Evaluation of the Effects Associated With the Administration of Akkermansia Muciniphila on Parameters of Metabolic Syndrome

Study Overview
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Brief Summary
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Overweight and obesity have reached worldwide epidemic level. Both overweight and obesity are characterized by comorbidities such as cardio-metabolic risk factors (i.e., insulin resistance, type 2 diabetes, hypertension, dyslipidemia, low-grade inflammation) representing a major public health problem. Therefore, it is urgent to find a therapeutic solution to target all these metabolic disorders. Among the environmental factors able to influence the individual susceptibility to gain weight and to develop metabolic disorders associated with obesity, more and more evidence show that the trillions of bacteria housed in our gastro-intestinal tract (i.e, gut microbiota) influence host metabolism. The investigators recently discovered a putative interesting microbial candidate, namely Akkermansia muciniphila (Akk). More exactly, we found that the administration of Akkermansia muciniphila reduced body weight gain, fat mass gain, glycemia and inflammatory markers in diet-induced obese mice. Moreover, in overweight/obese patients with cardiovascular risk factors subjected to a calorie restriction diet (calorie restriction diet for 6 weeks and an additional 6 weeks of weight maintenance), a higher abundance of Akkermansia muciniphila was associated with a better cardio-metabolic status in these patients. The investigators also discovered that patients having more Akkermansia muciniphila in their gut before the calorie restriction exhibited a greater improvement in glucose homoeostasis, blood lipids and body composition after calorie restriction. These observations suggested that the administration of Akkermansia muciniphila in overweight or obese people could be a very interesting therapeutic solution. Currently, no human study has investigated the beneficial effects of Akkermansia muciniphila administration on obesity and metabolic disorders. The overall objective of this study is to evaluate the effects associated with the administration of live or heat-killed Akkermansia muciniphila on the metabolic disorders (insulin-resistance, type-2 diabetes, dyslipidemia, inflammation) related to overweight and obesity in humans.

Official Title
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Evaluation of the Effects Associated With the Administration of Akkermansia Muciniphila on Parameters of Metabolic Syndrome Related to Obesity

Conditions
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Obesity, Metabolic Syndrome x, Glucose Metabolism Disorders, Dyslipidemias

Intervention / Treatment
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* Dietary Supplement: Placebo
* Dietary Supplement: Live Akk 9
* Dietary Supplement: Live Akk 10
* Dietary Supplement: Killed Akk


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged between 18 and 70 years old Caucasian Insulin resistance (based on HOMA single-value) BMI between 25 and 50 kg/m² Metabolic syndrome: presence of at least 3 of the following criteria Hypertension (blood pressure ≥ 130/85 mm Hg or antihypertensive treatment) Hypertriglyceridemia (triglyceridemia ≥ 150mg/dl) Low HDL-cholesterol (HDL-cholesterol < 40mg/dl for males, 50mg/dl for females) Visceral obesity (waist circumference > 102 cm for males, 88cm for females) Fasting hyperglycemia (fasting glycemia ≥ 110mg/dl) Informed consent signed by the patient Exclusion Criteria: Acute or chronic progressive or chronic unstabilized diseases Alcohol consumption (more than 2 glasses per day) Previous bariatric surgery Surgery in the 3 months prior the study or surgery planned in the next 6 months Pregnancy or pregnancy planned in the next 6 months More than 30 minutes of sports 3 times per week Consumption of dietary supplement (omega-3 fatty acids, probiotics, prebiotics, plant stanols/sterols) in the month prior the study Inflammatory bowel disease or irritable bowel syndrome Diabetic gastrointestinal autonomic neuropathy (such as gastroparesis or reduced gastrointestinal motility) Consumption of more than 30g of dietary fibers per day Vegetarian or unusual diet Lactose intolerance or milk protein allergy Gluten intolerance Medications influencing parameters of interest (antidiabetic drugs such as metformin, DPP-4 inhibitors, GLP-1 receptor agonists, acarbose, hypoglycemic sulfonamides,glinides, thiazolidinediones, SGLT2 inhibitors, insulin,lactulose, consumption of antibiotics in the 2 months prior the study, corticosteroids, immunosuppressive agents, statins, fibrate, orlistat, cholestyramine, ezetimibe) Glycated hemoglobin (HbA1c) > 7.5%

