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Biological Psychiatry Oct 2023Metabolic differences have been reported between individuals with and without major depressive disorder (MDD), but their consistency and causal relevance have been...
BACKGROUND
Metabolic differences have been reported between individuals with and without major depressive disorder (MDD), but their consistency and causal relevance have been unclear.
METHODS
We conducted a metabolome-wide association study of MDD with 249 metabolomic measures available in the UK Biobank (n = 29,757). We then applied two-sample bidirectional Mendelian randomization and colocalization analysis to identify potentially causal relationships between each metabolite and MDD.
RESULTS
A total of 191 metabolites tested were significantly associated with MDD (false discovery rate-corrected p < .05), which decreased to 129 after adjustment for likely confounders. Lower abundance of omega-3 fatty acid measures and a higher omega-6 to omega-3 ratio showed potentially causal effects on liability to MDD. There was no evidence of a causal effect of MDD on metabolite levels. Furthermore, genetic signals associated with docosahexaenoic acid colocalized with loci associated with MDD within the fatty acid desaturase gene cluster. Post hoc Mendelian randomization of gene-transcript abundance within the fatty acid desaturase cluster demonstrated a potentially causal association with MDD. In contrast, colocalization analysis did not suggest a single causal variant for both transcript abundance and MDD liability, but rather the likely existence of two variants in linkage disequilibrium with one another.
CONCLUSIONS
Our findings suggest that decreased docosahexaenoic acid and increased omega-6 to omega-3 fatty acids ratio may be causally related to MDD. These findings provide further support for the causal involvement of fatty acids in MDD.
Topics: Humans; Depressive Disorder, Major; Docosahexaenoic Acids; Fatty Acids, Unsaturated; Fatty Acids, Omega-3; Fatty Acid Desaturases; Mendelian Randomization Analysis; Genome-Wide Association Study
PubMed: 36764567
DOI: 10.1016/j.biopsych.2023.01.027 -
Journal of the American College of... Jul 2023The relationship between omega-3 fatty acids and atrial fibrillation (AF) remains controversial. (Meta-Analysis)
Meta-Analysis
BACKGROUND
The relationship between omega-3 fatty acids and atrial fibrillation (AF) remains controversial.
OBJECTIVES
This study aimed to determine the prospective associations of blood or adipose tissue levels of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with incident AF.
METHODS
We used participant-level data from a global consortium of 17 prospective cohort studies, each with baseline data on blood or adipose tissue omega-3 fatty acid levels and AF outcomes. Each participating study conducted a de novo analyses using a prespecified analytical plan with harmonized definitions for exposures, outcome, covariates, and subgroups. Associations were pooled using inverse-variance weighted meta-analysis.
RESULTS
Among 54,799 participants from 17 cohorts, 7,720 incident cases of AF were ascertained after a median 13.3 years of follow-up. In multivariable analysis, EPA levels were not associated with incident AF, HR per interquintile range (ie, the difference between the 90th and 10th percentiles) was 1.00 (95% CI: 0.95-1.05). HRs for higher levels of DPA, DHA, and EPA+DHA, were 0.89 (95% CI: 0.83-0.95), 0.90 (95% CI: 0.85-0.96), and 0.93 (95% CI: 0.87-0.99), respectively.
CONCLUSIONS
In vivo levels of omega-3 fatty acids including EPA, DPA, DHA, and EPA+DHA were not associated with increased risk of incident AF. Our data suggest the safety of habitual dietary intakes of omega-3 fatty acids with respect to AF risk. Coupled with the known benefits of these fatty acids in the prevention of adverse coronary events, our study suggests that current dietary guidelines recommending fish/omega-3 fatty acid consumption can be maintained.
Topics: Humans; Atrial Fibrillation; Biomarkers; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Prospective Studies; Risk Factors
PubMed: 37468189
DOI: 10.1016/j.jacc.2023.05.024 -
Journal of the International Society of... Dec 2023Resistance exercise training (RET) is a common and well-established method to induce hypertrophy and improvement in strength. Interestingly, fish oil supplementation... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Resistance exercise training (RET) is a common and well-established method to induce hypertrophy and improvement in strength. Interestingly, fish oil supplementation (FOS) may augment RET-induced adaptations. However, few studies have been conducted on young, healthy adults.
METHODS
A randomized, placebo-controlled design was used to determine the effect of FOS, a concentrated source of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), compared to placebo (PL) on RET-induced adaptations following a 10-week RET program (3 days·week). Body composition was measured by dual-energy x-ray absorptiometry (LBM, fat mass [FM], percent body fat [%BF]) and strength was measured by 1-repetition maximum barbell back squat (1RM) and bench press (1RM) at PRE (week 0) and POST (10 weeks). Supplement compliance was assessed via self-report and bottle collection every two weeks and via fatty acid dried blood spot collection at PRE and POST. An α-level of 0.05 was used to determine statistical significance and Cohen's was used to quantify effect sizes (ES).
RESULTS
Twenty-one of 28 male and female participants (FOS, = 10 [4 withdrawals]; PL, = 11 [3 withdrawals]) completed the 10-week progressive RET program and PRE/POST measurements. After 10-weeks, blood EPA+DHA substantially increased in the FOS group (+109.7%, < .001) and did not change in the PL group (+1.3%, = .938). Similar between-group changes in LBM (FOS: +3.4%, PL: +2.4%, = .457), FM (FOS: -5.2%, PL: 0.0%, = .092), and %BF (FOS: -5.9%, PL: -2.5%, = .136) were observed, although, the between-group ES was considered large for FM ( = 0.84). Absolute and relative (kg·kg [body mass]) 1RM was significantly higher in the FOS group compared to PL (FOS: +17.7% vs. PL: +9.7%, = .047; FOS: +17.6% vs. PL: +7.3%, = .011; respectively), whereas absolute 1RM was similar between conditions (FOS: +28.8% vs. PL: +20.5%, = .191). Relative 1RM was higher in the FOS group (FOS: +29.3% vs. PL: +17.9%, = .045).
CONCLUSIONS
When combined with RET, FOS improves absolute and relative 1RM upper-body and relative 1RM lower-body strength to a greater extent than that observed in the PL group of young, recreationally trained adults.
Topics: Female; Humans; Male; Body Composition; Dietary Supplements; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fish Oils; Muscle Strength; Muscle, Skeletal; Resistance Training
PubMed: 36822153
DOI: 10.1080/15502783.2023.2174704 -
Blood Aug 2023Neutrophils reside in the bone marrow (BM), ready for deployment to sites of injury/infection, initiating inflammation and its resolution. Here, we report that distal...
Neutrophils reside in the bone marrow (BM), ready for deployment to sites of injury/infection, initiating inflammation and its resolution. Here, we report that distal infections signal to the BM via resolvins to regulate granulopoiesis and BM neutrophil deployment. Emergency granulopoiesis during peritonitis evoked changes in BM resolvin D1 (RvD1) and BM RvD4. We found that leukotriene B4 stimulates neutrophil deployment. RvD1 and RvD4 each limited neutrophilic infiltration to infections, and differently regulated BM myeloid populations: RvD1 increased reparative monocytes, and RvD4 regulated granulocytes. RvD4 disengaged emergency granulopoiesis, prevented excess BM neutrophil deployment, and acted on granulocyte progenitors. RvD4 also stimulated exudate neutrophil, monocyte, and macrophage phagocytosis, and enhanced bacterial clearance. This mediator accelerated both neutrophil apoptosis and clearance by macrophages, thus expediting the resolution phase of inflammation. RvD4 stimulated phosphorylation of ERK1/2 and STAT3 in human BM-aspirate-derived granulocytes. RvD4 in the 1 to 100 nM range stimulated whole-blood neutrophil phagocytosis of Escherichia coli. RvD4 increased BM macrophage efferocytosis of neutrophils. Together, these results demonstrate the novel functions of resolvins in granulopoiesis and neutrophil deployment, contributing to the resolution of infectious inflammation.
Topics: Humans; Neutrophils; Inflammation; Phagocytosis; Fatty Acids, Unsaturated; Communicable Diseases; Escherichia coli; Docosahexaenoic Acids
PubMed: 37295018
DOI: 10.1182/blood.2022019145 -
Advances in Nutrition (Bethesda, Md.) Jan 2024
Topics: Humans; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Acids; Fish Oils; Dietary Supplements; Fatty Acids, Omega-3
PubMed: 38048908
DOI: 10.1016/j.advnut.2023.100161 -
American Journal of Obstetrics &... Feb 2024This clinical practice guideline on the supply of the omega-3 docosahexaenoic acid and eicosapentaenoic acid in pregnant women for risk reduction of preterm birth and... (Review)
Review
This clinical practice guideline on the supply of the omega-3 docosahexaenoic acid and eicosapentaenoic acid in pregnant women for risk reduction of preterm birth and early preterm birth was developed with support from several medical-scientific organizations, and is based on a review of the available strong evidence from randomized clinical trials and a formal consensus process. We concluded the following. Women of childbearing age should obtain a supply of at least 250 mg/d of docosahexaenoic+eicosapentaenoic acid from diet or supplements, and in pregnancy an additional intake of ≥100 to 200 mg/d of docosahexaenoic acid. Pregnant women with a low docosahexaenoic acid intake and/or low docosahexaenoic acid blood levels have an increased risk of preterm birth and early preterm birth. Thus, they should receive a supply of approximately 600 to 1000 mg/d of docosahexaenoic+eicosapentaenoic acid, or docosahexaenoic acid alone, given that this dosage showed significant reduction of preterm birth and early preterm birth in randomized controlled trials. This additional supply should preferably begin in the second trimester of pregnancy (not later than approximately 20 weeks' gestation) and continue until approximately 37 weeks' gestation or until childbirth if before 37 weeks' gestation. Identification of women with inadequate omega-3 supply is achievable by a set of standardized questions on intake. Docosahexaenoic acid measurement from blood is another option to identify women with low status, but further standardization of laboratory methods and appropriate cutoff values is needed. Information on how to achieve an appropriate intake of docosahexaenoic acid or docosahexaenoic+eicosapentaenoic acid for women of childbearing age and pregnant women should be provided to women and their partners.
Topics: Female; Infant, Newborn; Pregnancy; Humans; Fatty Acids, Omega-3; Docosahexaenoic Acids; Premature Birth; Eicosapentaenoic Acid; Risk Reduction Behavior
PubMed: 38070679
DOI: 10.1016/j.ajogmf.2023.101251 -
Lipids in Health and Disease Aug 2023It is well known that pregnancy-induced hypertension (PIH) contributes significantly to the mortality rates of both mothers and babies during pregnancy. The relationship...
BACKGROUND
It is well known that pregnancy-induced hypertension (PIH) contributes significantly to the mortality rates of both mothers and babies during pregnancy. The relationship between fatty acids (FAs) and PIH remains debatable, with the causality between the two yet to be definitively established.
METHODS
Two-sample univariable and multivariable Mendelian Randomization (MR) analyses were executed, based on pooled data from Genome-Wide Association Studies (GWAS), to investigate any causal impact of FAs on PIH. A suite of methods was employed to assess causality, including inverse variance weighting (IVW), weighted median, MR Egger, simple mode, and weighted mode. Subsequently, the data underwent a sensitivity analysis (using Leave-One-Out analysis), a heterogeneity test (with MR-PRESSO and Cochran's Q test), as well as a multiple validity test (using MR-Egger regression). In multivariable analyses, fatty acids were first grouped to observe the effect of individual FAs on PIH. Subsequently, factors such as diabetes, high blood pressure, and body mass index (BMI) were incorporated into a multivariable examination of the impact of each FA on PIH. During this process, the IVW, weighted median, MR-Lasso, and MR-Egger methods were employed.
RESULTS
A systematic investigation was conducted into the causal impact of each FA on PIH. The findings indicated that Polyunsaturated Fatty Acids (PUFA), Omega3, the ratio of Omega6 to Omega3, and Docosahexaenoic Acid (DHA) have a causal relationship with PIH. Increases in PUFA, Omega3, and DHA could potentially reduce the risk of PIH, while an increase in the Omega6/Omega3 ratio could heighten the risk. The impacts of other FAs (including Total Fatty Acids, Monounsaturated Fatty Acids (MUFA), Saturated Fatty Acids (SFA), and Omega 6) on PIH were not substantiated by the MR analysis. In the univariate leave-one-out analysis, rs174564 was identified in PUFA, Omega3, and DHA as having a significant role. The tests with MR-Egger and MR-PRESSO found that the results were not influenced by pleiotropy and heterogeneity. After adjusting for BMI, Diabetes Mellitus, and pre-existing hypertension in the multivariable analysis, the results mirrored those obtained univariable.
CONCLUSION
The research implies that elevated levels of circulating PUFA, DHA, and Omega3 may serve as a protective mechanism against PIH, while higher Omega6/Omega3 ratios could potentially increase the risk of PIH. These findings may inform clinical strategies for PIH prevention.
Topics: Infant; Female; Pregnancy; Humans; Fatty Acids; Hypertension, Pregnancy-Induced; Genome-Wide Association Study; Mendelian Randomization Analysis; Fatty Acids, Omega-3; Docosahexaenoic Acids
PubMed: 37587460
DOI: 10.1186/s12944-023-01889-x -
Journal of Controlled Release :... Aug 2023Atherosclerosis is a chronic inflammatory vascular disease that is characterized by the accumulation of lipids and immune cells in plaques built up inside artery walls....
Atherosclerosis is a chronic inflammatory vascular disease that is characterized by the accumulation of lipids and immune cells in plaques built up inside artery walls. Docosahexaenoic acid (DHA, 22:6n-3), an omega-3 polyunsaturated fatty acid (PUFA), which exerts anti-inflammatory and antioxidant properties, has long been purported to be of therapeutic benefit to atherosclerosis patients. However, large clinical trials have yielded inconsistent data, likely due to variations in the formulation, dosage, and bioavailability of DHA following oral intake. To fully exploit its potential therapeutic effects, we have developed an injectable liposomal DHA formulation intended for intravenous administration as a plaque-targeted nanomedicine. The liposomal formulation protects DHA against chemical degradation and increases its local concentration within atherosclerotic lesions. Mechanistically, DHA liposomes are readily phagocytosed by activated macrophages, exert potent anti-inflammatory and antioxidant effects, and inhibit foam cell formation. Upon intravenous administration, DHA liposomes accumulate preferentially in atherosclerotic lesional macrophages and promote polarization of macrophages towards an anti-inflammatory M2 phenotype, resulting in attenuation of atherosclerosis progression in both ApoE and Ldlr experimental models. Plaque composition analysis demonstrates that liposomal DHA inhibits macrophage infiltration, reduces lipid deposition, and increases collagen content, thus improving the stability of atherosclerotic plaques against rupture. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) further reveals that DHA liposomes can partly restore the complex lipid profile of the plaques to that of early-stage plaques. In conclusion, DHA liposomes offer a promising approach for applying DHA to stabilize atherosclerotic plaques and attenuate atherosclerosis progression, thereby preventing atherosclerosis-related cardiovascular events.
Topics: Humans; Plaque, Atherosclerotic; Docosahexaenoic Acids; Liposomes; Atherosclerosis; Anti-Inflammatory Agents; Apolipoproteins E
PubMed: 37406819
DOI: 10.1016/j.jconrel.2023.06.035 -
American Journal of Respiratory and... Oct 2023Inflammation contributes to lung function decline and the development of chronic obstructive pulmonary disease. Omega-3 fatty acids have antiinflammatory properties and...
Inflammation contributes to lung function decline and the development of chronic obstructive pulmonary disease. Omega-3 fatty acids have antiinflammatory properties and may benefit lung health. To investigate associations of omega-3 fatty acids with lung function decline and incident airway obstruction in a diverse sample of adults from general-population cohorts. Complementary study designs: ) longitudinal study of plasma phospholipid omega-3 fatty acids and repeated FEV and FVC measures in the NHLBI Pooled Cohorts Study and ) two-sample Mendelian randomization (MR) study of genetically predicted omega-3 fatty acids and lung function parameters. The longitudinal study found that higher omega-3 fatty acid levels were associated with attenuated lung function decline in 15,063 participants, with the largest effect sizes for the most metabolically downstream omega-3 fatty acid, docosahexaenoic acid (DHA). An increase in DHA of 1% of total fatty acids was associated with attenuations of 1.4 ml/yr for FEV (95% confidence interval [CI], 1.1-1.8) and 2.0 ml/yr for FVC (95% CI, 1.6-2.4) and a 7% lower incidence of spirometry-defined airway obstruction (95% CI, 0.89-0.97). DHA associations persisted across sexes and smoking histories and in Black, White, and Hispanic participants, with associations of the largest magnitude in former smokers and Hispanic participants. The MR study showed similar trends toward positive associations of genetically predicted downstream omega-3 fatty acids with FEV and FVC. The longitudinal and MR studies provide evidence supporting beneficial effects of higher levels of downstream omega-3 fatty acids, especially DHA, on lung health.
Topics: Adult; Humans; Fatty Acids, Omega-3; Longitudinal Studies; Lung; Pulmonary Disease, Chronic Obstructive; Airway Obstruction; Docosahexaenoic Acids
PubMed: 37470492
DOI: 10.1164/rccm.202301-0074OC -
Clinical Nutrition (Edinburgh, Scotland) Jan 2024Arachidonic acid (ARA) and docosahexaenoic acid (DHA) are important structural components of neural cellular membranes and possess anti-inflammatory properties. Very... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Arachidonic acid (ARA) and docosahexaenoic acid (DHA) are important structural components of neural cellular membranes and possess anti-inflammatory properties. Very preterm infants are deprived of the enhanced placental supply of these fatty acids, but the benefit of postnatal supplementation on brain development is uncertain. The aim of this study was to test the hypothesis that early enteral supplementation with ARA and DHA in preterm infants improves white matter (WM) microstructure assessed by diffusion-weighted MRI at term equivalent age.
METHODS
In this double-blind, randomized controlled trial, infants born before 29 weeks gestational age were allocated to either 100 mg/kg ARA and 50 mg/kg DHA (ARA:DHA group) or medium chain triglycerides (control). Supplements were started on the second day of life and provided until 36 weeks postmenstrual age. The primary outcome was brain maturation assessed by diffusion tensor imaging (DTI) using Tract-Based Spatial Statistics (TBSS) analysis.
RESULTS
We included 120 infants (60 per group) in the trial; mean (range) gestational age was 26 (22 - 28) weeks and postmenstrual age at scan was 41 (39 - 47+) weeks. Ninety-two infants underwent MRI imaging, and of these, 90 had successful T1/T2 weighted MR images and 74 had DTI data of acceptable quality. TBSS did not show significant differences in mean or axial diffusivity between the groups, but demonstrated significantly higher fractional anisotropy in several large WM tracts in the ARA:DHA group, including corpus callosum, the anterior and posterior limb of the internal capsula, inferior occipitofrontal fasciculus, uncinate fasciculus, and the inferior longitudinal fasciculus. Radial diffusivity was also significantly lower in several of the same WM tracts in the ARA:DHA group.
CONCLUSION
This study suggests that supplementation with ARA and DHA at doses matching estimated fetal accretion rates improves WM maturation compared to control treatment, but further studies are needed to ascertain any functional benefit.
CLINICAL TRIAL REGISTRATION
www.
CLINICALTRIALS
gov; ID:NCT03555019.
Topics: Pregnancy; Infant; Infant, Newborn; Humans; Female; Infant, Premature; Docosahexaenoic Acids; Diffusion Tensor Imaging; Placenta; White Matter; Dietary Supplements; Arachidonic Acid; Brain
PubMed: 38061271
DOI: 10.1016/j.clnu.2023.11.037