Endotoxin May Not Be the Major Cause of Postprandial Inflammation in Adults Who Consume a Single High-Fat or Moderately High-Fat Meal

J Nutr. 2020 May 1;150(5):1303-1312. doi: 10.1093/jn/nxaa003.


Background: Metabolic endotoxemia is considered a cause for high-fat diet (HFD)-induced inflammation. However, convincing experimental evidence in humans is scant.

Objective: We determined whether a HFD or moderately HFD increases LPS and LPS-mediated cytokine production in the postprandial blood (PPB).

Methods: Ninety-eight volunteers (age: 37.3 ± 1.5 y) from the cross-sectional phenotyping study (PS) and 62 volunteers (age: 26.8 ± 1.2 y) from the intervention study (IS) consumed a breakfast containing 60% kcal fat (HF) and 36% kcal fat (moderately HF), respectively. For the IS, only the results from the placebo group are presented. Blood samples were probed for LPS-mediated cytokine production by incubating them with LPS inhibitor polymyxin B (PMB) for 24 h at 37°C besides the Limulus amebocyte lysate (LAL) assay. Repeated-measures ANOVA was used to compare the temporal changes of metabolic profiles and treatment outcomes.

Results: At least 87.5% of the plasma LPS measurements in 32 PS volunteers from each time point were below the LAL assay sensitivity (0.002 EU/mL). PMB suppressed IL-1β (P = 0.035) and IL-6 (P = 0.0487) production in the 3 h PPB of the PS after 24 h incubation at 37°C compared to the vehicle control, suggesting the presence of LPS. However, the amount of LPS did not increase the cytokine concentrations in the 3 h PPB above the fasting concentrations. Such suppression was not detected in the PPB of the IS. Treating whole blood with lipoprotein lipase (LPL) significantly (P < 0.05) increased FFA and cytokine (IL-1β, IL-6, TNF-α) concentrations in both studies.

Conclusion: LPS may not be the major cause of postprandial inflammation in healthy adults consuming a moderately HF meal (36% kcal fat, similar to the typical American diet) or a HF meal (60% kcal fat). Plasma FFAs may modulate postprandial inflammation. The prevailing concept of HFD-induced metabolic endotoxemia requires careful re-evaluation. The PS was registered at clinicaltrials.gov as NCT02367287 and the IS as NCT02472171.

Keywords: clinical trials; diet and dietary lipids; diet effects/lipid metabolism; high-fat diet; inflammation; lipase/lipoprotein; macrophages/monocytes; plasma cytokines; postprandial metabolic endotoxemia; toll-like receptor.

Publication types

  • Randomized Controlled Trial
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Breakfast
  • Cross-Sectional Studies
  • Cytokines / blood
  • Diet, High-Fat / adverse effects*
  • Double-Blind Method
  • Fatty Acids, Nonesterified / blood
  • Female
  • Humans
  • Inflammation / blood*
  • Inflammation / etiology*
  • Lipopolysaccharides / antagonists & inhibitors
  • Lipopolysaccharides / blood*
  • Lipoprotein Lipase / metabolism
  • Male
  • Placebos
  • Polymyxin B / pharmacology
  • Postprandial Period / physiology*


  • Cytokines
  • Fatty Acids, Nonesterified
  • Lipopolysaccharides
  • Placebos
  • Lipoprotein Lipase
  • Polymyxin B

Associated data

  • ClinicalTrials.gov/NCT02367287
  • ClinicalTrials.gov/NCT02472171