Maternal and Neonatal Polyunsaturated Fatty Acid Intake and Risk of Neurodevelopmental Impairment in Premature Infants.

The N3 and N6 long chain polyunsaturated fatty acids (LCPUFA) docosahexaenoic acid (DHA) and arachidonic acid (AA) are essential for proper neurodevelopment in early life. These fatty acids are passed from mother to infant via the placenta, accreting into fetal tissues such as brain and adipose tissue. Placental transfer of LCPUFA is highest in the final trimester, but this transfer is abruptly severed with premature birth. As such, efforts have been made to supplement the post-natal feed of premature infants with LCPUFA to improve neurodevelopmental outcomes. This narrative review analyzes the current body of evidence pertinent to neurodevelopmental outcomes after LCPUFA supplementation in prematurely born infants, which was identified via the reference lists of systematic and narrative reviews and PubMed search engine results. This review finds that, while the evidence is weakened by heterogeneity, it may be seen that feed comprising 0.3% DHA and 0.6% AA is associated with more positive neurodevelopmental outcomes than LCPUFA-deplete feed. While no new RCTs have been performed since the most recent Cochrane meta-analysis in 2016, this narrative review provides a wider commentary; the wider effects of LCPUFA supplementation in prematurely born infants, the physiology of LCPUFA accretion into preterm tissues, and the physiological effects of LCPUFA that affect neurodevelopment. We also discuss the roles of maternal LCPUFA status as a modifiable factor affecting the risk of preterm birth and infant neurodevelopmental outcomes. To better understand the role of LCPUFAs in infant neurodevelopment, future study designs must consider absolute and relative availabilities of all LCPUFA species and incorporate the LCPUFA status of both mother and infant in pre- and postnatal periods.

Dietary fatty acids modulate cortisol concentrations and social dominance during social confrontations in adolescent male guinea pigs.

The hypothalamic-pituitary-adrenal (HPA)-axis and related glucocorticoid concentrations regulate physiology and behavior, which can be modulated by nutritional conditions, particularly by the dietary fatty acid composition. Omega-3 polyunsaturated fatty acids (PUFAs) have been shown to promote hypothalamic-pituitary-adrenal (HPA)-axis functions, whereas saturated fatty acids (SFAs) in general produce adverse effects and even increase baseline glucocorticoid concentrations. Glucocorticoids (e.g. cortisol) were further documented to modulate the establishment of dominance relationships, while the involvement of dietary fatty acids remains understudied. This study focused on different effects of PUFAs and SFAs on cortisol concentrations and social dominance in male guinea pigs. Three groups of animals were maintained on diets high in PUFAs (10 % w/w walnut oil), SFAs (10 % w/w coconut fat), or on an untreated control diet starting already prenatally. During adolescence, at an age of 60, 90, and 120 days, each individual's saliva cortisol concentrations and hierarchy index (calculated by initiated and received agonistic behavior) were measured during basal group housing conditions and stressful social confrontations with unfamiliar individuals of the other groups. SFA males showed highest baseline cortisol concentrations, lowest cortisol responses to social confrontations, and became subdominant. PUFA and control males showed significant cortisol responses. However, while control males became dominant during social confrontations, the hierarchy index in PUFA males decreased with age. Individual hierarchy indices during consecutive social confrontations revealed a high consistency. The findings presented here indicate that dietary fatty acids differently affect HPA-axis functions and social dominance but the underlying mechanisms remain to be determined.

Dynamic differences in dietary polyunsaturated fatty acid metabolism in sputum of COPD patients and controls.

