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Immunomodulatory Effects of Omega-3 Fatty Acids: Mechanistic Insights and Health Implications.

Omega-3 fatty acids play a significant role in immunomodulation, with nutrigenomic approaches highlighting their impact on gene expression related to immune responses. Research indicates that omega-3 fatty acids can modulate inflammatory pathways, potentially reducing chronic inflammation and enhancing immune function. This review discusses the intersection of nutrigenomics and nutriepigenomics, focusing on how omega-3 fatty acids influence gene expression, immune function, and overall health. The immune system is a complex network responsible for defending the body against pathogens and maintaining internal balance. Comprised of innate and adaptive immunity, the system involves various cells, tissues, and organs working together to combat infections and prevent diseases. Omega-3 polyunsaturated fatty acids (PUFAs), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), play a significant role in modulating the immune system. These fatty acids influence immune cell function, membrane fluidity, and signaling processes, enhancing immune responses and reducing inflammation. Furthermore, EPA and DHA affect several signaling pathways, reducing the expression of proinflammatory cytokines and inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation, a critical transcription factor in the inflammatory response. Additionally, they activate PPAR-γ, further diminishing inflammatory gene expression. As precursors to specialized proresolving lipid mediators, EPA and DHA help shift the lipid mediator profile from proinflammatory to antiinflammatory derivatives, thus aiding in the resolution of inflammation.

Humans

A randomized trial of omega-3 fatty acids plus inositol versus N-acetylcysteine for the treatment of depression and mania in emotionally dysregulated youth age 5-17 with and without autism traits.

The aim of this study was to assess the effectiveness of the nutraceutical treatments combined omega-3 fatty acid plus inositol (O3I) versus N-acetylcysteine (NAC) in children and adolescents with emotional dysregulation and the impact of the co-occurrence of autism traits (AT). Participants were male and female children (5-17) with emotional dysregulation and the presence/absence of AT, as defined by Child Behavior Checklist score, randomized to receive open-label O3I (1020 mg EPA and 1000-2000 mg Inositol) or NAC (1800-2700 mg) daily for 6 weeks. Clinicians measured severity and improvement of depression and mania with the NIMH Clinical Global Improvement Scale (CGI). Parents completed Parent-Youth Mania Rating Scale (P-YMRS) and Children's Depression Inventory (CDI). Both O3I and NAC resulted in modest improvements in mania and depression and did not differ significantly in between group comparison in their effectiveness. Participants taking O3I, but not NAC, demonstrated statistically significant within group improvement in depression per CDI. Participants taking NAC had a greater decrease in P-YMRS scores versus O3I, but the difference did not reach statistical significance. In the presence of AT, NAC was more effective than O3I for mania but not for depression. Further, participants taking NAC, but not O3I, demonstrated significant within group improvement in SRS and BRIEF scores. These results suggest that O3I and NAC may be beneficial for mania and depression in youth, with trends towards O3I more effective for depression and NAC more effective for mania. The presence of AT in youth with emotional dysregulation may moderate the impact of NAC.

Humans

Short-term diet intervention comprising of olive oil, vitamin D, and omega-3 fatty acids alters the small non-coding RNA (sncRNA) landscape of human sperm.

Offspring health outcomes are often linked with epigenetic alterations triggered by maternal nutrition and intrauterine environment. Strong experimental data also link paternal preconception nutrition with pathophysiology in the offspring, but the mechanism(s) routing effects of paternal exposures remain elusive. Animal experimental models have highlighted small non-coding RNAs (sncRNAs) as potential regulators of paternal effects. Here, we characterised the baseline sncRNA landscape of human sperm and the effect of a 6-week dietary intervention on their expression profile. This study involves sncRNAseq profiling, that was performed on a subset (n = 17) of the participants enrolled in the PREPARE trial: 9 from the control group and 8 from the intervention group. 5'tRFs, miRNAs and piRNAs were the most abundant sncRNA subtypes identified; their expression was associated with age, BMI, and sperm quality. Nutritional intervention with olive oil, vitamin D and omega-3 fatty acids altered expression of 3 tRFs, 15 miRNAs and 112 piRNAs, targeting genes involved in fatty acid metabolism and transposable elements in the sperm genome. PREPARE Trial registration number: ISRCTN50956936, Trial registration date: 10/02/2014.

Humans

Antimicrobial Resistance Phenotypes and Genotypes of Cecal Digesta Escherichia coli of Pullets Fed Omega-3 Fatty Acids or Yeast Bioactives (Glycobolites).

Antimicrobial resistance (AMR) is a significant threat to poultry production and food safety. In laying hens, commensal Escherichia coli can serve as a reservoir of AMR and virulence genes. Although omega-3 fatty acids (N-3 FAs), yeast bioactives (YB), and spacing allowance (SA) influence gut health and immunity, their combined effects on AMR profiles of gut bacteria remain unclear. A total of 2,832 chicks were raised in enriched cages under high (HSA, 348&#xa0;cm2/bird) or low (LSA, 284&#xa0;cm2/bird) SA and fed a control diet (C), C+3% N-3 FA, or C+0.05% YB. At 4, 16, and 35&#xa0;weeks of age (woa), cecal contents were cultured on ChromoCult agar to isolate E. coli. Susceptibilities of isolates to 14 antibiotics were determined. Of the 428 isolates, 35.7% were resistant to at least one antimicrobial, and overall, AMR prevalence decreased with age (P&#xa0;<&#xa0;0.05). At each of 4 and 16 woa, N-3 FA-fed birds showed the lowest prevalance of ampicillin-resistant (P&#xa0;<&#xa0;0.05). The prevalence of streptomycin resistance was higher in N-3 FA than in YB-fed birds at 16 woa (P&#xa0;=&#xa0;0.02) but lower than in control-fed birds. Whole-genome sequencing and analysis of 237 selected isolates identified 19 antimicrobial resistance genes (ARGs) and 29 plasmids, with the distribution of 15 (78.9%) ARGs and 19 (65.5%) plasmid replicons affected by either diet, SA, or age (P&#xa0;<&#xa0;0.05). Several virulence genes were identified in sequenced E. coli isolates, with the prevalence of those encoding fimbriae, pili, protectin, and toxins being higher in younger pullets (P&#xa0;<&#xa0;0.05). Overall, isolates of phylogroups A and B1 were predominant; however, at 4 woa, phylogroup D isolates were most prevalent, depending on diet and SA (P&#xa0;<&#xa0;0.05). Isolates of serotype O23:H16, ST2 were the most prevalent. Of the 237 sequenced isolates, 13 were related to human extraintestinal pathogenic Escherichia coli (ExPEC) strains. Overall, these findings suggest that N-3 FA YB and SA modulate AMR and virulence genotypes of E. coli in laying hens, highlighting their potential use of these agents in mitigating AMR.

Antimicrobial resistance

Lysine iminylation derived from &#x3c9;-3 polyunsaturated fatty acids.

Protein posttranslational modifications (PTMs) play a central role for regulating protein function and cellular processes, with many PTMs arising from reactions with electrophilic metabolites. Here we extend the known landscape of PTMs with the identification of "lysine C3-iminylation," the conjugation of protein lysine residues with propionaldehyde. To stabilize iminylation for mass spectrometric analyses and distinguish it from other isomeric PTMs, we developed a fixation and stable-isotope labeling approach based on parallel reduction of proteome with sodium borohydride and borodeuteride. Analyses of protein hydrolysates confirmed the presence of C3-iminylation in Caenorhabditis elegans and mouse. Additionally, proteomics results demonstrated specificity of this PTM in vitro and in vivo and revealed C3-iminylation in proteins related to critical metabolic pathways. Importantly, collective evidence from isotope tracing as well as genetic, dietary, and pharmacological manipulation experiments uncovered that C3-iminylation originates from cytochrome P450 (CYP)-mediated oxidation of omega-3 fatty acids. Correspondingly, C3-iminylation levels were elevated in C. elegans daf-2(e1370) mutants, an aging model, in which CYP activity is generally increased. These findings not only expand our understanding of the biochemical diversity of PTMs but also underscore the complex interplay between lipid metabolism and protein modifications, enabling further exploration of their biological and clinical implications.

Animals

Causal Relationship of Polyunsaturated Fatty Acids With Mental Disorders: A Systematic Review and Meta-analysis.

CONTEXT: Mental disorders (MDs) pose a important global health challenge, with a complex pathogenesis complicating treatment development. Nutritional interventions, particularly polyunsaturated fatty acids (PUFAs), have gained attention as potential therapeutic options. OBJECTIVE: This Mendelian randomization (MR) meta-analysis aimed to evaluate the potential causal relationship between PUFAs and MDs. DATA SOURCES: Genome-wide association study data were utilized to analyze the association between PUFAs (including omega-3, omega-3 percentage [omega-3%], omega-6, omega-6 percentage [omega-6%], and omega-6 to omega-3 ratio) and 12 major MDs. DATA EXTRACTION: Two-sample MR technology was used to assess the role of PUFAs in MDs. DATA ANALYSIS: The MR analysis revealed that genetically predicted omega-3 was causally linked to MDs, such as obsessive-compulsive disorder, bipolar disorder, schizophrenia, and major depressive disorder. Omega-3% exhibited protective effects against emotional personality disorder. Conversely, omega-6 was inversely correlated with attention-deficit/hyperactivity disorder risk, while a high omega-6 to omega-3 ratio was associated with an increased risk of depression and other mood disorders. CONCLUSION: High omega-3 levels and omega-3% may reduce the risk of MDs, whereas a high omega-6:omega-3 ratio may elevate the risk. These findings highlight the potential of PUFAs, particularly omega-3, in MD prevention and treatment, while underscoring the need for further research into the complex interactions between omega-3 and omega-6. The study provides a scientific foundation for future clinical trials and dietary intervention strategies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO no. CRD42024598472.

Humans

Genome-wide variation analysis of two Salvia hispanica L. genotypes and implication for associations with metabolic and adaptive traits.

BACKGROUND: Advances in next-generation sequencing have accelerated genome-wide exploration of genetic diversity in underutilized oilseed crops. Salvia hispanica L. (chia), a high-nutrient pseudocereal rich in omega-3 fatty acids, is increasingly valued for its health benefits and commercial potential, yet it remains poorly characterized at the genomic level. Understanding the scale and nature of genomic variation is essential for improving complex traits such as oil yield, stress tolerance, and seed quality. METHODS: Two contrasting chia genotypes, Black-chia (CACH-B) and White- chia (CACH-W), were resequenced using the Bio-Resequencing Toolkit (BRT) pipeline. High-coverage sequencing, with a mapping rate exceeding 99% and an average depth of approximately 28&#xd7;, facilitated the detection and annotation of single-nucleotide polymorphisms (SNPs), insertions and deletions (InDels), copy-number variations (CNVs), and structural variants (SVs). The functional classification of variant impacts enabled the identification of genes potentially linked to metabolic and adaptive traits. RESULTS: A total of 1.97 million SNPs, 401,493 InDels, 836 CNVs, and 15,288 SVs were identified across the chia genome. Notably, approximately 53% of exonic SNPs were non-synonymous (dN/dS&#xa0;&#x2248;&#xa0;1.28), predominantly affecting lipid metabolism, transcriptional regulation, and stress response pathways, potentially altering key agronomic traits. In addition, CNV hotspots were concentrated in chromosomes 3 and 6, overlapping MYB, WRKY, and bZIP transcription factor loci, may potentially be involved in stress tolerance and yield. Furthermore, structural rearrangements, including inversions and duplications within the FAD2, FAD3, and CYP450 gene clusters, were potentially associated with seed pigmentation and omega-3 biosynthesis, pointing to their potential breeding relevance. Observed heterozygosity (H&#x2092;&#xa0;&#x2248;&#xa0;0.71) and nucleotide diversity (&#x3c0;&#xa0;&#x2248;&#xa0;7&#xa0;&#xd7;&#xa0;10-3) indicated moderate to high allelic richness. In addition, the low FST value (0.038) indicates substantial genomic similarity between the two genotypes. CONCLUSION: This study presents the first comprehensive map integrating SNPs, CNVs, and SVs in S. hispanica L. The results reveal a structurally dynamic genome characterized by substantial sequence and structural variation, providing valuable insights into genomic diversity and potential adaptive mechanisms in chia. The coexistence of high SNP diversity and abundant structural variation underpins chia's nutritional specialization and environmental resilience. These results deliver a foundational genomic resource for marker-assisted breeding, genome-wide association studies, and the development of climate-resilient chia cultivars.

