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Concept: Linoleic acid

532

Over the last century, intakes of omega-6 (ω-6) fatty acids in Western diets have dramatically increased, while omega-3 (ω-3) intakes have fallen. Resulting ω-6/ω-3 intake ratios have risen to nutritionally undesirable levels, generally 10 to 15, compared to a possible optimal ratio near 2.3. We report results of the first large-scale, nationwide study of fatty acids in U.S. organic and conventional milk. Averaged over 12 months, organic milk contained 25% less ω-6 fatty acids and 62% more ω-3 fatty acids than conventional milk, yielding a 2.5-fold higher ω-6/ω-3 ratio in conventional compared to organic milk (5.77 vs. 2.28). All individual ω-3 fatty acid concentrations were higher in organic milk-α-linolenic acid (by 60%), eicosapentaenoic acid (32%), and docosapentaenoic acid (19%)-as was the concentration of conjugated linoleic acid (18%). We report mostly moderate regional and seasonal variability in milk fatty acid profiles. Hypothetical diets of adult women were modeled to assess milk fatty-acid-driven differences in overall dietary ω-6/ω-3 ratios. Diets varied according to three choices: high instead of moderate dairy consumption; organic vs. conventional dairy products; and reduced vs. typical consumption of ω-6 fatty acids. The three choices together would decrease the ω-6/ω-3 ratio among adult women by ∼80% of the total decrease needed to reach a target ratio of 2.3, with relative impact “switch to low ω-6 foods” > “switch to organic dairy products” ≈ “increase consumption of conventional dairy products.” Based on recommended servings of dairy products and seafoods, dairy products supply far more α-linolenic acid than seafoods, about one-third as much eicosapentaenoic acid, and slightly more docosapentaenoic acid, but negligible docosahexaenoic acid. We conclude that consumers have viable options to reduce average ω-6/ω-3 intake ratios, thereby reducing or eliminating probable risk factors for a wide range of developmental and chronic health problems.

Concepts: Nutrition, Fatty acid, Fatty acids, Omega-3 fatty acid, Butter, Eicosapentaenoic acid, Omega-6 fatty acid, Linoleic acid

216

Long chain polyunsaturated fatty acids (LCPUFA) are bioactive components of membrane phospholipids and serve as substrates for signaling molecules. LCPUFA can be obtained directly from animal foods or synthesized endogenously from 18 carbon precursors via the FADS2 coded enzyme. Vegans rely almost exclusively on endogenous synthesis to generate LCPUFA and we hypothesized that an adaptive genetic polymorphism would confer advantage. The rs66698963 polymorphism, a 22-bp insertion-deletion within FADS2, is associated with basal FADS1 expression, and coordinated induction of FADS1 and FADS2 in vitro. Here, we determined rs66698963 genotype frequencies from 234 individuals of a primarily vegetarian Indian population and 311 individuals from the US. A much higher I/I genotype frequency was found in Indians (68%) than in the US (18%). Analysis using 1000 Genomes Project data confirmed our observation, revealing a global I/I genotype of 70% in South Asians, 53% in Africans, 29% in East Asians, and 17% in Europeans. Tests based on population divergence, site frequency spectrum, and long-range haplotype consistently point to positive selection encompassing rs66698963 in South Asian, African, and some East Asian populations. Basal plasma phospholipid arachidonic acid (ARA) status was 8% greater in I/I compared with D/D individuals. The biochemical pathway product-precursor difference, ARA minus linoleic acid, was 31% and 13% greater for I/I and I/D compared with D/D, respectively. This study is consistent with previous in vitro data suggesting that the insertion allele enhances n-6 LCPUFA synthesis and may confer an adaptive advantage in South Asians because of the traditional plant-based diet practice.

Concepts: Genetics, Allele, Fatty acid, Fatty acids, Essential fatty acid, Omega-6 fatty acid, Linoleic acid, Arachidonic acid

