Omega‐3 PUFA supplementation and the response to evoked endotoxemia in healthy volunteers

Abstract

Scope Fish oil-derived n-3 PUFA may improve cardiometabolic health through modulation of innate immunity; however, findings in clinical studies are conflicting. We hypothesized that n-3 PUFA supplementation would dose-dependently reduce the systemic inflammatory response to experimental endotoxemia in healthy humans. Methods and Results The Fenofibrate and omega-3 Fatty Acid Modulation of Endotoxemia (FFAME) study was an 8-week randomized double-blind trial of placebo or n-3 PUFA supplementation (Lovaza 465mg EPA + 375mg DHA) at “low” (1/day, 900mg) or “high” (4/day, 3,600mg) dose in healthy individuals (N=60; age 18–45; BMI 18–30; 43% Female; 65% European-, 20% African-, 15% Asian-ancestry) before a low-dose endotoxin challenge (LPS 0.6ng/kg intravenous bolus). The endotoxemia-induced temperature increase was significantly reduced with high-dose (P =0.03) but not low-dose EPA+DHA compared to placebo. Although there was no statistically significant impact of EPA+DHA on individual inflammatory responses (TNFα, IL-6, MCP-1, IL-1RA, IL-10, CRP, SAA), there was a pattern of lower responses across all biomarkers with high-dose (9 of 9 observed), but not low-dose EPA+DHA. Conclusions EPA+DHA at 3,600mg/day, but not 900mg/day, reduced fever and had a pattern of attenuated LPS-induction of plasma inflammatory markers during endotoxemia. Clinically and nutritionally relevant long-chain n-3 PUFA regimens may have specific, dose-dependent, anti-inflammatory actions.

Bioactive products formed in humans from fish oils

“…The RBCs were added to an internal standard (dried using nitrogen gas) containing labeled fatty acids (d 8 at Ϫ 80°C until extraction. For the study Evoked Endotoxemia , RBCs were obtained from venous blood as described in ( 38 ).…”

“…Details on the analysis of the panel of infl ammatory responses to the administration of LPS, consisting of TNF-␣ , interleukin (IL)-6, IL-10, IL-1-receptor antagonist (RA), monocyte chemoattractant protein-1 (MCP-1), C-reactive protein (CRP), and serum amyloid A (SAA), have been published in ( 38 ).…”

“…Plasma samples were also available from a subset of healthy volunteers (n = 6), studied to evaluate the systemic infl ammatory response to experimental endotoxemia in subjects treated with lower doses of marine lipids delivered as Lovaza fi sh oil; please refer to ( 38 ) for further details (clinicaltrials.gov registration number: NCT01048502). In brief, this group of subjects was randomized to receive two capsules Lovaza TM twice a day (bid) for 8 weeks in a double-blinded fashion, followed by an intravenous bolus of US standard reference endotoxin (LPS; lot number CCRE-LOT-1 +2; Clinical Center, Pharmacy Department at the National Institutes of Health, Bethesda, MD) dosed at 0.6 ng/kg body weight ( Fig.…”

Characterization of inflammation and immune cell modulation induced by low-dose LPS administration to healthy volunteers

“…However, an endotoxemia model applying such relatively high LPS doses is not preferred as methodological tool in clinical pharmacology studies since the elicited immune response is so strong that potential effects of immune-modulating interventions may not be observed, other homeostatic mechanisms may be temporarily impaired, and, importantly, the elicited immune response at these LPS doses is not free of risk for the volunteer. Studies applying lower LPS doses have been performed [9,10], but thorough characterization of a human endotoxemia model at lower LPS dose levels is desired. In the current study, 0.5 ng/kg was selected as the lowest LPS dose to be administered intravenously because an LPS dose of 0.2 ng/kg was shown previously to elicit no cytokine response in vivo [11].…”

N-3 PUFAs and neuroinflammatory processes in cognitive disorders

“…However, even if most of randomized trials with LC n-3 PUFAs have reported consistent decreased inflammation in groups with high baseline inflammation (stressed students, elderly, diabetics, and hypertriglyceridemic subjects), results are mixed (Fritsche, 2006). Indeed, DHA/EPA dietary supplementation in healthy subjects blunted the endocrine stress response and the increase in body temperature, with or without impact on cytokine production after bacterial endotoxin administration (Ferguson et al, 2014;Michaeli et al, 2007). AD patients supplemented with a DHA-rich diet display reduced release of proinflammatory cytokines (IL-1β, IL-6, GM-CSF) from stimulated peripheral blood mononuclear cells (Vedin et al, 2008).…”