Effects of ω‐3 Polyunsaturated Fatty Acids on the Homeostasis of CD4+ T Cells and Lung Injury in Mice With Polymicrobial Sepsis

Background: Sepsis is a common cause of death in critically ill patients. An overwhelming inflammatory response and imbalance of helper T (Th) cells and regulatory T (Treg) cells are thought to be involved in the progression of sepsis. ω‐3 Polyunsaturated fatty acids (PUFAs) were found to have anti‐inflammatory and immunomodulatory properties. This study investigated the effects of ω‐3 PUFAs on the balance of Th subsets, Treg cells, and the inflammatory response in septic mice. Methods: Mice were randomly assigned to soybean oil (SO) and fish oil (FO) groups. The 2 groups received an identical nutrient distribution except for the sources of the fat. The SO group was fed soybean oil, while part of the soybean oil was replaced by fish oil in the FO group. The FO group had an ω‐6/ω‐3 PUFA ratio of 2:1. After feeding the diets for 3 weeks, sepsis was induced by cecal ligation and puncture (CLP), and mice were sacrificed on days 0, 1, and 3. Results: Compared with the SO group, the FO group had lower inflammatory mediator levels in the plasma and peritoneal lavage fluid after CLP. Also, the FO group had lower Th1, Th2, and Th17 percentages and a higher Th1/Th2 ratio in blood. In lung tissues, neutrophil infiltration was reduced, whereas peroxisome proliferator–activated receptor γ expression was upregulated. Conclusions: A fish oil diet with an ω‐6/ω‐3 PUFA ratio of 2:1 may elicit more balanced Th polarization, alleviate inflammatory responses, and attenuate lung injury in CLP‐induced sepsis.     

Soybean and Fish Oil Mixture With Different ω‐6/ω‐3 Polyunsaturated Fatty Acid Ratios Modulates Dextran Sulfate Sodium–Induced Changes in Small Intestinal Intraepithelial γδT‐Lymphocyte Expression in Mice

Background: This study investigated the effect of different ω‐6/ω‐3 polyunsaturated fatty acid (PUFA) ratios on dextran sulfate sodium (DSS)–induced changes to small intestinal intraepithelial lymphocyte (IEL) γδT‐cell expression. Methods: Mice were assigned to 3 control and 3 DSS‐treated groups and were maintained on a low‐fat semipurified diet. One of the control (S) groups and a DSS (DS) group were provided with soybean oil; the other 2 control (Hω‐3 and Lω‐3) groups and 2 other DSS (DHω‐3 and DLω‐3) groups were fed either a soybean and fish oil mixture with a ω‐6/ω‐3 ratio of 2:1 or 4:1. After feeding the respective diets for 2 weeks, the DSS groups were given distilled water containing 2% DSS, and the control groups were given distilled water for 5 days. All groups were further provided distilled water 5 days for recovery, and the small intestinal IEL γδT‐cell subset was isolated for analysis. Results: DSS treatment resulted in a lower small intestinal IEL γδT‐cell percentage and higher messenger RNA (mRNA) expressions of Reg IIIγ, keratinocyte growth factor (KGF), and complement 5a receptor (C5aR) by IEL γδT cells. Fish oil administration enhanced the proportion of small intestinal IEL γδT cells. Compared with the DLω‐3 group, the DHω‐3 group had lower Reg IIIγ, KGF, and C5aR mRNA expressions and higher expression of peroxisome proliferator‐activated receptor (PPAR)–γ gene by small intestinal IEL γδT cells. Conclusions: Fish oil diets with a ω‐6/ω‐3 PUFA ratio of 2:1 were more effective than those with a ratio of 4:1 in improving DSS‐induced small intestinal injury, and activation of PPAR‐γ in IEL γδT cells may be associated with resolution of small intestinal inflammation.     

