disease or a history of IBD
5. 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
6. Subject in an exclusion period after participating in another clinical trial
7. Adult person subject to legal protection or unable to consent.
8. Persons deprived of their liberty by judicial or administrative decision

Control subjects T2

1. 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

2. Subject with any acute or chronic disease which may influence the results of the study or to life-threatening. Including but not limiting:

   1. diabetic patients
   2. Subject with kidney disease: nephrotic syndrome, chronic renal failure and / or serum creatinine> 1.7 times the upper limit of the reference value
3. Adult person subject to legal protection or unable to consent.
4. Persons deprived of their liberty by judicial or administrative decision

Obese subjects candidates for surgery:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
urinary lactitol / mannitol ratio by an intestinal permeability test (IPT)	Measures of urinary lactitol / mannitol ratio by an intestinal permeability test (IPT) in obese patients before gastric bypass and 6 months after	before gastric bypass and 6 months after

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Institute of Cardiometabolism and Nutrition, France
• Investigators: Principal Investigator: Christine POITOU, MD, PhD, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): February 24, 2014
• Primary Completion (Actual): March 17, 2016
• Study Completion (Actual): March 17, 2016

Study Registration Dates

• First Submitted: November 12, 2014
• First Submitted That Met QC Criteria: November 14, 2014
• First Posted (Estimate): November 17, 2014

Study Record Updates

• Last Update Posted (Actual): January 20, 2021
• Last Update Submitted That Met QC Criteria: January 15, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: Obesity; Bariatric surgery; Intestinal permeability; Adipose tissue inflammation; Low grade systemic inflammation
• Additional Relevant MeSH Terms: Overnutrition; Overweight; Obesity; Body Weight; Nutrition Disorders; Metabolic Diseases; Physiological Effects of Drugs; Gastrointestinal Agents; Natriuretic Agents; Diuretics, Osmotic; Diuretics; Cathartics; Mannitol; Lactitol
• Other Study ID Numbers: P130402