Omega-3 Fatty Acid Deficiency Research Articles

Correction of omega-3 fatty acid deficiency and improvement in disease activity in patients with systemic lupus erythematosus treated with krill oil concentrate: a multicentre, randomised, double-blind, placebo-controlled trial

ObjectiveOmega-3 polyunsaturated fatty acids (PUFAs) play a critical role in regulating inflammation and lipid metabolism. This study sought to ascertain the frequency of omega-3 deficiency in patients with SLE and...

Nutritional Status of Breastfeeding Mothers and Impact of Diet and Dietary Supplementation: A Narrative Review.

Adequate nutrition during breastfeeding is crucial for ensuring the good health of mothers and babies. Despite the high energy and nutrient demands of breastfeeding, lactating women are often vulnerable from a nutritional perspective. The nutritional focus during breastfeeding tends to be on the newborn, often neglecting the mother's diet. Therefore, in the present narrative review, nutrient intakes were compared with the dietary reference values (DRVs) proposed by the European Food Safety Authority (EFSA) as well as by the World Health Organization/Food and Agriculture Organization (WHO/FAO). In the diets of lactating mothers, dietary inadequacies were observed in the intake of some vitamins, such as folic acid, vitamin B12, vitamin A, and vitamin D, and in the intake of certain minerals like calcium, iron, and iodine; polyunsaturated omega-3 fatty acid deficiencies, primarily in eicosapentaenoic acid and docosahexaenoic acid, were also observed. On the other hand, the debate on the necessity of supplementation during lactation continues; the need for nutritional supplementation during lactation depends on many factors, such us mothers' eating habits. There seems to be a positive association between nutritional supplementation of the lactating mother and the concentration of certain nutrients in human milk. The present narrative review provides an update on the nutritional status (fatty acids and micronutrients) of breastfeeding mothers and the impact of diet and dietary supplementation on human milk composition.

Determination of eicosapentaenoic acid and docosahexaenoic acid contents and the oxidation level of fish oil supplements from Bahrain market

Eicosapentaenoic acid and docosahexaenoic acid are two types of omega-3 fatty acids that provide numerous health benefits. It is thus important to gain the recommended daily intake of eicosapentaenoic acid and docosahexaenoic acid and compensate for omega-3 deficiency through supplements. However, supplements are very susceptible to oxidation, which affects their biological significance. This study aimed to examine the quality of fourteen different commercially available fish oil supplements in Bahrain markets by comparing their actual and labelled Eicosapentaenoic acid and docosahexaenoic acid contents, determination of their oxidation levels by measuring the peroxide value, anisidine value, and the total oxidation value. Fish oils were methylated, separated, and identified by Gas Chromatography. Measurement of peroxide value was conducted using titration, and the anisidine value using spectrophotometry. The total oxidation value was calculated based on anisidine value and peroxide value values. Results showed that most brands have lower actual total fish oil per capsule than the labelled values. Only two brands (14.29%) showed an approximately similar amount of Eicosapentaenoic acid and docosahexaenoic acid, whereas six brands (42.86%) have a lower actual amount of both Eicosapentaenoic acid and docosahexaenoic acid. In addition, five brands (35.71%) have higher actual EPA and lower DHA values. Only one brand has higher actual amounts of both Eicosapentaenoic acid and docosahexaenoic acid. The results also showed that 57.1% of the tested supplements (8 out of 14) exceeded the recommended levels of peroxide value, while only one brand (7.14%) exceeded the safe levels of anisidine value. Moreover, five brands (35.71%) recorded a total oxidation value level higher than the recommended. Compared to other studies in several countries, the oxidative levels of supplements in Bahrain are not very high; nonetheless, it must be improved by applying oxidation levels regulations and storage regulations regarding fish oil supplements.

Amphetamine-Related Fatalities and Altered Brain Chemicals: A Preliminary Investigation Using the Comparative Toxicogenomic Database.