Effects of the ω‐6:ω‐3 Fatty Acid Ratio of Fat Emulsions on the Fatty Acid Composition in Cell Membranes and the Anti‐Inflammatory Action

Background: This study investigated the effects of parenterally administered fish oil (FO) on the fatty acid composition in rats to determine the optimal ω‐6:ω‐3 polyunsaturated fatty acid (PUFA) ratio of fat emulsions to achieve an anti‐inflammatory effect. Methods: Male Sprague‐Dawley rats were infused a parenteral nutrition (PN) solution containing fat emulsions with different ω‐6:ω‐3 PUFA ratios. The fatty acid content of phospholipids in the membranes of splenocytes was analyzed by gas chromatography (experiment 1). In addition, the amounts of leukotriene (LT) B₄ and LTB₅ released from peritoneal polymorphonuclear leukocytes (PMNs) were measured by high‐performance liquid chromatography (experiment 2). Results: In experiment 1, after infusion of the fat emulsion containing FO, the ω‐3 PUFA content in cell membranes rose to 70% of the peak value on day 1 and nearly reached a plateau on day 3. The highest ratio of eicosapentaenoic acid (EPA) to arachidonic acid (AA) was achieved by administrating a PN solution with the smallest ω‐6:ω‐3 PUFA ratio. In experiment 2, a larger amount of LTB₅ was released from Ca‐ionophore‐stimulated PMNs taken from rats given a larger quantity of FO. The ratio of LTB₅:LTB₄ released from PMNs correlated positively with the EPA:AA ratio in the membranous phospholipid and in serum. Conclusions: The ω‐3 PUFAs were readily incorporated into the cell membrane within 3 days of infusion with the fat emulsion. The EPA:AA ratio in membranous phospholipid in PMNs was positively correlated with the LTB₅:LTB₄ production ratio and was a good indicator of anti‐inflammatory effects.     

Effect of Dietary Fatty Acid Composition on Th1/Th2 Polarization in Lymphocytes

Background: It has become increasingly clear that polyunsaturated fatty acids (PUFAs) have immunomodulatory effects. However, the intake of these fatty acids used in animal studies often greatly exceeds dietary human intake. Whether differences in the composition of fatty acids that are consumed in amounts consistent with normal dietary intake can influence immune function remains uncertain. Methods: We manufactured 3 types of liquid diet, related to modified fatty acid composition (ω‐6/ω‐3 = 0.25, 2.27 and 42.9), but excluding eicosapentaenoic acid and docosahexaenoic acid, based upon a liquid diet used clinically in humans. We assessed CD3‐stimulated cytokine production of splenocytes in female BALB/c mice (n = 4 per group) fed 1 of 3 liquid diets for 4 weeks. We also measured the cytokine production of peripheral blood mononuclear cells stimulated with phorbol myristate acetate and ionomycin in humans at the end of a 4‐week period of consumption of 2 different liquid diets (ω‐6/ω‐3 = 3 and 44). Results: We found that the ratio of interfero ω‐γ (IFN‐γ) / interleukin‐4 (IL‐4) was significantly higher in mice fed theω ‐3 rich diet than in others. In humans, IFN‐γ / IL‐4 was significantly higher after the ω‐3 versus the ω‐6 enhanced diet. Conclusions: Differences in the composition of ω‐3 andω ‐6 PUFAs induces a shift in the Th1/Th2 balance in both mouse and human lymphocytes, even when ingested in normal dietary amounts. An ω‐3 rich diet containing α‐linolenic acid modulates immune function.     