INTRODUCTION: Disturbances in onset and resolution of inflammation in chronic obstructive pulmonary disease (COPD) are incompletely understood. Dietary polyunsaturated fatty acids (PUFAs) can be converted into lipid mediators here collectively named oxylipins. These include classical eicosanoids, but also pro-resolving mediators. A balanced production of pro-inflammatory and pro-resolving oxylipins is of importance for adequate inflammatory responses and subsequent return to homeostasis. OBJECTIVES: Here we investigated if PUFA metabolism is disturbed in COPD patients. METHODS: Free PUFA and oxylipin levels were measured in induced sputum samples from the Bergen COPD cohort and COPD exacerbation study using liquid chromatography-mass spectrometry. Additionally, effects of whole cigarette smoke on PUFA metabolism in air-liquid interface cultures of primary bronchial epithelial cells were assessed. RESULTS: Significantly lower levels of free alpha-linolenic acid, linoleic acid and eicosapentaenoic acid (EPA) were detected in sputum from stable COPD patients compared to controls. During acute exacerbation (AE), levels of free arachidonic acid and docosapentaenoic acid were higher than in stable COPD patients. Furthermore, levels of omega-3 EPA- and docosahexaenoic acid-derived oxylipins were lower in sputum from stable COPD patients compared to controls. Cyclooxygenase-2-converted mediators were mostly increased during AE. In vitro studies additionally showed that cigarette smoke exposure may also directly contribute to altered epithelial PUFA metabolism, and indirectly by causing airway epithelial remodelling. CONCLUSIONS: Our findings show significant differences in PUFA metabolism in COPD patients compared to controls, further changed during AE. Airway epithelial remodelling may contribute to these changes. These findings provide new insight in impaired inflammatory resolution in COPD.

Long-Chain Polyunsaturated Fatty Acids and Clinical Outcomes of Preterm Infants.

Long-chain polyunsaturated fatty acids (LCPUFAs) play specific roles during the perinatal period and are very important nutrients to consider. The possible effects of LCPUFAs, particularly docosahexaenoic acid (DHA), on various clinical outcomes of preterm infants are discussed in this paper. Since DHA accumulates in the central nervous system during development, a lot of attention has focused on the effects of DHA on neurodevelopment. Experimental studies as well as recent clinical trials show that providing larger amounts of DHA than currently and routinely provided is associated with better neurological outcomes at 18 months to 2 years. This early advantage, however, does not seem to translate into detectable change in visual and neurodevelopmental outcomes or behavior when assessed in childhood. There is growing evidence that, in addition to effects on development, omega-3 LCPUFAs may reduce the incidence or severity of neonatal morbidities by affecting different steps of the immune and anti-inflammatory response. Studies in preterm infants suggest that the omega-3 LCPUFAs may play a significant role by reducing the risk of bronchopulmonary dysplasia, necrotizing enterocolitis and possibly retinopathy of prematurity and sepsis. Overall, evidence is increasing to support the benefits of high-dose DHA for various health outcomes of preterm infants. These findings are of major clinical relevance mainly because infants born preterm are at particularly high risk for a nutritional deficit in omega-3 fatty acids, predisposing to adverse neonatal outcomes. Further studies are warranted to address these issues as well as to more precisely determine the LCPUFA requirement in order to favor the best possible outcomes of preterm infants.

Beyond building better brains: bridging the docosahexaenoic acid (DHA) gap of prematurity.

Long-chain polyunsaturated fatty acids (LCPUFA) including docosahexaenoic acid (DHA) are essential for normal vision and neurodevelopment. DHA accretion in utero occurs primarily in the last trimester of pregnancy to support rapid growth and brain development. Premature infants, born before this process is complete, are relatively deficient in this essential fatty acid. Very low birth weight (VLBW) infants remain deficient for a long period of time due to ineffective conversion from precursor fatty acids, lower fat stores and a limited nutritional provision of DHA after birth. In addition to long-term visual and neurodevelopmental risks, VLBW infants have significant morbidity and mortality from diseases specific to premature birth, including bronchopulmonary dysplasia, necrotizing enterocolitis, and retinopathy of prematurity. There is increasing evidence that DHA has protective benefits against these disease states. The aim of this article is to identify the unique needs of premature infants, review the current recommendations for LCPUFA provision in infants and discuss the caveats and innovative new ways to overcome the DHA deficiency through postnatal supplementation, with the long-term goal of improving morbidity and mortality in this at-risk population.

Lipid needs of preterm infants: updated recommendations.

Long-chain polyunsaturated fatty acids (LCPUFAs) are of nutritional interest because they are crucial for normal development of the central nervous system and have potential long-lasting effects that extend beyond the period of dietary insufficiency. Here we review the recent literature and current recommendations regarding LCPUFAs as they pertain to preterm infant nutrition. In particular, findings that relate to fetal accretion, LCPUFA absorption and metabolism, effects on development, and current practices and recommendations have been used to update recommendations for health care providers. The amounts of long-chain polyunsaturated fatty acids (LCPUFAs) used in early studies were chosen to produce the same concentrations as in term breast milk. This might not be a wise approach for preterm infants, however, particularly for very and extremely preterm infants, whose requirements for LCPUFAs and other nutrients exceed what is normally provided in the small volumes that they are able to tolerate. Recent studies have reported outcome data in preterm infants fed milk with a docosahexaenoic acid (DHA) content 2-3 times higher than the current concentration in infant formulas. Overall, these studies show that providing larger amounts of DHA supplements, especially to the smallest infants, is associated with better neurologic outcomes in early life. We emphasize that current nutritional management might not provide sufficient amounts of preformed DHA during the parenteral and enteral nutrition periods and in very preterm/very low birth weight infants until their due date, and that greater amounts than used routinely likely will be needed to compensate for intestinal malabsorption, DHA oxidation, and early deficit. Research should continue to address the gaps in knowledge and further refine adequate intake for each group of preterm infants.

Arachidonic acid and lipoxin A4 as possible endogenous anti-diabetic molecules.

In both type 1 and type 2 diabetes mellitus, increased production of pro-inflammatory cytokines and reactive oxygen species (ROS) occurs that induce apoptosis of ß cells and cause peripheral insulin resistance respectively though the degree of their increased production is higher in type 1 and less in type 2 diabetes mellitus. Despite this, the exact mechanism(s) that lead to increased production of pro-inflammatory cytokines: interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) and ROS is not known. Studies showed that plasma concentrations of arachidonic acid (AA) and lipoxin A4 (LXA4) are low in alloxan-induced type 1 diabetes mellitus in experimental animals and patients with type 2 diabetes mellitus. Prior administration of AA, eicosapentaenoic and docosahexaenoic acids (EPA and DHA, respectively) and transgenic animals that produce increased amounts of EPA and DHA acids were protected from chemical-induced diabetes mellitus that was associated with enhanced formation of LXA4 and resolvins, while protectin D1 ameliorated peripheral insulin resistance. AA, LXA4, resolvins and protectins inhibit IL-6 and TNF-α production and suppress ROS generation. Thus, AA and lipoxins, resolvins and protectins may function as endogenous anti-diabetic molecules implying that their administration could be useful in the prevention and management of both types of diabetes mellitus.

Could polyunsaturated fatty acids deficiency explain some dysfunctions found in ADHD? Hypotheses from animal research.

OBJECTIVES: The objective is to evaluate possible mechanisms explaining the link between polyunsaturated fatty acid (PUFA) deficiencies and ADHD, based on findings from animal research. METHOD: The authors consulted peer-reviewed publications from the last 10 years (Medline and resulting reference lists). RESULTS: PUFA deficiency in rodents results in behavioral changes (increased motor activity and decreased learning abilities) and dysregulations of monoamine neurotransmission. Behavioral improvement following a PUFA recovery diet is observed, but recovery of brain monoamine dysregulation is not fully demonstrated. Anti-inflammatory processes could damage neural membranes, but the direct link with ADHD model is not documented. Synaptic growth and neurogenesis impairment could account for working memory dysregulations, but research is at its early start. CONCLUSION: Induced PUFA deficiencies in animals show several noteworthy similarities with brain dysregulations seen in ADHD human children. However, the mechanisms of partial recovery after PUFA supplementation are not fully understood, and rigorous clinical trials have yet to show PUFA supplementation is an effective complementary treatment for ADHD.

Effects of prolonged breastfeeding and colostrum fatty acids on allergic manifestations and infections in infancy.

BACKGROUND: In developed countries World Health Organization recommendation of 6 months' exclusive breastfeeding is under debate. OBJECTIVE: We assessed the impact of predominant breastfeeding (PBF) duration and colostrum long-chain polyunsaturated fatty acids (LC-PUFAs) profile on the risk of allergic manifestations (wheezing and atopic eczema) and infections [low respiratory tract infections (LRTIs) and gastroenteritis] in infancy. METHODS: Information on child feeding practices was obtained from 580 infants of a pregnancy cohort. Presence of infant's health outcomes was documented through questionnaires at 6 and 14 months of age. The LC-PUFAs were measured in colostrum. Adjusted odds ratios (adjOR) and 95% confidence intervals (CI) were estimated using multivariable logistic regression models. RESULTS: In comparison with never breastfeeding, PBF for 4-6 months was associated with lower risk of wheezing (adjOR = 0.53; 95% CI, 0.32, 0.89), LRTIs (adjOR = 0.51; 95% CI, 0.31, 0.83) and atopic eczema (adjOR = 0.58; 95% CI, 0.32, 1.04) between months 7 and 14 of life. Results of a risk period-specific analysis (restricted to infants at risk for outcome onset after 6 months of age), showed no indication for reverse causation (results were not very different compared with an overall analysis). Predominantly breastfeeding for 4-6 months was associated with lower risk of gastroenteritis during the first 6 months of life (adjOR = 0.34; 95% CI, 0.18, 0.64). Among breastfed infants higher doses of arachidonic acid (AA), docosahexaenoic acid, and total n-3 in were associated with a decreased risk of gastroenteritis, but no association was found for allergic manifestations or LRTI. CONCLUSIONS AND CLINICAL RELEVANCE: Promotion of PBF for 4-6 months could reduce the burden of allergic manifestations and infections in infancy. Beneficial effects of breastfeeding on gastroenteritis were explained in part by exposure to higher doses of n-3 and AA received from colostrum. No significant effects from fatty acid dose were found on risk of allergic manifestations or LRTIs.

The potential of dietary polyunsaturated fatty acids to modulate eicosanoid synthesis and reproduction in Daphnia magna: a gene expression approach.

Nutritional ecology of the aquatic model genus Daphnia has received much attention in past years in particular with regard to dietary polyunsaturated fatty acids (PUFAs) which are crucial for growth and reproduction. Besides their significant role as membrane components, C20 PUFAs serve as precursors for eicosanoids, hormone-like mediators of reproduction, immunity and ion transport physiology. In the present study we investigate transcriptomic changes in Daphnia magna in response to different algal food organisms substantially differing in their PUFA composition using quantitative real-time PCR and relate them to concomitantly documented life history data. The selection of target genes includes representatives that have previously been shown to be responsive to the eicosanoid biosynthesis inhibitor ibuprofen. The beneficial effect of C20 PUFA-rich food on reproduction and population growth rates was accompanied by an increased vitellogenin (DmagVtg1) gene expression in D. magna. Additionally, genes involved in eicosanoid signaling were particularly influenced by dietary C20 PUFA availability. For example, the cyclooxygenase gene (Cox), coding for a central enzyme in the eicosanoid pathway, was highly responsive to the food treatments. Our results suggest that dietary PUFAs are fundamental in D. magna physiology as substrate for eicosanoid synthesis and that these eicosanoids are important for D. magna reproduction.

Polyunsaturated fatty acid intake and blood pressure in adolescents.

Evidence that intake of polyunsaturated fatty acids (PUFAs) may modify blood pressure (BP) is generally limited to middle-aged or hypertensive populations. This study examined cross-sectional associations between BP and dietary intake of PUFAs in 814 adolescents aged 13-15 years participating in the Western Australian Pregnancy Cohort (Raine) Study. Fatty acid intakes were assessed using 3-day diet records and resting BP was determined using multiple oscillometric readings. In multivariate regression models, systolic BP was inversely associated with intakes of polyunsaturated (b=-0.436, P<0.01), omega-3 (b=-2.47, P=0.02), omega-6 (b=-0.362, P=0.04) and long chain omega-3 fatty acids (b=-4.37, P=0.04) in boys. Diastolic BP and mean arterial pressure were inversely associated with intakes of long chain omega-3 fatty acids in boys (b=-3.93, P=0.01, b=-4.05, P=0.01, respectively). For specific long-chain omega-3s, significant inverse associations were observed between eicosapentaenoic acid (EPA) and docosahexaenoic acid, such as systolic BP decreasing by 4.7 mm Hg (95% CI -9.3 to -0.1) for a quarter gram increase in EPA, but no significant associations were observed with docosapentaenoic acid. No significant associations were observed in girls, or with the omega-6 to omega-3 ratio. Our results suggest that gender may moderate relationships between fatty acid intake and BP in adolescence.

Role of ω3 long-chain polyunsaturated fatty acids in reducing cardio-metabolic risk factors.

Cardiovascular disease is the leading cause of mortality in many economically developed nations, and its incidence is increasing at a rapid rate in emerging economies. Diet and lifestyle issues are closely associated with a myriad of cardiovascular disease risk factors including abnormal plasma lipids, hypertension, insulin resistance, diabetes and obesity, suggesting that diet-based approaches may be of benefit. Omega-3 longchain-polyunsaturated fatty acids (ω3 LC-PUFA) are increasingly being used in the prevention and management of several cardiovascular risk factors. Both the ω3 and ω6 PUFA families are considered essential, as the human body is itself unable to synthesize them. The conversion of the two precursor fatty acids - linoleic acid (18:2ω6) and α-linoleic acid (α18:3ω3) - of these two pathways to longer (≥C(20)) PUFA is inefficient. Although there is an abundance of ω6 PUFA in the food supply; in many populations the relative intake of ω3 LC-PUFA is low with health authorities advocating increased consumption. Fish oil, rich in eicosapentaenoic (EPA, 20:5ω3) and docosahexaenoic (DHA, 22:6ω3) acids, has been found to cause a modest reduction in blood pressure at a dose level of >3g/d both in untreated and treated hypertensives. Whilst a multitude of mechanisms may contribute to the blood pressure lowering action of ω3 LC-PUFA, improved vascular endothelial cell function appears to play a central role. Recent studies which evaluated the potential benefits of fish oil in type-2 diabetes have helped to alleviate concerns raised in some previous studies which used relatively large dose (5-8 g/d) and reported a worsening of glycemic control. Several meta-analyses have confirmed that the most consistent action of ω3 LC-PUFA in insulin resistance and type-2 diabetes is the reduction in triglycerides. In some studies, fish oil has been found to cause a small rise in LDL-cholesterol, but a change in the LDL particle size, from the smaller more atherogenic form to the larger, less damaging particle size, have also been noted. ω3 LC-PUFA are effective modulators of the inflammation that accompanies several cardio-metabolic abnormalities. Taking into consideration the pleiotropic nature of their actions, it can be concluded that dietary supplementation with ω3 LC-PUFA will lead to improvements in cardio-metabolic health parameters. These fatty acids pose only minor side effects and more importantly, do not interact adversely with the common drug therapies used in the management and treatment of hypertension, dyslipidemia, type-2 diabetes, and obesity/metabolic syndrome, but in some instances work synergistically, thereby providing additional cardiovascular benefits.

Stress, food, and inflammation: psychoneuroimmunology and nutrition at the cutting edge.

Inflammation is the common link among the leading causes of death. Mechanistic studies have shown how various dietary components can modulate key pathways to inflammation, including sympathetic activity, oxidative stress, transcription factor nuclear factor-kappaB activation, and proinflammatory cytokine production. Behavioral studies have demonstrated that stressful events and depression can also influence inflammation through these same processes. If the joint contributions of diet and behavior to inflammation were simply additive, they would be important. However, several far more intriguing interactive possibilities are discussed: stress influences food choices; stress can enhance maladaptive metabolic responses to unhealthy meals; and diet can affect mood as well as proinflammatory responses to stressors. Furthermore, because the vagus nerve innervates tissues involved in the digestion, absorption, and metabolism of nutrients, vagal activation can directly and profoundly influence metabolic responses to food, as well as inflammation; in turn, both depression and stress have well-documented negative effects on vagal activation, contributing to the lively interplay between the brain and the gut. As one example, omega-3 fatty acid intake can boost mood and vagal tone, dampen nuclear factor-kappaB activation and responses to endotoxin, and modulate the magnitude of inflammatory responses to stressors. A better understanding of how stressors, negative emotions, and unhealthy meals work together to enhance inflammation will benefit behavioral and nutritional research, as well as the broader biomedical community.

Nutritional issues in treating phenylketonuria.

A phenylalanine (Phe)-restricted diet is the mainstay of phenylketonuria (PKU) treatment, and, in recent years, the nutritional management of PKU has become more complex in order to optimize patients' growth, development and diet compliance. Dietary restriction of Phe creates a diet similar to a vegan diet, and many of the nutritional concerns and questions applicable to vegans who wish to avoid animal products are also relevant to patients with PKU. Owing to their nutritional characteristics, breast milk and breastfeeding should be given greater consideration as a useful food in patients with PKU and in those with other inborn errors of metabolism. Further key issues for consideration include the quality of the available amino acid substitutes, the neurotrophic and neuroprotective effects of added long-chain polyunsaturated fatty acids (e.g. docosahexaenoic acid), micronutrient deficiencies, bone disease and antioxidant status. Long-term dietary guidance and monitoring of the nutritional status of patients with PKU should be part of a follow-up programme that continues for life.

Long-chain polyunsaturated fatty acids stimulate cellular fatty acid uptake in human placental choriocarcinoma (BeWo) cells.

Supplementation of long-chain polyunsaturated fatty acids (LCPUFAs) is advocated during pregnancy in some countries although very little information is available on their effects on placental ability to take up these fatty acids for fetal supply to which the fetal growth and development are critically dependent. To identify the roles of LCPUFAs on placental fatty acid transport function, we examined the effects of LCPUFAs on the uptake of fatty acids and expression of fatty acid transport/metabolic genes using placental trophoblast cells (BeWo). Following 24 h incubation of these cells with 100 microM of LCPUFAs (arachidonic acid, 20:4n-6, eicosapentaenoic acid, 20:5n-3, or docosahexaenoic acid, 22:6n-3), the cellular uptake of [(14)C] fatty acids was increased by 20-50%, and accumulated fatty acids were preferentially incorporated into phospholipid fractions. Oleic acid (OA, 18:1n-9), on the other hand, could not stimulate fatty acid uptake. LCPUFAs and OA increased the gene expression of ADRP whilst decreased the expression of ACSL3, ACSL4, ACSL6, LPIN1, and FABP3 in these cells. However, LCPUFAs but not OA increased expression of ACSL1 and ACSL5. Since acyl-CoA synthetases are involved in cellular uptake of fatty acids via activation for their channelling to lipid metabolism and/or for storage, the increased expression of ACSL1 and ACLS5 by LCPUFAs may be responsible for the increased fatty acid uptake. These findings demonstrate that LCPUFA may function as an important regulator of general fatty acid uptake in trophoblast cells and may thus have impact on fetal growth and development.

The role of fatty acids in the treatment of ADHD.

Several arguments have been proposed to support the hypothesis that supplementation with essential fatty acids (EFAs) could be valuable in the treatment of attention deficit-hyperactivity disorder (ADHD). Indeed, this disorder seems to involve the monoaminergic systems which have been shown to be affected by polyunsaturated fatty acid (PUFA) status, at least in animal models. In addition, several studies have reported abnormal nutritional status with regard to EFAs in ADHD, indicating that lower levels of long-chain PUFAs occur more frequently in the plasma and/or red blood cells of ADHD subjects. Few nutritional EFA supplementation studies have been reported in ADHD to date, but several of them have shown increased blood EFA levels, although their effects on ADHD-related symptoms were not or were only partly successful. The current findings have not yet been clearly proved and require further investigation.