174

OBJECTIVE: To assess whether three novel interventions, formulated based on a systems medicine therapeutic concept, reduced disease activity in patients with relapsing-remitting multiple sclerosis (MS) who were either treated or not with disease-modifying treatment. DESIGN: A 30-month randomised, double-blind, placebo-controlled, parallel design, phase II proof-of-concept clinical study. SETTINGS: Cyprus Institute of Neurology and Genetics. PARTICIPANTS: 80 participants were randomised into four groups of 20 each. A total of 41 (51%) patients completed the 30-month trial. The eligibility criteria were an age of 18-65; a diagnosis of relapsing-remitting MS according to the McDonald criteria; a score of 0.0-5.5 on the Expanded Disability Status Scale (EDSS); MRI showing lesions consistent with MS; at least one documented clinical relapse and either receiving or not a disease-modifying treatment within the 24-month period before enrolment in the study. Patients were excluded because of a recent (<30 days) relapse, prior immunosuppressant or monoclonal antibody therapy, pregnancy or nursing, other severe disease compromising organ function, progressive MS, history of recent drug or alcohol abuse, use of any additional food supplements, vitamins or any form of polyunsaturated fatty acids, and a history of severe allergic or anaphylactic reactions or known specific nutritional hypersensitivity. INTERVENTIONS: The first intervention (A) was composed of Ω-3 and Ω-6 polyunsaturated fatty acids at 1:1 wt/wt. Specifically, the Ω-3 fatty acids were docosahexaenoic acid and eicosapentaenoic acid at 3:1 wt/wt, and the Ω-6 fatty acids were linoleic acid and γ-linolenic acid at 2:1 wt/wt. This intervention also included minor quantities of other specific polyunsaturated, monounsaturated and saturated fatty acids as well as vitamin A and vitamin E (α-tocopherol). The second intervention (B, PLP10) was a combination of A and γ-tocopherol. The third intervention (C) was γ-tocopherol alone. The fourth group of 20 participants received placebo. The interventions were administered per os (by mouth) once daily, 30 min before dinner for 30 months. MAIN OUTCOME MEASURES: The primary end point was the annualised relapse rate (ARR) of the three interventions versus the placebo at 2 years. The secondary end point was the time to confirmed disability progression at 2 years. RESULTS: A total of 41 (51%) patients completed the 30-month trial. Overall, for the per-protocol analysis of the 2-year primary end point, eight relapses were recorded in the PLP10 group (n=10; 0.40 ARR) versus 25 relapses in the placebo group (n=12; 1.04 ARR), representing a 64% adjusted relative rate reduction for the PLP10 group (RRR 0.36, 95% CI 0.15 to 0.87, p=0.024). In a subgroup analysis that excluded patients on monoclonal antibody (natalizumab) treatment, the observed adjusted RRR became stronger (72%) over the 2 years (RRR 0.28, 95% CI 0.10 to 0.79, p=0.016). The per-protocol analysis for the secondary outcome at 2 years, the time to disability progression, was significantly longer only for PLP10. The cumulative probability of disability progression at 2 years was 10% in the PLP10 group and 58% in the placebo group (unadjusted log-rank p=0.019). In a subgroup analysis that excluded patients on natalizumab, the cumulative probability of progression was 10% for the 10 patients in the PLP10 group and 70% for the 12 patients in the placebo group, representing a relative 86% decrease in the risk of the sustained progression of disability in the PLP10 group (unadjusted log-rank p=0.006; adjusted HR, 0.11; 95% CI 0.01 to 0.97, p=0.047). No adverse events were reported. Interventions A (10 patients) and C (9 patients) showed no significant efficacy. CONCLUSIONS: In this small proof-of-concept, randomised, double-blind clinical trial; the PLP10 treatment significantly reduced the ARR and the risk of sustained disability progression without any reported serious adverse events. Larger studies are needed to further assess the safety and efficacy of PLP10. TRIAL REGISTRATION: International Standard Randomised Controlled Trial, number ISRCTN87818535.

Concepts: Clinical trial, Nutrition, Fatty acid, Fatty acids, Essential fatty acid, Omega-3 fatty acid, Multiple sclerosis, Linoleic acid

174

Fatty acid binding proteins (FABPs), in particular FABP5 and FABP7, have recently been identified by us as intracellular transporters for the endocannabinoid anandamide (AEA). Furthermore, animal studies by others have shown that elevated levels of endocannabinoids resulted in beneficial pharmacological effects on stress, pain and inflammation and also ameliorate the effects of drug withdrawal. Based on these observations, we hypothesized that FABP5 and FABP7 would provide excellent pharmacological targets. Thus, we performed a virtual screening of over one million compounds using DOCK and employed a novel footprint similarity scoring function to identify lead compounds with binding profiles similar to oleic acid, a natural FABP substrate. Forty-eight compounds were purchased based on their footprint similarity scores (FPS) and assayed for biological activity against purified human FABP5 employing a fluorescent displacement-binding assay. Four compounds were found to exhibit approximately 50% inhibition or greater at 10 µM, as good as or better inhibitors of FABP5 than BMS309403, a commercially available inhibitor. The most potent inhibitor, γ-truxillic acid 1-naphthyl ester (ChemDiv 8009-2334), was determined to have K(i) value of 1.19±0.01 µM. Accordingly a novel α-truxillic acid 1-naphthyl mono-ester (SB-FI-26) was synthesized and assayed for its inhibitory activity against FABP5, wherein SB-FI-26 exhibited strong binding (K(i) 0.93±0.08 µM). Additionally, we found SB-FI-26 to act as a potent anti-nociceptive agent with mild anti-inflammatory activity in mice, which strongly supports our hypothesis that the inhibition of FABPs and subsequent elevation of anandamide is a promising new approach to drug discovery. Truxillic acids and their derivatives were also shown by others to have anti-inflammatory and anti-nociceptive effects in mice and to be the active component of Chinese a herbal medicine (Incarvillea sinensis) used to treat rheumatism and pain in humans. Our results provide a likely mechanism by which these compounds exert their effects.