Intravenous ω‐3 Fatty Acids Plus Gemcitabine

Background: Marine‐derived ω‐3 fatty acids (ω‐3FAs) have proven antitumor activity in vivo and in vitro and improve quality of life (QOL) in clinical cancer studies. These changes may be mediated by reduction in circulating proangiogenic and proinflammatory factors. In this first study of intravenous ω‐3FAs as a therapy in cancer patients, we aimed to assess if it could augment the antitumor activity of gemcitabine in patients with advanced pancreatic cancer and improve QOL. Materials and Methods: Patients were administered gemcitabine 1000 mg/m³ weekly followed by up to 100 g (200 mg/mL) of ω‐3 rich lipid emulsion for 3 weeks followed by a rest week. This was continued for up to 6 cycles, progression, unacceptable toxicity, patient request, or death. The primary outcome measure was objective response rate, with secondary outcome measures of overall and progression free survival, QOL scores, and adverse events. Results: Fifty patients were recruited. Response rate was 14.3% and disease control rate was 85.7%. Overall and progression free survival were 5.9 and 4.8 months, respectively. Increase in global health of > 10% over baseline was seen in 47.2% of patients. More than 50% of patients had > 10% increase in QOL scores in generic symptom scores and both disease‐specific domains. Grade 3/4 adverse events were thrombocytopenia (8%), neutropenia (12%), nausea or vomiting (4%), and chills (6%). Conclusion: Intravenous ω‐3FAs in combination with gemcitabine shows evidence of improved activity and benefit to QOL in patients with advanced pancreas cancer and is worthy of investigation in a randomized phase III trial.     

Impact of the omega-3 to omega-6 polyunsaturated fatty acid ratio on cytokine release in human alveolar cells

Background: ω‐3 polyunsaturated fatty acids (PUFAs) and ω‐6 PUFAs have opposing influences on inflammation. The objective was to determine whether lipopolysaccharide (LPS)–induced cytokine release by human alveolar cells was affected by changes in the ω‐3/ω‐6 ratio of cell membranes induced by different supplies of PUFAs. Methods: After LPS challenge, PUFAs were added to alveolar cells as docosahexaenoic acid (DHA, ω‐3) and arachidonic acid (AA, ω‐6) in 4 different DHA/AA ratios (1:1, 1:2, 1:4, and 1:7), and the effects on cytokine release were measured. Results: The supply of 1:1 and 1:2 DHA/AA ratios reversed the baseline predominance of ω‐6 over ω‐3 in the ω‐3/ω‐6 PUFA ratio of cell membranes. The release of proinflammatory cytokines (tumor necrosis factor α, interleukin‐6, and interleukin‐8) was reduced by 1:1 and 1:2 DHA/AA ratios (P < .01 to P < .001) but increased by 1:4 and 1:7 DHA/AA ratios (P < .01 to P < .001) vs control. The 1:1 and 1:2 ratios increased the release of anti‐inflammatory interleukin‐10 (P < .001). The balance between proinflammatory and anti‐inflammatory cytokines showed an anti‐inflammatory response with 1:1 and 1:2 ratios and a proinflammatory response with 1:4 and 1:7 ratios (P < .001). Conclusions: This study showed that proinflammatory cytokine release was dependent on the proportion of ω‐3 in the ω‐3/ω‐6 ratio of alveolar cell membranes, being reduced with the supply of a high proportion of DHA and increased with a high proportion of AA, respectively. These results support the biochemical basis for current recommendations to shift the PUFA supply from ω‐6 to ω‐3 in nutrition support of patients with acute lung injury.     

Liver Disease,Systemic Inflammation,and Growth Using a Mixed Parenteral Lipid Emulsion,Containing Soybean Oil,Fish Oil,and Medium Chain Triglycerides,Compared With Soybean Oil in Parenteral Nutrition–Fed Neonatal Piglets