Copy-number variation, structural variation

Prostaglandins and polyunsaturated fatty acids in heart muscle.

1. Dietary lipids modify fatty acid composition of cardiac lipids. Polyunsaturated fatty acids replace less unsaturated fatty acids in phospholipds. 2. Mortality following isoproterenol-stimulation increase with decreasing amount of arachidonic acid in cardiac phospholipds. 3. In normal human heart muscle the ratio of essential, omega-6/nonessential, omega-3 fatty acids diminshes from age 17 to age 50 years. 4. In sudden cardiac death the ratio of prostaglandin substrate, C20:4, to prostaglandin inhibitor, C22:6, is frequently much higher than expected.

Age Factors

Haemostatic function and platelet polyunsaturated fatty acids in Eskimos.

Death from cardiovascular disease is rare among Eskimos. Haemostasis was investigated in twenty-one Greeland Eskimos and twenty-one age and sex matched Danish controls. Platelet lipid analysis demonstrated that a high consumption of omega-3 polyunsaturated fatty acids (such as cis 5, 8, 11, 14, 17-eicosapentaenoic acid [C20:5]) by Eskimos increased the proportion of omega-3 polyunsaturated fatty acids in the platelets. The Eskimos had a significantly longer bleeding-time due to a reduction in platelet aggregation. It is suggested that C20:5 in the platelets is converted by the vascular-wall tissue to an anti-aggregatory prostacyclin. Partial dietary substitution of arachidonic acid by eicosapentaenoic acid may reduce the incidence of thrombotic disorders, including myocardial infarction.

Adult

Vegan multinutrient supplementation significantly increases Omega-3 index and 25-OH-vitamin D status: a randomized, double-blind, placebo-controlled trial in healthy young vegans.

In this randomized, double-blind, placebo-controlled trial, 72 healthy vegan adults (aged 19-57 years) received a multinutrient supplement consisting of a vitamin and mineral supplement (providing 26 &#xb5;g vitamin D) and an omega-3 supplement administered in either a single dose (EPA 98.7 mg, DHA 171.0 mg, additional vitamin D 36 &#xb5;g, vitamin E 3.7 mg) or a double dose (EPA 197.4 mg, DHA 342.0 mg, additional vitamin D 72 &#xb5;g, vitamin E 7.4 mg) or placebo capsules for 4 months. Nutrient biomarkers were assessed at baseline and at the end of the intervention after 4 months. An analysis of covariance was employed to test for between-group differences (p < 0.05) and adjusted for multiple testing using the Bonferroni-Holm method. Compared to the control group, which showed on average a significant decline in both the omega-3-index and 25-hydroxyvitamin D, participants in both intervention groups demonstrated significant increase in these parameters (p < 0.001). Although the double dose group exhibited numerically greater increases in omega-3 index and vitamin D compared to the simple dose group, the differences between these dosing regimens were not statistically significant. As expected, vitamin E levels remained unchanged, reflecting its inclusion solely for antioxidative protection in the omega-3 supplement rather than as a critical nutrient in vegan diets. In conclusion, supplementation significantly improved omega-3 and vitamin D status in healthy vegans, with no significant benefit from doubling the dose. Although clinical endpoints were not evaluated, improved nutrient status may have potential implications for health. The study has been registered at the German Clinical Trials Register (DRKS00028151).

Humans

Omega-1, Omega-2 and Omega-3 hydroxylation of long-chain fatty acids, amides and alcohols by a soluble enzyme system from Bacillus megaterium.

A soluble enzyme preparation from Bacillus megaterium, previously shown to hydroxylate free fatty acids to isomeric mixtures of Omega-1, Omega-2 and Omega-3 monohydroxy fatty acids in the presence of NADPH and O2, has now been shown to act also on fatty amides but not only hydrocarbons or fatty acid methyl esters. Using 14-C-labelled substrates, both the chain-length specificity and the positional specificity of hydroxylation was determined for fatty acids, alcohols and amides. The most active saturated fatty acid (pentadecanoic) was hydroxylated at a rate 10 times greater than the most active amide (myristamide) and 14 times faster than the most active alcohol (1-tetradecanol). Among the saturated fatty acids, the order of activity as hydroxylation substrates was C15 greater than C16 greater than C14 greater than C17 greater than C13 greater than C18 = C12. For amides the order was C14 greater than C12 greater than C15 greater than C16 while for alcohols it was C14 greater than C13 = C15 greater than C12 greater than C15. Four cis-monounsaturated fatty acids were also tested. Oleic, palmitoleic and cis-12-octadecenoic acids were more active than their saturated analogs but cis-5-tetradecenoate was less active than myristate. For all of the substrates mentioned above, with the possible exception of several unsaturated acids, the alkyl chains were monohydroxylated to give isomeric mixtures of the Omega-1, Omega-2 and Omega-3 derivatives. The distribution of these three isomers varied with chain-length and type of substrate but generally, the Omega-2 position was favored. The terminal methyl (Omega) group of these substrates was never hydroxylated and there did not appear to be significant hydroxylation of methylene carbons beyond the Omega-3 position. Based on the data presented here and in a previous paper, a model is proposed for the enzyme-substrate complex which involves hydrophobic binding and sequestering of the terminal methyl group of the substrate and electrostatic binding of the substrate's polar functional group.

Amides

Protection against carbon tetrachloride-induced lipid peroxidation in the rat by dietary vitamin E, selenium, and methionine as measured by ethane evolution.

Dietary vitamin E, selenium (Se), and methionine were tested for their ability to inhibit carbon tetrachloride (CCL4)-induced lipid peroxidation. Peroxidation, in vivo, was monitored by the evolution of ethane, an autoxidation product of omega-3-unsaturated fatty acids. Weanling rats were fed a basal diet low in vitamin E, Se, and sulfur-containing amino acids, or diets individually supplemented with these factors. After 3 to 7 weeks, the rats were injected with CCL4 (ip) and ethane was collected for 9 hours. Cumulative ethane evolution was increased by CCl4 in all groups. Vitamin E, Se, and methionine reduced ethane evolution from CCl4-treated rats by 82%, 74%, and 60%, respectively. The toxicity of CCl4 was decreased in correlation with ethane evolution. Thus, methionine and Se, probably by maintaining intracellular glutathione and glutathione peroxidase, protected against CCl4-induced lipid peroxidation, as did vitamin E. Substitution of cod liver oil, which is rich in omega-3-unsaturated fat, for lard in the basal diet increased CCl4-induced ethane evolution six-fold. Relative inhibition by the dietary supplements was not changed. Thus, the feeding of cod liver oil greatly increased ethane production which facilitated the detection and measurement of lipid peroxidation in vivo.

Animals

Lipid metabolism, atherogenesis, and haemostasis in Eskimos: the role of the prostaglandin-3 family.

In Eskimos coronary heart disease is a rarity. This can partly be explained by their favorable plasma lipid levels. An additional factor seems, however, to be that in Eskimo food polyunsaturated fatty acids of the omega-3 series replace those of the omega-6 series. C20:5, omega-3 can be converted by the vessel wall to an antiaggregatory substance, whereas it has no proaggregatory effect on platelets. Consistent with these findings Eskimos were found to have a nearly 2-fold longer bleeding time than Danes. Platelet aggregability, too, was markedly depressed when exposing platelets from Eskimos to ADP and collagen.