Concepts: Pharmacology, Fatty acid, Enzyme inhibitor, Drug discovery, Inhibitor, Oleic acid, Linoleic acid, Fatty acid-binding protein

169

BACKGROUND: The objective of this study was to evaluate the mediating role of maternal early pregnancy plasma levels of long chain polyunsaturated fatty acids (LCPUFAs) in the association of interpregnancy interval (IPI) with birth weight and smallness for gestational age (SGA) at birth. METHODS: We analysed a subsample of the Amsterdam Born Children and their Development (ABCD) cohort, comprising 1,659 parous pregnant women recruited between January 2003 and March 2004. We used linear and logistic regression to evaluate the associations between fatty acid status, interpregnancy interval and pregnancy outcome. RESULTS: Low plasma phospholipids concentrations of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and dihomo-gamma-linolenic acid (DGLA), and high concentrations of arachidonic acid (AA) during early pregnancy were associated with reduced birth weight and/or an increased risk of SGA. Short IPIs (< 6 months, with 18--23 months as a reference) were associated with a mean decrease of 207.6 g (SE: +/- 73.1) in birth weight (p = 0.005) and a twofold increased risk of SGA (OR: 2.05; CI: 0.93--4.51; p = 0.074). Adjustment for maternal fatty acid concentrations did not affect these results to any meaningful extent. CONCLUSIONS: Despite the observed association of maternal early pregnancy LCPUFA status with birth weight and SGA, our study provides no evidence for the existence of an important role of maternal EPA, DHA, DGLA or AA in the association of short interpregnancy intervals with birth weight and SGA.

Concepts: Fatty acid, Fatty acids, Essential fatty acid, Eicosapentaenoic acid, Omega-6 fatty acid, Linoleic acid, Arachidonic acid, Polyunsaturated fatty acid

138

The small intestine plays an essential role in the health and well-being of animals. Previous studies have shown that Lactobacillus has a protective effect on intestinal morphology, intestinal epithelium integrity and appropriate maturation of gut-associated tissues. Here, gene expression in jejunum tissue of weaned piglets was investigated by RNA-seq analysis after administration of sterile saline, Lactobacillus reuteri, or an antibiotic (chlortetracycline). In total, 401 and 293 genes were significantly regulated by chlortetracycline and L. reuteri, respectively, compared with control treatment. Notably, the HP, NOX1 and GPX2 genes were significantly up-regulated in the L. reuteri group compared with control, which is related to the antioxidant ability of this strain. In addition, the expression of genes related to arachidonic acid metabolism and linoleic acid metabolism enriched after treatment with L. reuteri. The fatty acid composition in the jejunum and colon was examined by GC-MS analysis and suggested that the MUFA C18:1n9c, and PUFAs C18:2n6c and C20:4n6 were increased in the L. reuteri group, verifying the GO enrichment and KEGG pathway analyses of the RNA-seq results. The results contribute to our understanding of the probiotic activity of this strain and its application in pig production.

Concepts: Gene expression, Bacteria, Fatty acid, Probiotic, Omega-6 fatty acid, Linoleic acid, Arachidonic acid, Essential fatty acid interactions

75

Background: Choline status has been associated with stunting among young children. Findings from this study showed that an egg intervention improved linear growth by a length-for-age z score of 0.63.Objective: We aimed to test the efficacy of eggs introduced early in complementary feeding on plasma concentrations of biomarkers in choline pathways, vitamins B-12 and A, and essential fatty acids.Design: A randomized controlled trial, the Lulun (“egg” in Kichwa) Project, was conducted in a rural indigenous population of Ecuador. Infants aged 6-9 mo were randomly assigned to treatment (1 egg/d for 6 mo; n = 80) and control (no intervention; n = 83) groups. Socioeconomic data, anthropometric measures, and blood samples were collected at baseline and endline. Household visits were made weekly for morbidity surveillance. We tested vitamin B-12 plasma concentrations by using chemiluminescent competitive immunoassay and plasma concentrations of choline, betaine, dimethylglycine, retinol, essential fatty acids, methionine, dimethylamine (DMA), trimethylamine, and trimethylamine-N-oxide (TMAO) with the use of liquid chromatography-tandem mass spectrometry.Results: Socioeconomic factors and biomarker concentrations were comparable at baseline. Of infants, 11.4% were vitamin B-12 deficient and 31.7% marginally deficient at baseline. In adjusted generalized linear regression modeling, the egg intervention increased plasma concentrations compared with control by the following effect sizes: choline, 0.35 (95% CI: 0.12, 0.57); betaine, 0.29 (95% CI: 0.01, 0.58); methionine, 0.31 (95% CI: 0.03, 0.60); docosahexaenoic acid, 0.43 (95% CI: 0.13, 0.73); DMA, 0.37 (95% CI: 0.37, 0.69); and TMAO, 0.33 (95% CI: 0.08, 0.58). No significant group differences were found for vitamin B-12, retinol, linoleic acid (LA), α-linolenic acid (ALA), or ratios of betaine to choline and LA to ALA.Conclusion: The findings supported our hypothesis that early introduction of eggs significantly improved choline and other markers in its methyl group metabolism pathway. This trial was registered at clinicaltrials.gov as NCT02446873.

