Evaluating the effects of dietary docosahexaenoic acid along with arachidonic acid during the development of the immune system in early life.

• Author / Creator

  Patel, Dhruvesh B

• The immune system is immature at birth and the dietary fats provided during early life play an important role in the development of the infant’s immune system. The precursor omega-3 (n-3) and n-6 polyunsaturated fatty acids (PUFAs) α-linolenic acid and linoleic acids, respectively, are essential for our body. The bioconversion of precursors into long-chain PUFA (LCPUFA), docosahexaenoic (DHA, n-3) and arachidonic acids (ARA, n-6) is ineffective. Therefore, dietary supply of LCPUFAs is vital. It is hypothesized that the immunomodulatory properties of LCPUFAs can influence the development of immune system during early life. Evidence suggests that infants with high n-3 LCPUFA status are less likely to develop atopic conditions such as asthma and food allergies. In infants with genetic predispositions to developing food allergies, a T-helper-type-2 (Th2) skewed condition, supplementation of fish oil (containing DHA) has been reported to reduce allergen-specific immunoglobulin-(Ig) response associated with food allergies. The specific suppression of immune response is known as oral tolerance (OT). However, the effect of DHA supplementation, along with ARA, on the development of the infant immune system has not been fully elucidated. Thus, this thesis aims to understand the essentiality of dietary LCPUFAs in the development of the immune system and oral tolerance in healthy and allergy-prone conditions using pre-clinical rodent models during early life.
  We conducted a series of animal experiments to study the effects of LCPUFAs supplementation during early life (suckling and/or weaning period) on the development of the immune system and OT in rodent offspring. OT was induced using repetitive oral exposure to ovalbumin (ova) followed by systemic challenge with ova and adjuvant. First, using a healthy Sprague Dawley rat model, we determine the effect of feeding stearidonic acid (SDA)-enriched diet (3% of total fat) on the LCPUFA status and immune functions in dams and offspring after suckling and weaning. During lactation, supplementing the maternal diet with SDA increased the breastmilk levels of n-3 LCPUFAs (eicosapentaenoic (EPA) and docosapentaenoic acid (DPA) and DHA). Providing an SDA-diet during suckling and weaning only increased the splenocyte phospholipid levels of EPA and DPA while DHA and ARA showed no difference. In 6-week-old offspring supplemented with SDA-diet, lower levels of inflammatory cytokines; interleukin(IL)-6 and tumor necrosis factor-alpha (TNF-α), and higher anti-inflammatory cytokine (IL-10) were seen in splenocytes stimulated with lipopolysaccharide (LPS) ex-vivo than the control group (all P’s < 0.05). Therefore, SDA may have increased in-vivo biosynthesis of EPA and DHA but not DHA, which could have promoted an anti-inflammatory effect in 6-week offspring.
  Next, we used allergy-prone rodent models to evaluate the effects of LCPUFAs, DHA and ARA on the development of the immune system and OT. Using Brown Norway rat offspring, we showed that dietary DHA (0.8% in suckling and 0.5% in weaning period) alongside ARA (0.5% in suckling and weaning), promoted OT development (35% lower plasma ovalbumin (ova)-specific-IgG, P = 0.04) in the offspring fed DHA+ARA-diet compared to control. More importantly, DHA+ARA during weaning promoted higher Th1 specific cytokines (TNF-α and interferon(IFN)-γ) by splenocytes stimulated with phorbol-myristate-acetate and ionomycin (PMAi, non-specific lymphocyte stimulant), compared to control group. Further, DHA+ARA during weaning was associated with a higher proportion of adaptive immune cells such as OX12+ and IgG+ B-cells in the spleen.
  We then used suckling and weaning diets supplemented with DHA (derived from a plant-based source) and ARA (1% of total fat each) to study the immune system and OT development using another allergy-prone model, BALB/c mouse. Feeding lactating dams DHA+ARA showed an increase in breast milk DHA level (60%, P<0.001). In pups (3-wk and 6-wk), DHA+ARA increased the splenocyte level of DHA without affecting ARA. Suckling period supplementation showed higher inflammatory cytokines (IL-1β, IFN-γ and TNF-α) production by LPS-stimulated splenocytes from 3-week offspring in comparison to controls. Furthermore, DHA+ARA resulted in higher T-cell cytokines (IL-2, IFN-γ and IL-1β) upon stimulation with anti-CD3/anti-CD28 and lower inflammatory-response by LPS-stimulated splenocytes. Last, DHA+ARA during weaning resulted in lower Th2 cytokines (IL-4 and IL-6) by ova-stimulated splenocytes and plasma levels of ova-IgE compared to the control, which may be beneficial for OT.
  Overall, we showed that dietary supplementation of n-3 and n-6 LCPUFAs during early life can positively modulate the development of the immune system and OT in neonates prone to developing allergies. 

• Subjects / Keywords

  • Docosahexaenoic acid
  • Arachidonic acid
  • Infant immune system
  • omega-3
  • omega-6

• Graduation date

  Spring 2023

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-k4ak-cg88

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.