Akkermansia and Weight Maintenance
Condition: Obesity; Microtia; Metabolic Syndrome; Weight Loss
MeSH terms: Congenital Microtia; Metabolic Syndrome; Body Weight; Weight Loss
Study type: Interventional

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.
    

Intervention name(s): Akkermansia muciniphila; Placebo
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): During the weight management period (weeks 8 to 32), the pasteurized A. muciniphila product will be orally consumed in water at least 15 min before breakfast for a period of 6 months (24 weeks) capsules. It appears as a white homogenous powder.
.; During the weight management period (weeks 8 to 32), the placebo product will be orally consumed in water at least 15 min before breakfast for a period of 6 months (24 weeks). It appears as a white homogenous powder.
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: A double-blind, placebo-controlled randomised intervention study
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention