Effect of Alcohol Consumption on Markers of Inflammation
Condition: Alcohol Consumption; Inflammation
MeSH terms: Inflammation; Alcohol Drinking
Study type: Interventional

Summary: 
      Rationale: High-density lipoprotein (HDL), which is consistently increased after moderate
      alcohol consumption, is an abundant plasma lipoprotein that is generally thought to be
      anti-inflammatory in both health and infectious disease. HDL binds and neutralizes the
      bioactivity of potent bacterial remnants such as lipopolysaccharides (LPS) which stimulate
      the host innate immune responses.

      Primary objective: To explore whether prolonged moderate alcohol consumption affects in vivo
      cytokine response after a low dose of LPS in young, normal-weight men.
    

Detailed description: 
      Cytokine response in a human model of low-grade systemic inflammation Lipopolysaccharide
      (LPS) or endotoxin is a constituent of the Gram-negative bacterial cell wall. It circulates
      in the plasma of healthy human subjects at low concentrations (between 1 and 200 pg/mL).
      Furthermore, the human gut is host to ~100 trillion organisms, which together contribute to
      an enteric reservoir of ~1 g LPS (4).

      Upon introduction in the bloodstream endotoxin binds to LPS-binding protein (LBP) and this
      complex binds to CD14 on monocytes. CD14 does not have an intracellular domain but signals
      through Toll-like receptor 4, leading eventually to activation of the transcription factor
      NF-κB and to production of Tumor Necrosis Factor alpha (TNF-α,) and interleukin 6 (IL-6) and
      a systemic inflammatory response.

      Endotoxin administration to humans, when given in a low dose, is a well-established model of
      systemic inflammation (5). The low dose of endotoxin elicits an acute mild systemic
      inflammation with a significant and reproducible cytokine and leucocyte response without
      increases in body temperature (2;3). This model thus resembles the levels reported in chronic
      low-grade inflammatory conditions such as type 2 diabetes and arthrosclerosis.

      High-density lipoprotein (HDL) is a group of lipoprotein particles which have the highest
      density in the circulation. HDL has several anti-atherogenic effects, including the ability
      to transport excess cellular cholesterol to the liver for excretion, to protect low-density
      lipoprotein (LDL) against oxidation and to inhibit platelet aggregation. Besides its pivotal
      role in protecting against atherosclerosis, accumulating evidence also suggest that HDL
      possesses anti-inflammatory effects and plays an important role in modulating the
      inflammatory response to lipopolysaccharides.

      Although all lipoprotein classes have been demonstrated to bind LPS, when added to whole
      human normal blood, it mainly binds to HDL (60%), in addition to LDL (25%) and VLDL (12%)
      (6). In vitro, LPS bound to lipoprotein was 20- to 1000-fold less active than the unbound
      form in inducing monocytes and macrophages to release cytokines (7). When transgenic mice
      with 2-fold elevation of plasma HDL levels were injected with LPS, they had more LPS bound to
      HDL, lower plasma cytokine levels, and improved survival rates compared with control mice
      (8). In humans Ex vivo reconstituted HDL abolished the LPS-induced overproduction of
      cytokines in patients with severe cirrhosis and controls (9) and intravenous infusion of
      reconstituted HDL protected humans from the toxic effects of LPS (10).

      It has never been studied whether the alcohol-induced increase in HDL could attenuate the
      effects of LPS on cytokine response both ex vivo and in vivo. Given the fact that alcohol
      induces an increase in HDL (1) and that HDL has LPS-neutralizing properties, it is
      hypothesized that moderate alcohol consumption attenuates the LPS-induced cytokine response
      of TNF-α and IL-6 in young, normal-weight men.

      In addition, because HDL causes down regulation of CD14 expression in monocytes (10) and
      because CD14 modulates the pro-inflammatory response to LPS (11), the effects of HDL on CD14
      expression and expression of other genes related to inflammation will be determined in
      monocytes over time after both in vivo and ex vivo LPS administration. Since HDL also affects
      endothelial function (12;13) and since eicosanoids are important messengers during systemic
      inflammatory processes (14) these markers will also be investigated.
    

Intervention name(s): Alcohol + orange juice; Orange juice
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): 100 mL Vodka (37.5 vol%; 30 gram of alcohol/day) + 200 mL orange juice; 200 mL orange juice
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Alcohol Consumption; High Density Lipoprotein (HDL); lipopolysaccharides (LPS); Apolipoproteins; Inflammation