Adenosine Diphosphate

Fatty-acid composition of rat brain lipids. Determined by support-coated open-tubular gas chromatography.

The nonhydroxy fatty acid composition of rat brain lipids (except gangliosides) was determined by support-coated open-tubular (SCOT) gas chromatography. Fatty acids of both odd and even chain lengths ranging from C14 to C26 were detected. Brain lipids contained 49% saturated, 29% monounsaturated, and 22% polyunsaturated fatty acids. Monoenoic fatty acids were mainly of the omega-9 and omega-7 series with minor amounts of omega-10 and amega-11 isomers. Dienes and trienes consisted of omega-6, amega-7, and omega-9 series. Tetraenes were of the omega-6 series. Small amounts of omega-6 and omega-3 pentaenes were detected. The most abundant polyunsaturated fatty acid was 22:6omega-3. The advantages of support-coated open-tubular columns over wall-coated open-tubular columns for the analysis of brain lipid fatty acids are discussed.

Animals

Fatty acids and breast cancer: Epidemiology, subtype-specific metabolism, immune regulation, and clinical translation.

Fatty acids (FAs) are bioactive dietary and metabolic molecules that participate in membrane architecture, energy homeostasis, inflammatory signaling, gene regulation and immune function, all of which intersect with breast cancer (BC) risk, progression and treatment response. In this narrative review we integrate epidemiological, clinical, translational and mechanistic evidence on the role of FAs in BC. Saturated, monounsaturated, trans- and polyunsaturated FAs (PUFAs) are treated as distinct biological exposures rather than interchangeable measures of total fat intake. Similarly, evidence from dietary assessment, circulating biomarkers, erythrocyte membrane composition, adipose tissue stores and tumor lipid signatures is interpreted separately, because each captures exposure and biology at a different level. BC subtypes differ in FA synthesis, uptake, oxidation, storage and remodeling: luminal tumors are frequently linked to hormone-regulated lipogenesis, human epidermal growth factor receptor 2 (HER2)-positive tumors to growth-factor-driven lipid metabolism, and triple-negative tumors to exogenous FA uptake, inflammatory lipid mediators and ferroptosis-related vulnerabilities. FA-derived mediators also shape immune-cell polarization, cytokine signaling and the tumor microenvironment, and dietary FAs may reshape the gut microbiota; the fiber-derived short-chain FAs it produces, distinct from dietary FAs, likewise help regulate immune and inflammatory tone. Clinical data suggest possible roles for fat-quality modification and selected n-3 PUFA interventions, but findings are heterogeneous and not yet sufficient to support routine biomarker-guided precision onco-nutrition. Candidate biomarkers, such as erythrocyte n-6:n-3 composition, require prospective validation before clinical implementation. FA biology thus represents a modifiable but complex axis in BC prevention, tumor biology and supportive care.

Humans

Hydrocarbon gases produced during in vitro peroxidation of polyunsaturated fatty acids and decomposition of preformed hydroperoxides.

Hydrocarbon gases have been used previously as an index of lipid peroxidation in vivo and in vitro. In vitro experiments are reported on the formation of hydrocarbon gases from peroxidizing omega-3 and omega-6 fatty acids. Hydrocarbon gases were not released during a 20-hr peroxidation phase but were released following the decomposition of hydroperoxides by addition of excess ascorbic acid. The major hydrocarbon gas products in iron, copper, or hematin catalyzed peroxidation systems were ethane or ethylene from linolenic acid, and pentane from linoleic acid and arachidonic acid. Calculations of the ratios of hydrocarbon gases formed were based on fatty acid decrease and/or change in diene conjugation and peroxide values. Depending on the fatty acid, catalyst, and calculation basis used, pentane formation was as high as 1.3 mol %, ethane 4.3 mol %, and ethylene 10.6 mol %.

Chemical Phenomena