Amphetamine is a psychostimulant drug with a high risk of toxicity and death when misused. Abuse of amphetamines is associated with an altered organic profile, which includes omega fatty acids. Low omega fatty acid levels are linked to mental disorders. Using the Comparative Toxicogenomic Database (CTD), we investigated the chemical profile of the brain in amphetamine-related fatalities and the possibility of neurotoxicity. We classified amphetamine cases as low (0-0.5 g/mL), medium (>0.5 to 1.5 g/mL), and high (>1.5 g/mL), based on amphetamine levels in brain samples. All three groups shared 1-octadecene, 1-tridecene, 2,4-di-tert-butylphenol, arachidonic acid (AA), docosahexaenoic acid (DHA), eicosane, and oleylamide. We identified chemical-disease associations using the CTD tools and predicted an association between DHA, AA and curated conditions like autistic disorder, disorders related to cocaine, Alzheimer's disease, and cognitive dysfunction. An amphetamine challenge may cause neurotoxicity in the human brain due to a decrease in omega-3 fatty acids and an increase in oxidative products. Therefore, in cases of amphetamine toxicity, a supplement therapy may be needed to prevent omega-3 fatty acid deficiency.

Dietary omega-3 fatty acid deficiency from pre-pregnancy to lactation affects expression of genes involved in hippocampal neurogenesis of the offspring

Maternal n-3 PUFA (omega-3) deficiency can affect brain development in utero and postnatally. Despite the evidence, the impacts of n-3 PUFA deficiency on the expression of neurogenesis genes in the postnatal hippocampus remained elusive. Since postnatal brain development requires PUFAs via breast milk, we examined the fatty acid composition of breast milk and hippocampal expression of neurogenesis genes in n-3 PUFA deficient 21d mice. In addition, the expression of fatty acid desaturases, elongases, free fatty acids signaling receptors, insulin and leptin, and glucose transporters were measured. Among the genes involved in neurogenesis, the expression of brain-specific tenascin-R (TNR) was downregulated to a greater extent (∼31 fold), followed by adenosine A2A receptor (A2AAR), dopamine receptor D2 (DRD2), glial cell line-derived neurotrophic factor (GDNF) expression in the n-3 PUFA deficient hippocampus. Increasing dietary LA to ALA (50:1) elevated the ARA to DHA ratio by ∼8 fold in the n-3 PUFA deficient breast milk, with an overall increase of total n-6/n-3 PUFAs by ∼15:1 (p<0.05) compared to n-3 PUFA sufficient (LA to ALA: 2:1) diet. The n-3 PUFA deficient mice exhibited upregulation of FADS1, FADS2, ELOVL2, ELOVL5, ELOVL6, GPR40, GPR120, LEPR, IGF1 and downregulation of GLUT1, GLUT3, and GLUT4 mRNA expression in hippocampus (p<0.05). Maternal n-3 PUFA deficiency affects the hippocampal expression of key neurogenesis genes in the offspring with concomitant expression of desaturase and elongase genes, suggesting the importance of dietary n-3 PUFA for neurodevelopment.

Effects of Omega-3 Intake on Adolescent Health

The phrase "omega-3" refers to a group of polyunsaturated fatty acids that are essential for both physical growth and illness prevention. According to relevant scientific research, Omega-3 has a certain effect on puberty, its role is very important, and it may cover most of the characteristics of puberty. Through research, omega-3 intake has a profound impact on all aspects of adolescents, and most adolescents are deficient in omega-3. This article compares the various impacts of omega-3 on the human body and analyzes the physiological and psychological functions of omega-3 intake about adolescents, and the possible effects of insufficient intake on adolescents' bodies, so as to summarize the diseases that may be caused by omega-3 deficiency and its harmful effects on physical health. In general, Omega-3 has huge potential nutritional value, and its potential academic value has also received high attention from all walks of life. Its popularity is likely to continue to rise in the future, and it will have a broader market in the field of youth health care products.

Effects and Reversibility of Pre- and Post-natal Iron and Omega-3 Fatty Acid Deficiency, Alone and in Combination, on Bone Development in Rats.

Both iron and omega-3 (n-3) polyunsaturated fatty acids may play an important role in bone development. The aim of this study was to investigate the effects of pre- and post-natal iron and n-3 fatty acid deficiency (FAD), alone and in combination, on bone development in rats, and to determine whether effects are reversible when a sufficient diet is provided post-weaning. Using a 2×2-factorial design, 56 female Wistar rats were allocated to one of four diets: (1) control, (2) iron deficient (ID), (3) n-3 FAD or (4) ID and n-3 FAD, and were maintained on the respective diets throughout gestation and lactation. At weaning (post-natal day [PND] 21), offspring (n = 24/group; male:female=1:1) were randomly allocated to either continue with their respective diets or to switch to the control diet until PND 42-45. Bone mineral density (BMD) and bone strength were determined using dual X-ray absorptiometry and three-point bending tests, respectively. Pre- and post-natal ID resulted in significantly lower BMD in the spine and bone strength in the left femur. Both ID and n-3 FAD resulted in lower BMD in the right femur, with an additive reduction in the combined ID and n-3 FAD group vs. controls. While negative effects of pre- and post-natal ID alone were reversed in offspring switched to a control diet post-weaning, lower BMD and bone strength persisted in offspring with combined ID and n-3 FAD during the prenatal and early post-natal period. Effects were not sex-specific. These results indicate that ID during early life may negatively influence bone development, with potential additive effects of n-3 FAD. While the effects of ID alone seem reversible, a combined ID and n-3 FAD may result in irreversible deficits in bone development.

The structure of nutrition of Russian students as a risk factor for the development of nutritional diseases

The paper analyzes the literature data on the peculiarities of nutrition of students studying in higher educational institutions of various regions of Russia, and the risks of developing food-related diseases. They are largely associated with the adaptation of students to study at a university, the lack of self-organization skills and a lack of knowledge in matters of rational nutrition. The actual nutrition of students, on the one hand, is characterized by a lack of macronutrients and micronutrients intake, on the other hand, by excessive consumption of substances that contribute to the development of obesity. The results of numerous studies show a general pattern of unbalanced nutrition of students in terms of the ratio of saturated and polyunsaturated fatty acids, insufficient consumption of dietary fiber, full-fledged proteins, and excessive intake of simple carbohydrates. Dietary fiber deficiency can lead to changes in the composition of the microbiocenosis of the digestive tract, a deficiency of omega-3 fatty acids, and consequently, the imbalance of fatty acid composition of the blood cell membrane. 20–40 % of Russian students show signs of severe hypovitaminosis, especially calciferol, which is caused not only by its deficiency in the diet, but also by physical, geographical, climatic and seasonal factors. The analysis of the content of the main minerals in students shows a sufficient content of calcium in the body, an excess of sodium and a lack of magnesium, potassium and iron, which is due to both the composition of the food consumed and the peculiarities of the accumulation and excretion of these ions. An analysis of the actual nutrition of students shows the need for counseling young people, especially in the first years of study. The introduction of an educational program on optimal nutrition is possible through the practice of curatorial work during the adaptation of the first-year students to student’s life.

Chronic consumption of a high linoleic acid diet during pregnancy, lactation and post-weaning period increases depression-like behavior in male, but not female offspring

Polyunsaturated fatty acids (PUFAs) play an essential role in brain development. Emerging data have suggested a possible link between an imbalance in PUFAs and cognitive behavioral deficits in offspring. A diet rich in high linoleic acid (HLA), typically from preconception to lactation, leads to an increase in the ratio of omega-6 (n-6) to omega-3 (n-3) fatty acids in the fetus. Arising research has suggested that a deficiency in omega-3 fatty acids is a potential risk factor for inducing autism spectrum disorder (ASD)-like behavioral deficits. However, the impact of a high n- diet during preconception, pregnancy, lactation, and post-weaning on the brain development of adolescent offspring are yet to be determined. This study examined whether consumption of an HLA diet during pregnancy, lactation, and post-weaning induced social and cognitive impairments in female and male offspring rats that resemble autistic phenotypes in humans. Female Wistar Kyoto rats were fed with either HLA or low linoleic acid (LLA) control diet for 10 weeks before mating, then continued with the same diet throughout the pregnancy and lactation period. Female and male offspring at 5 weeks old were subjected to behavioral tests to assess social interaction behavior and depression-/anxiety-like behavior. Our result showed that chronic consumption of an HLA diet did not affect sociability and social recognition memory, but induced depression-like behavior in male but not in female offspring.

Impact of Amerind ancestry and FADS genetic variation on omega-3 deficiency and cardiometabolic traits in Hispanic populations

Long chain polyunsaturated fatty acids (LC-PUFAs) have critical signaling roles that regulate dyslipidemia and inflammation. Genetic variation in the FADS gene cluster accounts for a large portion of interindividual differences in circulating and tissue levels of LC-PUFAs, with the genotypes most strongly predictive of low LC-PUFA levels at strikingly higher frequencies in Amerind ancestry populations. In this study, we examined relationships between genetic ancestry and FADS variation in 1102 Hispanic American participants from the Multi-Ethnic Study of Atherosclerosis. We demonstrate strong negative associations between Amerind genetic ancestry and LC-PUFA levels. The FADS rs174537 single nucleotide polymorphism (SNP) accounted for much of the AI ancestry effect on LC-PUFAs, especially for low levels of n-3 LC-PUFAs. Rs174537 was also strongly associated with several metabolic, inflammatory and anthropomorphic traits including circulating triglycerides (TGs) and E-selectin in MESA Hispanics. Our study demonstrates that Amerind ancestry provides a useful and readily available tool to identify individuals most likely to have FADS-related n-3 LC-PUFA deficiencies and associated cardiovascular risk.

Omega-3 Index and Clinical Outcomes of Severe COVID-19: Preliminary Results of a Cross-Sectional Study.

The potentially detrimental effects of the worldwide deficiency of Omega-3 fatty acids on the COVID-19 pandemic have been underestimated. The Omega-3 Index (O3I), clinical variables, biometric indices, and nutritional information were directly determined for 74 patients with severe COVID-19 and 10 healthy quality-control subjects. The relationships between the OI3 and mechanical ventilation (MV) and death were analyzed. Results: Patients with COVID-19 exhibited low O3I (mean: 4.15%; range: 3.06–6.14%)—consistent with insufficient fish and Omega-3 supplement consumption, and markedly lower than the healthy control subjects (mean: 7.84%; range: 4.65–10.71%). Inverse associations were observed between O3I and MV (OR = 0.459; C.I.: 0.211–0.997) and death (OR = 0.28; C.I.: 0.08–0.985) in severe COVID-19, even after adjusting for sex, age, and well-known risk factors. Conclusion: We present preliminary evidence to support the hypothesis that the risk of severe COVID-19 can be stratified by the O3I quartile. Further investigations are needed to assess the value of the O3I as a blood marker for COVID-19.

Old and new adventures with fatty acids and their oxylipins: The road towards personalised clinical nutrition

After paying homage to the work of E. Chevreul, Prof. Robert Gibson went on in a lighthearted way to find similarities in the way they both approached their respective fields of research, as well as their way of life. Prof. Robert Gibson, who was awarded the 2021 Chevreul Medal, reported that “his huge delight was to witness the massive growth of lipid research and to have played a role in elucidating the role of dietary fats in the health of mothers and their babies”. Prof. Gibson highlighted some of the major results he collected from Australian clinical studies conducted on the role of omega-3 fatty acids on the health outcomes of mothers and their infants. He first discussed the role of fish oil on visual acuity of babies and demonstrated that infant formulas supplying more than 1% of linolenic acid (ALA) seemed adequate to ensure optimal visual and cognitive development of term infants. However, in preterm infants, whether there is a specific need for DHA above the benefit provided by ALA, still needs to be clarified. He reported a small beneficial impact on the cognitive development of preterm infants receiving DHA enriched breast milk of their mothers (1% of total fatty acids). He then discussed data from his large randomised clinical trials conducted on pregnant women receiving a DHA dietary treatment (800 mg/d DHA) or placebo, that suggested that DHA may decrease the risk of preterm birth (DOMInO trial, 2400 women). This effect was confirmed in the ORIP trial (5400 women) which found that preterm birth could be prevented by a DHA supplement treatment mainly in women with a singleton pregnancy who had a low omega-3 status in the first trimester. In the last part of his review, Robert Gibson described the use of a new low cost, rapid and efficient method to monitor changes in blood levels of omega-3 fatty acids with clinical outcomes: the Dried Blood Spots (DBS) technology. The validation of this technique has been demonstrated in large trials like N3RO and ORIP involving large cohorts of women, which could not have been obtained easily by classical analysis of lipids. He went on to point out that free fatty acids (generally not explored despite their importance in many metabolic disorders) and oxylipins, are both stable and easily identified when they are preserved in a dry state on a paper matrix (DBS), thus opening new fields of research. To conclude, the major impact of Prof. Robert Gibson’s work was identifying and overcoming one of the causes of early preterm birth (omega-3 deficiency), developing a tool to rapidly assess omega-3 status (the DBS technique) that together is close to being implemented into the world health system.

Maternal dietary omega-3 deficiency worsens the deleterious effects of prenatal inflammation on the gut-brain axis in the offspring across lifetime.

Maternal immune activation (MIA) and poor maternal nutritional habits are risk factors for the occurrence of neurodevelopmental disorders (NDD). Human studies show the deleterious impact of prenatal inflammation and low n-3 polyunsaturated fatty acid (PUFA) intake on neurodevelopment with long-lasting consequences on behavior. However, the mechanisms linking maternal nutritional status to MIA are still unclear, despite their relevance to the etiology of NDD. We demonstrate here that low maternal n-3 PUFA intake worsens MIA-induced early gut dysfunction, including modification of gut microbiota composition and higher local inflammatory reactivity. These deficits correlate with alterations of microglia-neuron crosstalk pathways and have long-lasting effects, both at transcriptional and behavioral levels. This work highlights the perinatal period as a critical time window, especially regarding the role of the gut-brain axis in neurodevelopment, elucidating the link between MIA, poor nutritional habits, and NDD.

Development of a Natural Product Rich in Bioavailable Omega-3 DHA from Locally Available Ingredients for Prevention of Nutrition Related Mental Illnesses

Objectives: Poor mental health remains a serious public concern worldwide. The most vulnerable individuals are children and adolescents in developing countries. Nutritional deficiency of long-chain omega-3 fatty acids, particularly docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), have long been recognized as a major contributing factor for mental health illnesses. Provision of ready-to-use natural product rich in preformed Omega-3 DHA and EPA could address this problem. However, most commonly used products are expensive and contain less or no preformed Omega-3 DHA and EPA, making them less suitable for prevention of mental illnesses in resource-poor countries. The main objective of this study was to develop a natural product rich in preformed Omega-3 DHA and EPA from locally available ingredients.Methods: Linear programing (LP) was used to formulate a natural product rich in preformed Omega-3 DHA and other essential nutrients using locally available ingredients other than fish and dairy products. Laboratory analysis was then performed to validate the nutritional value of the LP-formulation using standard analytical methods. The relative difference between the LP tool calculated values, and the laboratory-analyzed values were calculated. Sensory testing was also done to evaluate consumer acceptance of the final product.Results: Optimal formulation contained about 220 mg of preformed Omega-3 DHA + EPA, enough to meet the RDI for children aged 2-10 years. The LP analysis further showed that the cost of the developed product is USD 0.15/100 g, which is 50% lower than that of Plumpy’nut. Laboratory analysis revealed similar results as that of LP at P = 0.05.Conclusions: These findings indicate that ready-to-use natural food rich in preformed DHA and EPA can be developed from locally available ingredients.

Abstract MP67: Fatty Acid Desaturase Gene-induced Omega-3 Deficiency In Amerindian-Ancestry Hispanic Populations

Hispanic populations in the US have increased risk of obesity, elevated circulating triglycerides, nonalcoholic fatty liver disease, and diabetes. Our previous studies suggest that ancestry-related differences in the frequency of variants in the fatty acid desaturase ( FADS) gene cluster in the context of the modern Western diet can lead to inadequate circulating and tissues levels of n-3 long-chain (LC-; ≥ 20 carbons) polyunsaturated fatty acids (PUFA); these deficiencies in turn have the capacity to increase metabolic disease risk. Specifically, we and others have demonstrated Amerindian (AI)-Ancestry populations have high frequencies of FADS gene variants that may lead to less efficient n-3 LC-PUFA biosynthesis. To test this hypothesis, concentrations of fatty acids, including LC-PUFAs in plasma phospholipids were analyzed in 1,102 Hispanic American participants from Multi-Ethnic Study of Atherosclerosis (MESA) cohort, which represent six Hispanic subgroups based on self-reported region of origin: Central America, South America, Mexico, Cuba, Dominican Republic, and Puerto Rico. These data revealed a striking inverse relationship between genome-wide AI-ancestry and levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Additional analyses revealed that the genotype at FADS SNP rs174537, for which the frequency of the T allele increases with AI-ancestry, could primarily explain the associations. There also was a strong association between the number of T alleles (additive model) at rs174537 and circulating triglycerides (18.5 mg/dL per T allele; P =2.0 x 10 -5 ) as well as an important marker of vascular inflammation sICAM-1 (β=12.7 ng/mL, P =0.02). We also genotyped the FADS SNP, rs174537, in a separate adult Arizona Hispanic cohort (Arizona Insulin Resistance [AIR] registry) and compared the FADS genotypic frequencies with other racial/ethnic groups. Importantly, the TT genotype associated with limited LC-PUFA biosynthesis ranges from &lt;1% in African-Ancestry populations to 40.2% in AI-Ancestry Hispanics in the AIR Registry, with ~11 % in European-Ancestry populations. These data demonstrate that high AI-ancestry populations have a dramatically higher frequency of the TT genotype versus African and European populations. Importantly similar to MESA, there also was a significant association between the number of T alleles and plasma triglycerides (p = 0.0036; GG = 125±8.18 mg/dl, GT = 135±5.63 mg/dl, TT = 143±5.58 mg/dl) again suggesting the AI-associated TT genotype places this population at higher risk of hypertriglyceridemia. Together, these data reveal that FADS gene*dietary PUFA interactions give rise to n-3 LC-PUFA deficiencies and may enhance metabolic and inflammatory diseases in a large proportion of individuals in AI-Ancestry Hispanic populations.

Omega-3 fatty acids and mental health

Nutrition plays a key role in brain development, mental health, and psychiatric disorders. The role of omega-3 polyunsaturated fatty acids in physical health is well established, and their role in mental health is becoming increasingly evident. Omega-3 fatty acids are involved in a wide range of physiological functions that are related to neurogenesis, neurotransmission, and neuroinflammation; therefore, they play fundamental roles in the development, functioning, and aging of the brain. In humans, dietary deficiencies of omega-3 fatty acids are associated with an increased risk of developing various psychiatric disorders, including depression, bipolar disorder, schizophrenia, dementia, attention-deficit/hyperactivity disorder, and autism. In particular, eicosapentaenoic and docosahexaenoic acid have been linked to the maintenance of mental health, and their deficits have been implicated in the pathophysiology of mental disorders. This may be mediated by the modulation of inflammatory processes and their direct effects on neuronal membrane fluidity and receptor function. However, randomized clinical trials that have investigated the therapeutic effects of omega-3 fatty acids have yielded inconclusive results, thereby limiting the use of these nutrients in psychiatric practice. High-quality clinical trials should be conducted to examine the efficacy of omega-3 fatty acids in preventing and treating mental disorders. The undesirable side effects of omega-3 fatty acid supplementation should also be considered. These effects may become apparent after many years of administration, and therefore, they may not be detected in most cases.

Depressive-like phenotype evoked by lifelong nutritional omega-3 deficiency in female rats: Crosstalk among kynurenine, Toll-like receptors and amyloid beta oligomers

Depression is one of the most common psychiatric diseases and the prevalence of depressive symptoms in women is almost twice compared to men, although the reasons of this gender difference are not fully understood yet. Recently, soluble amyloid beta (Aβ)1-42 peptide has been receiving great importance in the development of depression, also considering that depression is highly comorbid with Alzheimer’s disease and other neurodegenerative illnesses. The central role played by Aβ in the development of depressive-like symptoms in rodents has been evidenced in environmental rodent model of depression. Indeed, we have previously found that lifelong exposure to n-3 polyunsaturated fatty acids (PUFA) deficient diet in female rats at 8 weeks of life leads to depressive like- symptoms and higher susceptibility to stress associated with increased Aβ levels. In order to understand if such effects were maintained over time, rats were exposed to the same diet regimen until 6 or 21 weeks of life. We found that both timepoints of exposure to n-3 PUFA deficient diet lead to depressive-like phenotype. Furthermore, a significant alteration in brain neurochemistry was retrieved. In particular, in hippocampal area a significant reduction in serotonin (5-HT) and noradrenaline (NA) content was evidenced. Considering the prominent role of NA in counterbalancing neuroinflammatory state, we quantified in the same brain area kynurenine levels, a metabolite of tryptophan implicated in inflammatory state and brought to the fore for its implication in depression. Interestingly, kynurenine levels were significantly increased in hippocampus (HIPP) of female rats exposed to such diet. In addition, lifelong deficiency in n-3 PUFA dietary intake led to systemic increase of corticosterone, hence hypothalamic pituitary adrenal (HPA) axis hyperactivation, and higher proinflammatory cytokine production. Increased production of kynurenine, along with HPA axis hyperactivation, have been associated with immune system modulation, particularly through Toll-like receptor type 2 (TLR2) and Toll-like receptor type 4 (TLR4) involvement. In addition, it has been shown that soluble forms of Aβ1-42 can induced depressive like-phenotype in consequence to a crosstalk between TLR4 and 5-HTergic system. Thus, considering that in this model we have previously reported increased plasma Aβ1-42 level, we quantified TRL2 and 4 expression in HIPP of treated rats. We found that chronic exposure to a diet characterized by very low n-3 PUFA content led to higher expression of TLR2 and TLR4 in HIPP of female treated rats, indicating an activation of the immune system and was accompanied by increased expression of oligomeric Aβ.Taken together, our data indicate that the pro-depressive effects induced by a diet poor in n-3 PUFA can be attributable to a shift of hippocampal tryptophan metabolism toward inflammatory metabolite ultimately corresponding to altered immune response and increased Aβ oligomerization.

Mfsd2a Attenuates Blood-Brain Barrier Disruption After Sub-arachnoid Hemorrhage by Inhibiting Caveolae-Mediated Transcellular Transport in Rats.

Blood-brain barrier (BBB) disruption is one of the critical mechanisms of brain injury induced by subarachnoid hemorrhage (SAH). Past studies have often focused on the tight junctions of endothelial cells. However, low transcellular transport levels also play an important role in the normal functioning of the BBB. Major facilitator superfamily domain-containing 2a (Mfsd2a) has been demonstrated to be essential for the maintenance of the normal BBB. Our present study aimed to explore the roles and mechanisms of Mfsd2a in BBB disruption after SAH. In this study, a prechiasmatic cistern single-injection model was used to produce experimental SAH in Sprague-Dawley rats. Specific small-interfering RNA and plasmids were used to downregulate and upregulate the expression of Mfsd2a prior to assessments in our SAH model. Omega-3 fatty acid deficiency diet was used to reduce DHA in rat brain. The expression level of Mfsd2a decreased significantly after SAH and reached its lowest level at 72h post-SAH, which then gradually recovered. At 72h after SAH, BBB function was disrupted; upregulation of Mfsd2a reversed this damage, whereas downregulation of Mfsd2a exacerbated this damage. These effects were primarily mediated through transcellular transport, especially for changes in caveolae compared to those of tight junctions. After stopping the supply of omega-3 fatty acids, the effect of Mfsd2a on inhibition of caveolae and protection of the blood-brain barrier was eliminated. Taken together, Mfsd2a inhibits caveolae-based transcellular transport by transporting omega-3 fatty acids to protect the BBB after SAH.

Omega-3 Fatty Acids as a Treatment for Pediatric Depression. A Phase III, 36 Weeks, Multi-Center, Double-Blind, Placebo-Controlled Randomized Superiority Study.

Background: Depressive disorders in childhood and adolescence are a major health problem and often follow a chronic course with severe consequences in later life. Depressive disorders cause the highest burden of disease in this age group across all medical conditions. Treatment adherence is usually very poor, and the use of antidepressant drugs is heavily debated, as suicidal ideations may increase, in particular in the early phase of treatment. Omega-3 fatty acids rich in eicosapentaenoic acid have shown some promising results in over a dozen small scale randomized controlled trials (RCTs) in adult major depressive disorders, with only very few published RCTs in children and adolescents. High-quality phase III RCTs are missing. Methods and Design: The omega-3-pMDD trial is a carefully designed phase III RCT to assess the efficacy and safety of omega-3 fatty acids in the early course of pediatric major depressive disorder (MDD). The study is designed as a multi-center, double-blinded, placebo-controlled, randomized clinical trial enrolling 220 patients aged 8 to 17 years meeting DSM-IV criteria for major depressive disorder of at least moderate symptom severity. After a single-blinded placebo-lead-in phase (7 to 10 days) patients are randomly assigned to omega-3 fatty acids or placebo over 36 weeks. Primary outcomes are changes in depression severity, as well as remission and recovery rates. Secondary outcome measures include the omega-3 index and inflammatory parameters as predictors of response. Data analysis will be performed in the intention-to-treat sample using a (generalized) linear random intercept regression model. Through sampling of blood, hair, saliva, and urine, further putative biological markers for depression and omega-3 fatty response will be investigated. Discussion: This trial addresses if omega-3 fatty acids play a role in the pathogenesis of pediatric MDDs and have antidepressant properties, in particular in clinically depressed children and adolescents with a pre-existing omega-3 fatty acid deficiency, increased markers of oxidative stress, and/or markers of (low grade) inflammation. Ethics and Dissemination: The study was approved by the local ethics committees. The results will be published in peer-reviewed journals irrespective of specific outcomes. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03167307.

Perinatal dietary omega-3 fatty acid deficiency reduces maternal nurturing behavior in rats: dissociation from elevated pro-inflammatory signaling

ABSTRACT Objectives: Maternal-pup nurturing behavior has previously been shown to impact offspring neurodevelopment independent of diet. Here we investigated the effects of perinatal maternal n-3 fatty acid deficiency on maternal-pup nurturing behavior and potential associations with pro-inflammatory signaling. Methods: Eight-week-old virgin female Long-Evans hooded rats were randomized to a control diet containing alpha-linolenic acid (ALA, 18:3n-3) (CON, n = 10) or an ALA-free diet (Deficient, DEF, n = 11) 30 d prior to mating. On postnatal day 2 (P2) litters were culled to eight per dam. On P3, P6, and P9 dams and their litters were video recorded and maternal nurturing behaviors, including licking/grooming of pups and arched-back nursing, were scored by a blinded rater. Following weaning on P21, dam postmortem central (prefrontal cortex, PFC) and peripheral (red blood cell, RBC) fatty acid composition and central (PFC IL-1β, IL-2, IL-6, TNFα, cPLA2, COX-2 mRNA) and peripheral (plasma IL-1β, IL-2, IL-6, TNFα, CRP) pro-inflammatory biostatus assessed. Results: DEF dams exhibited significantly lower RBC (p ≤ 0.0001) and PFC (p ≤ 0.0001) docosahexaenoic acid (DHA) levels compared with CON dams. Irrespective of diet dams exhibited significantly lower RBC, but not PFC, DHA levels compared with non-parous rats. DEF dams exhibited less licking/grooming (p = 0.008), arched-back nursing (p ≤ 0.0001) and blanket nursing (p = 0.003), and exhibited more passive nursing (p = 0.003) but not time off pups (p = 0.1), compared with CON dams. PFC and plasma inflammatory measures did not differ significantly between groups. Discussion: Perinatal dietary n-3 fatty acid deficiency reduces maternal nurturing behavior and this effect is not associated with enduring elevations in pro-inflammatory signaling.