Inverse Association between the Omega-3 Index and Neutrophil-Lymphocyte Ratio: Pooled Results from Four Supplementation Trials

BACKGROUND: The omega-3 Index [O3I, erythrocyte eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) content], has been inversely correlated with neutrophil-lymphocyte ratio (NLR) and red blood cell (RBC) distribution width (RDW) in observational studies. OBJECTIVES: We evaluated the effects of omega-3 interventions (EPA+DHA) on O3I, NLR, and RDW values in healthy adults and tested the hypothesis that changes in O3I (ΔO3I) modified NLR and, separately, RDW. METHODS: We performed a de novo, individual level analysis of baseline (b) and post (p) intervention O3I, NLR and RDW values from three randomized, placebo-controlled trials and one omega-3 supplementation trial followed by an equivalent duration washout (combined n =436). Primary outcome effect estimates were obtained using linear mixed effects models with a statistical significance threshold set at 0.05. RESULTS: EPA+DHA supplementation (mean dose=1160 mg/d) increased O3I (ΔO3I =3.28%, p<0.001, n=253) whereas O3I decreased (ΔO3I= -0.62, p<0.001, n=183) in the CONTROL group. NLR decreased in individuals treated with EPA+DHA (ΔNLR=-0.15, p<0.001) vs CONTROL (-0.02, 95% CI: -0.10, 0.06), a statistically significant difference (p<0.05). In contrast, EPA+DHA supplementation was not associated with changes in RDW (p=0.62) whereas RDW increased ∼1% in CONTROL individuals (ΔRDW =0.09, p<0.01). ΔNLR values were inversely correlated with ΔO3I in unadjusted (Model 1, r=-0.08, p<0.05) and models which adjusted for baseline NLR (bNLR), age and sex (Model 2, r=-0.07, p<0.05). There was no evidence of an association between ΔO3I and ΔRDW (Model 2, r=0.003, p=0.37). CONCLUSIONS: In healthy adults, EPA+DHA increased O3I and reduced NLR. ΔO3I was inversely correlated with ΔNLR but not with ΔRDW. Further clinical trials are needed to determine if omega-3 supplementation causes biologically relevant changes in NLR, and possibly RDW, to affect clinical outcomes in individuals with elevated NLR and RDW, and their associated increased risk of morbidity and mortality.