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo corresponds to a solution of Phosphate buffer saline (PBS) and glycerol, that is the carrier used in the 3 other groups receiving the bacteria (active arms) | Dietary Supplement: Placebo<br>* Consumption of one dose-sachet per day. This dose-sachet contains a placebo (PBS/Glycerol)<br>|
| Experimental: Live Akk 9<br>Live Akkermansia muciniphila (Akk) at the dose of 10exp9 live bacteria (one billion of live bacteria) per day | Dietary Supplement: Live Akk 9<br>* Consumption of one dose-sachet per day. This dose-sachet contains Live Akkermansia muciniphila (one billion per dose-sachet)<br>|
| Experimental: Live Akk 10<br>Live Akkermansia muciniphila (Akk) at the dose of 10exp10 live bacteria (ten billion of live bacteria) per day | Dietary Supplement: Live Akk 10<br>* Consumption of one dose-sachet per day. This dose-sachet contains Live Akkermansia muciniphila (ten billion per dose-sachet)<br>|
| Experimental: Killed Akk<br>This group corresponds to Akkermansia muciniphila that have been heat-killed. The initial quantity of bacteria before the heating procedure was of 10exp10 bacteria. | Dietary Supplement: Killed Akk<br>* Consumption of one dose-sachet per day. This dose-sachet contains heat-killed Akkermansia muciniphila<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerance | self reporting of gastrointestinal symptoms (nausea, bloating, flatulence, cramp, borborygmi and gastric reflux) | 15 days | 
| Tolerance | self reporting of gastrointestinal symptoms (nausea, bloating, flatulence, cramp, borborygmi and gastric reflux) | 3 months | 
| Concentration of urea (mg/dl) | measure of urea as marker of renal function | 15 days | 
| Concentration of urea (mg/dl) | measure of urea as marker of renal function | 3 months | 
| Glomerular filtration rate (mL/min/1.73m2) | measure of glomerular filtration rate as marker of renal function | 15 days | 
| Glomerular filtration rate (mL/min/1.73m2) | measure of glomerular filtration rate as marker of renal function | 3 months | 
| Concentration of creatinine (mg/dl) | measure of creatinine as marker of renal function | 15 days | 
| Concentration of creatinine (mg/dl) | measure of creatinine as marker of renal function | 3 months | 
| Concentration of liver transaminases | measure of alanine aminotransferase (U/L); aspartate aminotransferase (U/L); gamma glutamyl transpeptidase (U/L). Lactate dehydrogenase (UI/L) as markers of hepatic inflammation | 15 days | 
| Concentration of liver transaminases | measure of alanine aminotransferase (U/L); aspartate aminotransferase (U/L); gamma glutamyl transpeptidase (U/L). Lactate dehydrogenase (UI/L) as markers of hepatic inflammation | 3 months | 
| Concentration of white blood cells (10exp3/µl) | measured as a marker of inflammation | 15 days | 
| Concentration of white blood cells (10exp3/µl) | measured as a marker of inflammation | 3 months | 
| concentration of CRP (c-reactive protein) (mg/dl) | measured as a marker of inflammation | 15 days | 
| concentration of CRP (c-reactive protein) (mg/dl) | measured as a marker of inflammation | 3 months | 
| Insulin resistance | HOMA-Homeostasis Model Assessment calculated from fasted glycemia and insulinemia | 3 months | 
| Concentration of blood lipids | Analysis of circulating lipids : total, LDL and HDL cholesterol (mg/dl), triglycerides (md/dl) | 3 months | 
| Obesity | Body weight | 3 months | 
| Adiposity | Fat mass evaluated by bioimpedance measurements | 3 months | 
| Visceral adiposity | Waist and hip circumference | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure of the concentration of Akkermansia in the feces (bacterial cells/g of feces) | Metagenomic analysis of the gut bacteria by using sequencing technology and by using quantitative polymerase chain reaction (qPCR). | 3 months | 
| Gut barrier function | Fecal calprotectin, fecal zonulin, plasma lipopolysaccharides (LPS) binding protein (LBP) | 3 months | 
| Metabolic endotoxemia | Plasma lipopolysaccharides (LPS) by the limulus amebocyte lysate kinetic chromogenic methodology | 3 months | 
| Gut microbial-related metabolites in urine | Metabolomic analysis of the bacterial metabolites present in the urine by combining nuclear magnetic resonance (1H-NMR) and mass spectrometry | 3 months | 
| Gut microbial-related metabolites in plasma | Metabolomic analysis of the bacterial metabolites present in the plasma by combining nuclear magnetic resonance (1H-NMR) and mass spectrometry | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gut microbiota, Akkermansia muciniphila