Clinical trial NCT05417360: Akkermansia and Weight Maintenance
Official title: Effect of Pasteurized Akkermansia Muciniphilia on Maintenance of Body Weight After a Low Calorie Diet
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Obesity
Microtia
Metabolic Syndrome
Weight Loss
Lead sponsor: Maastricht University Medical Center
Sponsor class: OTHER
First posted: 2022-06-14
Enrollment: 90
Sex: ALL
Minimum age (years): 20
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A double-blind, placebo-controlled randomised intervention study
Primary purpose: PREVENTION

Brief summary: Obesity and related disorders such as type 2 diabetes are a worldwide diet-related problem. As such new treatment options are constantly being developed. Bacteria living in the gut seem to be a key player in the treatment of obesity and related metabolic diseases by influencing energy balance and the immune system. In terms of newly identified bacteria species, Akkermansia muciniphila (A. muciniphila) has been found to be related to obesity. Several animal studies have shown the beneficial impact of A. muciniphila on the treatment of body weight as well as insulin sensitivity.

The growth requirements of live A. muciniphila as well as its oxygen sensitivity rendered this bacterium unsuitable for human investigations or putative therapeutic opportunities. Therefore, pasteurization, a mild heating method, and its impact on diet-induced metabolic disorders in mice were investigated. Unexpectedly, this method of inactivation did not negate the effect of A. muciniphila, but improved its beneficial metabolic effects. Pilot studies have provided further evidence that pasteurization of A. muciniphila is safe for human use and has the potential to beneficially affect the control of body weight and glucose metabolism.

In this project, The investigators hypothesize that pasteurized A. muciniphila will be superior to placebo intervention in maintaining body weight after a phase of weight loss (low caloric diet) in adult participants with overweight or obesity.

Detailed description: RATIONALE This study will examine the influence of specific beneficial gut bacteria in relation to weight maintenance. The worldwide prevalence of obesity, obesity-associated insulin resistance, and type 2 Diabetes Mellitus (T2DM) has grown dramatically over the last couple of decades; in every region of the world, obesity prevalence has more than tripled since 1975. Even though obesity treatment strategies, such as lifestyle interventions (focussed on diet and/or physical activity) and bariatric surgery have improved, there is extensive variability in responses. In the short term, reducing body weight is relatively easy, for most people. However, maintaining weight loss in the long term is a challenge. Hence, novel strategies to reduce these pandemics and support weight maintenance are strongly warranted.

The gut microbiome has emerged as an important regulator of host energy metabolism, thereby contributing to the etiology of obesity and obesity-related insulin resistance. However, scientific evidence is mainly derived from animal experiments and association studies, and support for causality in humans using mechanistic studies is limited. The influence of a newly identified bacterium, A. muciniphila. has been shown to be associated with a healthy intestine, and its abundance is inversely correlated to several disease states amongst others obesity and insulin resistance. However, the growth requirements of live A. muciniphila as well as its oxygen sensitivity(12) rendered this bacterium unsuitable for human investigations or putative therapeutic opportunities. Therefore, pasteurization, a mild heat inactivation method (30 min at 70 degrees Celsius), and its impact on diet-induced metabolic disorders in mice were investigated. Unexpectedly, this method of inactivation did not abolish the effect of A. muciniphila but even exacerbated its beneficial impacts. In mice, daily administration of pasteurized A. muciniphila alleviates diet-induced obesity. Moreover, a randomized, double-blind, placebo-controlled proof-of-concept study in overweight/obese insulin-resistant adults showed that the daily supplementation with pasteurized A. muciniphila for 12 weeks improved several metabolic parameters such as insulin sensitivity, insulinemia, plasma total cholesterol, as well as relevant blood markers for liver dysfunction and inflammation independently from any caloric restriction or modification of the physical activity. The investigators hypothesize that pasteurized A. muciniphila will be superior to placebo intervention in maintaining body weight after a low caloric diet in participants with overweight or obesity.

OBJECTIVES

1. To investigate the effects of pasteurized A. muciniphila on the maintenance of body weight after a phase of weight loss.
2. To investigate the effects of pasteurized A. muciniphila on body composition and body fat distribution, glucose homeostasis and insulin sensitivity, and metabolic health.
3. To investigate the effects of pasteurized A. muciniphila on the fecal bacterial composition and functionality, systemic inflammation, and gut barrier function and identify relevant biomarkers.

