To better understand how docosahexaenoic acid (DHA) improves the effects of doxorubicin (DOX), we examined DHA AE DOX on changes in whole cell and lipid raft phospholipids (PL) of MDA-MB-231 and MCF-7 breast cancer cells. We sought to confirm whether the relative changes in PL DHA content of MDA-MB-231 cells could be extended to PL from MDA-MB-231 tumors grown in mice fed a DHA supplemented diet AEDOX. Treatment with DHA did not change PL composition yet DOX increased the proportion of phosphatidylserine in MCF-7 cell lipid rafts by twofold (p < 0.001). Regardless of DOX, the relative percent incorporation of DHA was higher in MDA-MB-231 cells compared to MCF-7 cells in phosphatidylserine, phosphatidylethanolamine, and phosphatidylcholine (whole cell and lipid rafts); and higher in phosphatidylethanolamine vs. phosphatidylcholine (4.4-fold in MCF-7 and 6-fold in MDA-MB-231 cells respectively). DHA treatment increased eicosapentaenoic acid and docosapentaenoic acid in MDA-MB-231 cells but not MCF-7 cells. Increased DHA content in MDA-MB-231 cells, MCF-7 cells, and MDA-MB-231 tumors in all PL moieties (except sphingomyelin) corresponded with reduced arachidonic acid (p < 0.05). Feeding mice 2.8% (w/w of fat) DHA AE DOX increased tumor necrotic regions

Background A T helper type-2 (Th2) skewed immune response is associated with food allergies. Docosahexaenoic (DHA) and arachidonic acid (ARA) have been shown to promote oral tolerance (OT) in healthy rodents. Objectives To study the effect of combined ARA + DHA supplementation during suckling and weaning period on OT and immune system development in Th2 skewed Brown Norway rat offspring. Methods Dams were fed ARA + DHA (0.45% ARA, 0.8% DHA w/w of total fat; n = 10) as suckling period diet (SPD) or control SPD (0% ARA, 0% DHA, n = 8). At 3-weeks, offspring from each SPD groups received ARA + DHA (0.5% ARA, 0.5% DHA w/w of total fat) weaning diet (WD) or control until 8 weeks. For OT, offspring were orally exposed to either, ovalbumin (Ova) or placebo between 21–25 days followed by systemic immunization with Ova + adjuvant at 7-week. Primary outcomes, ex-vivo cytokine production by splenocytes and plasma Ova-specific-immunoglobulins, were analysed using a 3-way ANOVA. Results At 8-week, despite no lasting effect of SPD on splenocytes fatty acids, ARA + DHA WD resulted in 2x higher DHA in splenocyte phospholipid compositions without affecting ARA. OT development was observed in Ova exposed groups with 15% lower plasma Ova-IgE (P = 0.04) and 35% lower Ova-IgG1 (P = 0.01) than placebo. ARA + DHA SPD resulted in 35% lower Ova-IgG1 and interleukin-6 (P = 0.04) when stimulated with lipopolysaccharide, and a higher proportion of mature B cells (OX12+, P = 0.0004 and IgG+, P = 0.008). ARA + DHA WD resulted in 20% higher Th1 cytokines (Tumor-necrosis-factor-α and interferon-γ) production to lymphocyte stimulant and higher splenocyte proportion of CD45RA+ (pan-B cells) and OX6+ (dendritic cells) than control WD (P’s &lt; 0.05). Conclusions Combined supplementation of ARA and DHA is beneficial for the OT development, especially in the suckling period. Further, ARA + DHA supplementation can also counteract the Th2 skewed immunity of Brown Norway offspring through higher Th1 cytokines production by lymphocytes.

Background Long-chain n–3 PUFAs (LCPUFAs) improve immune development and reduce atopic disease risk in infants. Stearidonic acid (SDA) can be a substrate for biosynthesis of n–3 LCPUFAs. Objective We aimed to determine the effect of feeding an SDA-enriched diet during suckling and weaning on offspring immunity and ability to develop oral tolerance (OT). Methods Pregnant Sprague-Dawley rats were randomly assigned to consume either SDA (3 g SDA/100 g fat) or a control (no SDA) diet, 5 d before parturition and through lactation (21 d). For the OT treatment, 10-d-old pups were fed ovalbumin (Ova; 200 μL of 8 mg/mL) or placebo daily for 5 d. At 21 d, pups (both sexes) were weaned to their respective maternal diet until 6 wk of age or killed. Systemic immunization was induced using Ova (in 3-wk-old pups) or Ova + adjuvant (in 6-wk-old pups). The effect of suckling diet (in 3-wk-old pups) or weaning diet (in 6-wk-old pups) and OT treatment on immune function (main outcome) in spleen and blood was compared using 2-factor ANOVA. Results An SDA-enriched maternal diet, compared with the control diet, resulted in higher plasma phospholipid (PL) EPA (15 times higher), docosapentaenoic acid (DPA; 3 times higher), and DHA (1.3 times higher) content in 3-wk-old pups, accompanied by higher B-cell function [plasma ovalbumin-specific IgG1 (Ova-IgG1), 2 times higher] ( P &lt; 0.05). Compared with pups fed a control diet, the splenocytes from these pups had more (23%) helper T (Th) cells (CD3+CD4+) and activated (12%) Th cells (CD4+CD28+) (P &lt; 0.02) than controls. At 6 wk, the SDA group had 30% more CD4+CD25+ splenocytes, and when stimulated ex vivo with LPS, produced less inflammatory IL-6 (50%) and TNF-α (30%) and more immunoregulatory IL-10 (45%) cytokines (P &lt; 0.05) than the control group. The Ova-exposed group had less (30%) plasma Ova-IgG1 than the placebo group. Splenocytes and plasma PLs from the 6-wk-old SDA group had more EPA (2x) and DPA (3.5x) (P &lt; 0.05), but not DHA, than the control group. Conclusions Feeding SDA during lactation and weaning altered immune responses in directions believed to be beneficial.

The immune system requires an adequate supply of nutrients, although current dietary recommendations may not account for optimal immune function in healthy adults. Nutrient inadequacies due to the growing influence of the western diet pose a risk for immune dysfunction. This review aims to determine the beneficial effects of supplementing: dietary fats, nutrients that modulate gut microbiota, and specific micronutrients, on systemic immune functions (concentrations of plasma cytokines, antibodies and acute phase proteins) during health and acute inflammatory conditions, including COVID-19. We discussed micronutrients (selenium, zinc and vitamin D) with compelling evidence supporting immunomodulatory properties. Additionally, the synergistic effects of physical activity and dietary interventions on systemic immune markers are explored. Briefly, evidence suggests that dietary consumption of monounsaturated (oleic and palmitoleic acids) and omega-3 polyunsaturated fatty acids (eicosapentaenoic and docosahexaenoic acids) promotes anti-inflammatory properties. Food sources (fiber, prebiotics, probiotics, omega-3) and patterns (Mediterranean diet) increase the production of short-chain fatty acids, beneficially altering gut microbiota composition, which subsequently enhances the immunomodulatory properties of circulating immune cells. A positive synergistic role of nutrient supplementation (omega-3 and fiber) and physical activity on circulating C-reactive protein and interleukin-6 levels have been observed. Lastly, omega-3 supplementation during COVID-19 infection may reduce circulating C-reactive protein and pro-inflammatory cytokines and improves pain and fatigue symptoms. This review highlights recent findings that support the beneficial role of specific nutrients in promoting systemic immune function in healthy adults. However, to establish specific dietary recommendations to support optimal immune function, more research is required.

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