Concepts: Nutrition, Fatty acid, Fatty acids, Essential fatty acid, Omega-3 fatty acid, Vitamin B12, Omega-6 fatty acid, Linoleic acid

51

Eicosapentaenoic acid (EPA, C20:5n-3), docosahexaenoic acid (DHA, C22:6n-3) and arachidonic acid (AA, C20:4n-6) are long-chain polyunsaturated fatty acids (LCPUFAs) with relevant roles in the organism. EPA and DHA are synthesized from the precursor alpha-linolenic acid (ALA, C18:3n-3), whereas AA is produced from linoleic acid (LA, C18:2n-6) through the action of Δ5 and Δ6-desaturases. High-fat diet (HFD) decreases the activity of both desaturases and LCPUFA accretion in liver and other tissues. Hydroxytyrosol (HT), a natural antioxidant, has an important cytoprotective effects in different cells and tissues.

Concepts: Nutrition, Fatty acid, Fatty acids, Essential fatty acid, Eicosapentaenoic acid, Omega-6 fatty acid, Linoleic acid, Arachidonic acid

50

Soybean oil consumption is increasing worldwide and parallels a rise in obesity. Rich in unsaturated fats, especially linoleic acid, soybean oil is assumed to be healthy, and yet it induces obesity, diabetes, insulin resistance, and fatty liver in mice. Here, we show that the genetically modified soybean oil Plenish, which came on the U.S. market in 2014 and is low in linoleic acid, induces less obesity than conventional soybean oil in C57BL/6 male mice. Proteomic analysis of the liver reveals global differences in hepatic proteins when comparing diets rich in the two soybean oils, coconut oil, and a low-fat diet. Metabolomic analysis of the liver and plasma shows a positive correlation between obesity and hepatic C18 oxylipin metabolites of omega-6 (ω6) and omega-3 (ω3) fatty acids (linoleic and α-linolenic acid, respectively) in the cytochrome P450/soluble epoxide hydrolase pathway. While Plenish induced less insulin resistance than conventional soybean oil, it resulted in hepatomegaly and liver dysfunction as did olive oil, which has a similar fatty acid composition. These results implicate a new class of compounds in diet-induced obesity-C18 epoxide and diol oxylipins.

Concepts: Nutrition, Fatty acid, Fatty acids, Omega-3 fatty acid, Fat, Omega-6 fatty acid, Linoleic acid, Olive oil

50

Demand for organic milk is partially driven by consumer perceptions that it is more nutritious. However, there is still considerable uncertainty over whether the use of organic production standards affects milk quality. Here we report results of meta-analyses based on 170 published studies comparing the nutrient content of organic and conventional bovine milk. There were no significant differences in total SFA and MUFA concentrations between organic and conventional milk. However, concentrations of total PUFA and n-3 PUFA were significantly higher in organic milk, by an estimated 7 (95 % CI ���1, 15) % and 56 (95 % CI 38, 74) %, respectively. Concentrations of ��-linolenic acid (ALA), very long-chain n-3 fatty acids (EPA+DPA+DHA) and conjugated linoleic acid were also significantly higher in organic milk, by an 69 (95 % CI 53, 84) %, 57 (95 % CI 27, 87) % and 41 (95 % CI 14, 68) %, respectively. As there were no significant differences in total n-6 PUFA and linoleic acid (LA) concentrations, the n-6:n-3 and LA:ALA ratios were lower in organic milk, by an estimated 71 (95 % CI ���122, ���20) % and 93 (95 % CI ���116, ���70) %. It is concluded that organic bovine milk has a more desirable fatty acid composition than conventional milk. Meta-analyses also showed that organic milk has significantly higher ��-tocopherol and Fe, but lower I and Se concentrations. Redundancy analysis of data from a large cross-European milk quality survey indicates that the higher grazing/conserved forage intakes in organic systems were the main reason for milk composition differences.

Concepts: Nutrition, Fatty acid, Fatty acids, Omega-3 fatty acid, Oleic acid, Omega-6 fatty acid, Linoleic acid, Arachidonic acid