STUDY DESIGN The proposed study is a 32-week double-blind placebo-controlled randomized trial in 108 healthy overweight/ obese (BMI ≥ 28 kg/m2 \< 40 kg/m2) Dutch adults, aged 20-70 years. All participants will follow a commercially-prepared low-calorie diet, with 15-20 energy % from fat, 35-40 energy % from protein, and 45-50 energy % from carbohydrates for a period of 8 weeks, to lose 8% of their body weight. In addition to these prepared meals, participants will be allowed limited consumption of specific low-calorie vegetables. Participants will be randomized to either the placebo or the intervention group following the weight-loss period. The weight loss phase will be followed by a 24-week supplementation placebo or active ingredient and a weight maintenance period. Prior to, as well as during both phases of the study participants will receive regular weigh-ins (weeks 0, 1, 4, 8, 16, 24, and 32) and counseling from a registered dietician. In addition to measuring changes in weight and physical measurements, participants will fill in questionnaires, and provide blood and fecal samples at weeks 0, 8, and 32.

QUALITY ASSURANCE Study activities will be carried out by qualified trained personnel, following standard operating procedures (SOP's). All research activities, including data entry and SOP compliance, will be monitored by an independent monitoring board, Clinical trial center Maastricht (CTCM). Data will be analyzed and handled according to the data management and statistical analysis plan.

Eligibility criteria: Inclusion Criteria:

* BMI ≥ 28 kg/m2 \< 40 kg/m2
* Weight stable for at least 3 months (± 2 kg).

Exclusion Criteria:

* Type 2 diabetes mellitus (fasting plasma glucose ≥ 7.0 mmol/L)
* Gastroenterological diseases
* Surgery on the gastrointestinal tract (ex.Bariatric surgery)
* Cardiovascular diseases, cancer, liver or kidney malfunction, a disease with a life expectancy of \< 5 years;
* Alcohol (\>15 standard drinks per week) or drug abuse
* Excessive nicotine use is defined as \>20 cigarettes per day;
* Use of prebiotics or probiotics 3 months prior to the start of the study;
* Intensive exercise training, \> 3 hours a week;
* Use of any medication influencing glucose or fat metabolism (ex. lipid-lowering-drugs e.g. PPAR γ (peroxisome proliferator-activated receptors) or PPARα (fibrates) agonists), glucose-lowering agents (including all sulfonylureas, biguanides, α-glucosidase inhibitors, thiazolidinediones, repaglinide, nateglinide, and insulin), inflammation (e.g. anti-inflammatory or immunosuppressive drugs) and anti-oxidants);
* Regular use of laxatives
* Use of antibiotics in the last 3 months
* Vegan
* Lactose intolerance
* Pregnancy or lactation
* Concomitant participation in another study

Primary outcomes:
measure: Body weight
timeFrame: 6 months
Secondary outcomes:
measure: Body composition
timeFrame: 8 months
measure: Body fat distribution
timeFrame: 8 months
measure: Glucose metabolism
timeFrame: 8 months
measure: Insulin sensitivity
timeFrame: 8 months
measure: Lipid profile
timeFrame: 8 months
measure: Adipose tissue activity
timeFrame: 8 months
measure: Gut barrier function
timeFrame: 8 months
measure: Psychological well-being - mental health
timeFrame: 8 months
measure: Psychological well-being - sleep quality
timeFrame: 8 months
measure: Psychological well-being - stress
timeFrame: 8 months
measure: Psychological well-being - General
timeFrame: 8 months
measure: Gastrointestinal symptoms - bowel movements
timeFrame: 8 months
measure: Gastrointestinal symptoms
timeFrame: 8 months
measure: Heart rate
timeFrame: 8 months
measure: Blood pressure
timeFrame: 8 months
measure: Renal function
timeFrame: 8 months
measure: Liver function
timeFrame: 8 months
measure: Inflammation
timeFrame: 8 months
measure: Microbiota
timeFrame: 8 months
measure: Short chain fatty acid production
timeFrame: 8 months
Other outcomes:
measure: Physical activity
timeFrame: 8 months
measure: Diet
timeFrame: 8 months
Locations:
city: Maastricht
country: Netherlands
facility: Department of Human Biology, Maastricht University Medical Centre
state: Limburg
Study officials:
References: