High-fat Challenge Induced Trained Innate Immunity (SHAKE Study)
Condition: Cardiovascular Diseases
MeSH terms: Cardiovascular Diseases
Study type: Interventional

Summary: 
      The goal of this randomized controlled cross-over trial is to investigate whether a single
      high-fat challenge can induce trained innate immunity in healthy volunteers. The main
      question it aims to answer is: Can a single high-fat challenge induce a persistent
      pro-inflammatory and pro-atherogenic monocyte phenotype, as detected by an augmented cytokine
      production capacity? To study this, participants will receive an oral high-fat and reference
      shake in a cross-over design and blood will be drawn before and at 1, 2, 4, 6, 24, and 72
      hours after the shakes.
    

Detailed description: 
      Rationale: Atherosclerosis is characterized by a persistent inflammation of the arterial
      wall.

      Monocyte-derived macrophages are the most abundant immune cells in atherosclerotic plaques.
      It has recently been shown that not only immune cells of the adaptive immune system, but
      innate immune cells as well are able to adopt a long-term pro-inflammatory phenotype upon
      stimulation. This nonspecific memory of innate immune cells is mediated by epigenetic and
      metabolic reprogramming and is termed "trained innate immunity." Previous findings from our
      lab have shown that not only bacterial components such as LPS, but also pro-atherogenic
      particles such as oxidized LDL can induce trained immunity in monocytes. Interestingly, this
      memory-effect of trained immunity indicates that even temporary triggers could induce the
      persistent inflammation in atherosclerosis.

      Triglyceride-rich lipoproteins (TRL) have been identified as an important independent risk
      factor for atherosclerosis. Moreover, elevated plasma levels of these lipoproteins are
      associated with increased pro-inflammatory markers. TRLs, however, are characterized by
      alternating plasma levels, with brief elevations following (fat containing) meals. Notably, a
      high-fat meal not only contributes to the transient increase of TRL plasma levels, but also
      induces a brief elevation in LPS levels by briefly increasing the permeability of the gut.

      We now aim to investigate whether a single high-fat meal can induce trained innate immunity,
      since this concept might explain how brief postprandial effects can translate into a
      long-term pro-inflammatory and pro-atherogenic monocyte phenotype.

      Objective: The primary objective is to determine whether a high-fat meal can induce a
      persistent pro-inflammatory monocyte phenotype, characterized by an increased cytokine
      production capacity upon ex vivo stimulation. Secondary objectives are metabolic and
      epigenetic reprogramming of monocytes at these time points as well as the capacity of serum,
      isolated before and 1-6h after an oral fat load, to induce an increased cytokine production
      in healthy human monocytes.

      Study design: Randomized cross-over high-fat challenge intervention study.

      Study population: Healthy human volunteers, aged between 18 and 40 years.

      Intervention: A single high-fat challenge (milkshake containing 95g of fat) and 'control'
      shake (comparable to an average breakfast).

      Main study parameters/endpoints: Blood will be drawn at t=0h (before) and at t=1h, t=2h,
      t=4h, t=6h, t=24 and t=72h after an oral fat load and at the same time points after a
      'control' shake. The primary endpoint is the monocyte TNFα production upon ex vivo
      stimulation with LPS at the 72h time point. Additional secondary endpoints are the production
      of other cytokines and chemokines upon ex vivo stimulation at t=0h, t=4h, t=24h and t=72h,
      the monocytes' inflammatory phenotype as assessed by flowcytometry analysis and serum induced
      persistent cytokine production capacity.
    

Intervention name(s): High-fat shake; Reference shake
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): The high-fat shake consisted of 53% (w/v) fresh cream, 3% (w/v) sugar and 44% (w/v) water; The reference shake consisted of 43% (w/v) full cream milk, 48% (w/v) full cream yoghurt, 4% (w/v) lemonade, 4% (w/v) fantomalt (Nutricia B.V., the Netherlands) and 1% (w/v) wheat fiber
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Basic Science