Evaluation of the Effects Associated With the Administration of Akkermansia Muciniphila on Parameters of Metabolic Syndrome (Microbes4U)

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

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.

Study Overview

• Status: Completed
• Conditions: Glucose Metabolism Disorders; Obesity; Dyslipidemias; Metabolic Syndrome x
• Intervention / Treatment: Dietary supplement: Placebo; Dietary supplement: Live Akk 9; Dietary supplement: Live Akk 10; Dietary supplement: Killed Akk

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1200
    • Cliniques universitaires Saint-Luc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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%

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo; 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; Consumption of one dose-sachet per day. This dose-sachet contains a placebo (PBS/Glycerol)
EXPERIMENTAL: Live Akk 9; Live Akkermansia muciniphila (Akk) at the dose of 10exp9 live bacteria (one billion of live bacteria) per day	Dietary supplement: Live Akk 9; Consumption of one dose-sachet per day. This dose-sachet contains Live Akkermansia muciniphila (one billion per dose-sachet)
EXPERIMENTAL: Live Akk 10; Live Akkermansia muciniphila (Akk) at the dose of 10exp10 live bacteria (ten billion of live bacteria) per day	Dietary supplement: Live Akk 10; Consumption of one dose-sachet per day. This dose-sachet contains Live Akkermansia muciniphila (ten billion per dose-sachet)
EXPERIMENTAL: Killed Akk; 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; Consumption of one dose-sachet per day. This dose-sachet contains heat-killed Akkermansia muciniphila

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Patrice D. Cani
• Collaborators: Cliniques universitaires Saint-Luc- Université Catholique de Louvain
• Investigators: Study Director: Patrice D. Cani, Professor, Université Catholique de Louvain

Publications and helpful links

General Publications

• Schneeberger M, Everard A, Gomez-Valades AG, Matamoros S, Ramirez S, Delzenne NM, Gomis R, Claret M, Cani PD. Akkermansia muciniphila inversely correlates with the onset of inflammation, altered adipose tissue metabolism and metabolic disorders during obesity in mice. Sci Rep. 2015 Nov 13;5:16643. doi: 10.1038/srep16643.
• Dao MC, Everard A, Aron-Wisnewsky J, Sokolovska N, Prifti E, Verger EO, Kayser BD, Levenez F, Chilloux J, Hoyles L; MICRO-Obes Consortium; Dumas ME, Rizkalla SW, Dore J, Cani PD, Clement K. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut. 2016 Mar;65(3):426-36. doi: 10.1136/gutjnl-2014-308778. Epub 2015 Jun 22.
• Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, Guiot Y, Derrien M, Muccioli GG, Delzenne NM, de Vos WM, Cani PD. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A. 2013 May 28;110(22):9066-71. doi: 10.1073/pnas.1219451110. Epub 2013 May 13.
• Depommier C, Vitale RM, Iannotti FA, Silvestri C, Flamand N, Druart C, Everard A, Pelicaen R, Maiter D, Thissen JP, Loumaye A, Hermans MP, Delzenne NM, de Vos WM, Di Marzo V, Cani PD. Beneficial Effects of Akkermansia muciniphila Are Not Associated with Major Changes in the Circulating Endocannabinoidome but Linked to Higher Mono-Palmitoyl-Glycerol Levels as New PPARalpha Agonists. Cells. 2021 Jan 19;10(1):185. doi: 10.3390/cells10010185.
• Depommier C, Flamand N, Pelicaen R, Maiter D, Thissen JP, Loumaye A, Hermans MP, Everard A, Delzenne NM, Di Marzo V, Cani PD. Linking the Endocannabinoidome with Specific Metabolic Parameters in an Overweight and Insulin-Resistant Population: From Multivariate Exploratory Analysis to Univariate Analysis and Construction of Predictive Models. Cells. 2021 Jan 5;10(1):71. doi: 10.3390/cells10010071.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 1, 2015
• Primary Completion (ACTUAL): February 20, 2018
• Study Completion (ACTUAL): February 20, 2018

Study Registration Dates

• First Submitted: December 10, 2015
• First Submitted That Met QC Criteria: December 17, 2015
• First Posted (ESTIMATE): December 22, 2015

Study Record Updates

• Last Update Posted (ACTUAL): May 17, 2019
• Last Update Submitted That Met QC Criteria: May 15, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: Gut microbiota; Akkermansia muciniphila
• Additional Relevant MeSH Terms: Pathologic Processes; Disease; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Insulin Resistance; Hyperinsulinism; Lipid Metabolism Disorders; Syndrome; Obesity; Metabolic Syndrome; Dyslipidemias; Metabolic Diseases; Glucose Metabolism Disorders
• Other Study ID Numbers: 2015/02JUL/369; B403201525111 (OTHER: Université catholique de Louvain)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED