Objective: To investigate the preliminary efficacy of a high n‐3 plus low n‐6 (H3‐L6) dietary intervention in improving mood stability in Bipolar Disorder (BD) when compared to dietary intervention with usual U.S. levels of n‐6 and n‐3 polyunsaturated fatty acid (PUFA) intakes (control diet, CD).Methods: This 2‐arm, parallel‐group, randomized, modified double‐blind, controlled 48‐week study of 12‐week intensive diet intervention in subjects with BD was conducted at a single suburban‐rural site in the mid‐Atlantic region. Participants with DSM‐IV TR BD I or II with hypomanic or depressive symptoms were randomized, stratified on gender (N = 82). The intervention included the provision of group‐specific study foods and dietary counseling. Variability of mood symptoms was measured by a twice‐daily, 12‐week ecological momentary analysis (EMA) paradigm, and group differences were analyzed using multilevel models. Circulating n‐3 and n‐6 fatty acids were measured at baseline and after 4, 8, and 12 weeks of diet exposure.Results: All 82 randomized participants were included in biochemical analyses. Seventy participants completed at least 2 EMA surveys and were included in primary EMA analyses. Variability in mood, energy, irritability, and pain as measured using EMA was reduced in the H3‐L6 group compared to the CD group. No significant differences in mean ratings of mood symptoms, or any other symptom measures, were detected. The dietary intervention effect on target PUFAs significantly differed by the group over time.Conclusions: A dietary intervention adjunctive to usual care showed preliminary efficacy in improving variability in mood symptoms in participants with BD.Trial Registration: ClinicalTrials.Gov NCT02272010.

Cystic fibrosis lung disease is characterized by chronic bacterial infections in the setting of mucus abnormalities. Patients experience periodic exacerbations that manifest with increased respiratory symptoms that require intensification of therapy with enhanced airway clearance and intravenous (IV) antibiotics. In an observational study we tested if the profile of metabolites in serum distinguished the pre-from post-exacerbation state and which systemically measurable pathways were affected during the process to recovery. Serum collected within 48 h of start and completion, respectively of IV antibiotics was collected from people with CF ages 6–30 years. Three day food records were collected prior to each sample. To reduce variation between subjects only subjects who had pancreatic insufficiency, had similar CF mutations, and did not have CF liver disease or diabetes were included. Metabolomic profiling was conducted by Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy with metabolites being identified based on retention time/index, mass to charge ratio and comparison to known compounds. Biostatistical analyses used paired t-test with correction for multiple comparisons and orthogonal partial least square discriminant analysis. Thirty subjects (20 male) with a mean ± SEM age of 15.3 ± 1.2 years participated, 17 of whom had matched food-records. Lung function was significantly improved post-therapy compared to pre-therapy, (mean ± SEM) 75 ± 4% vs. 68 ± 4% predicted (n = 26). Serum metabonomics showed distinction of the pre-vs. post-therapy groups with 123 compounds contributing to the differentiation pre-versus post-antibiotics by multiple biostatistical analyses. Compounds and pathways affected included bile acids and microbial derived amino acid metabolites, increases in lipid classes of the glycerophospholipid, glycerolipids, cholesterol, phopsholipids, and most pronounced, the class of sphingolipids. Changes in n6/n3 fatty acids, decreased polyamines but increased metabolites in the nitric oxide pathway, and changes in the tryptophan-kynurenine pathway indicated decreased inflammation at resolution of exacerbation. Changes in serum metabolites that distinguished CF pulmonary exacerbation vs. resolution of symptoms showed evidence of decreased inflammation and improvement from a catabolic state.

Natural variations in the ¹³C:¹²C ratio (carbon-13 isotopic abundance [δ¹³C]) of the food supply have been used to determine the dietary origin and metabolism of fatty acids, especially in the n-3 PUFA biosynthesis pathway. However, n-6 PUFA metabolism following linoleic acid (LNA) intake remains under investigation. Here, we sought to use natural variations in the δ¹³C signature of dietary oils and fatty fish to analyze n-3 and n-6 PUFA metabolism following dietary changes in LNA and eicosapentaenoic acid (EPA) + DHA in adult humans. Participants with migraine (aged 38.6 ± 2.3 years, 93% female, body mass index of 27.0 ± 1.1 kg/m²) were randomly assigned to one of three dietary groups for 16 weeks: 1) low omega-3, high omega-6 (H6), 2) high omega-3, high omega-6 (H3H6), or 3) high omega-3, low omega-6 (H3). Blood was collected at baseline, 4, 10, and 16 weeks. Plasma PUFA concentrations and δ¹³C were determined. The H6 intervention exhibited increases in plasma LNA δ¹³C signature over time; meanwhile, plasma LNA concentrations were unchanged. No changes in plasma arachidonic acid δ¹³C or concentration were observed. Participants on the H3H6 and H3 interventions demonstrated increases in plasma EPA and DHA concentration over time. Plasma δ¹³C-EPA increased in total lipids of the H3 group and phospholipids of the H3H6 group compared with baseline. Compound-specific isotope analysis supports a tracer-free technique that can track metabolism of dietary fatty acids in humans, provided that the isotopic signature of the dietary source is sufficiently different from plasma δ¹³C.

A previous report showed that 12-week lowering of dietary omega-6 linoleic acid (LA) coupled with increased omega-3 polyunsaturated fatty acid (PUFA) intake (H3-L6 diet) reduced headache frequency and improved quality of life in patients with chronic daily headaches (CDHs) compared to dietary LA reduction alone (L6 diet). The trial also showed that targeted dietary manipulation alters PUFA-derived lipid mediators and endocannabinoids. However, several additional classes of lipid mediators associated with pain in preclinical models were not measured. The current secondary analysis investigated whether the clinical benefits of the H3-L6 diet were related to changes in plasma unesterified PUFA-derived lipid mediators known to be involved in nociception, including prostanoids. Lipid mediators were measured by ultra-high-pressure liquid chromatography coupled with tandem mass-spectrometry. Compared to baseline, dietary LA lowering with or without added omega-3 fatty acids did not alter unesterified n-6 PUFA-derived lipid mediators, although several species derived from LA, di-homo-gamma-linolenic acid, and arachidonic acid were positively associated with headache frequency and intensity, as well as mental health burden. Alpha-linolenic acid (ALA)-derived metabolites were also associated with increased headache frequency and intensity, although they did not change from the baseline in either dietary group. Compared to baseline, docosahexaenoic acid (DHA)-derived epoxides were more elevated in the H3-L6 group compared to the L6 group. Diet-induced elevations in plasma DHA-epoxides were associated with reduced headache frequency, better physical and mental health, and improved quality of life (p < 0.05). Prostanoids were not detected, except for PGF2-alpha, which was not associated with any outcomes. This study demonstrates that diet-induced changes in DHA-epoxides were associated with pain reduction in patients with chronic headaches, whereas n-6 PUFA and ALA metabolites were associated with nociception. Lipid mediator associations with mental health and quality of life paralleled pain management outcomes in this population. The findings point to a network of multiple diet-modifiable lipid mediator targets for pain management in individuals with CDHs.