Background: The optimal parenteral lipid emulsion for neonates should reduce the risk of intestinal failure–associated liver disease and inflammation, while supporting growth and development. This could be best achieved by balanced content of ω‐6 and ω‐3 polyunsaturated fatty acids (PUFAs). Using a neonatal piglet model of parenteral nutrition (PN), we compared a 100% soy oil–based emulsion (ω‐6:ω‐3 PUFA: 7:1) with a mixed lipid emulsion comprising 30% soy oil, 30% medium‐chain triglycerides, 25% olive oil, and 15% fish oil (ω‐6:ω‐3 PUFA: approximately 2.5:1) with regard to liver disease, inflammation, and fatty acid content in plasma and brain. Method: Neonatal piglets, 3–6 days old, underwent jugular catheter insertion for isonitrogenous, isocaloric PN delivery over 14 days. The IL group (n = 8) was treated with Intralipid; the ML group (n = 10) was treated with the mixed lipid (SMOFlipid). Bile flow, liver chemistry, C‐reactive protein (CRP), and PUFA content in plasma phospholipids and brain were compared. Results: Compared with the IL group, ML‐treated piglets had increased bile flow (P = .008) and lower total bilirubin (P = .001) and CRP (P = .023) concentrations. The ω‐6 long‐chain PUFA content was lower in plasma and brain for the ML group. The key ω‐3 long‐chain PUFA for neonatal development, docosahexaenoic acid (DHA), was not different between groups. Conclusion: The mixed lipid, having less ω‐6 PUFA and more ω‐3 PUFA, was able to prevent liver disease and reduce systemic inflammation in PN‐fed neonatal piglets. However, this lipid did not increase plasma or brain DHA status, which would be desirable for neonatal developmental outcomes.     

Prefeeding With ω‐3 Fatty Acids Suppresses Inflammation Following Hemorrhagic Shock

Background: Hemorrhagic shock followed by resuscitation stimulates an inflammatory response. This study tests the hypothesis that prefeeding with fish oil rich in ω‐3 fatty acids (FAs) will attenuate that response. Methods: Male Sprague‐Dawley rats (n = 60; 350 ± 30 g) were randomly but unequally assigned to 3 groups: sham (n = 12), control (n = 24), and fish oil (n = 24). In the fish oil group, rat chow was supplemented with fish oil (600 mg/kg/d, 25% ω‐3 FA). Control and sham group diets were supplemented with corn oil. Under fluothane, hemorrhagic shock was induced, and arterial pressure was maintained at 25 to 30 mm Hg for 30 minutes. Resuscitation was carried out by giving 21 mL/kg lactated Ringer's solution and returning shed blood to the animal. Half of each group was killed at 30 minutes and at 4 hours postresuscitation. Liver samples were assayed for indicators of inflammation and heat shock protein 25 (Hsp25). Lung edema was measured. Results: All animals survived. At 30 minutes postresuscitation, expression of mRNA for inducible nitric oxide synthase (iNOS) was significantly elevated in the control group but normal in the fish oil group. At 4 hours, expression of mRNA for Hsp25 was significantly increased in the fish oil group. Lung edema index was significantly lower in the fish oil group than in either sham or control groups. Conclusions: Fish oil prefeeding in a rodent model of hemorrhagic shock was associated with increased liver mRNA expression of Hsp25, reduced liver mRNA expression of iNOS, and decreased lung edema. These findings support the validity of the study hypothesis.     

A New Intravenous Fat Emulsion Containing Soybean Oil,Medium‐Chain Triglycerides,Olive Oil,and Fish Oil

Background: SMOFlipid 20% is an intravenous lipid emulsion (ILE) containing soybean oil, medium‐chain triglycerides, olive oil, and fish oil developed to provide energy, essential fatty acids (FAs), and long‐chain ω‐3 FAs as a mixed emulsion containing α‐tocopherol. The aim was to assess the efficacy and safety of this new ILE in pediatric patients receiving home parenteral nutrition (HPN) compared with soybean oil emulsion (SOE). Methods: This single‐center, randomized, double‐blind study included 28 children on HPN allocated to receive either SMOFlipid 20% (n = 15) or a standard SOE (Intralipid 20%, n = 13). ILE was administered 4 to 5 times per week (goal dose, 2.0 g/kg/d) within a parenteral nutrition regimen. Assessments, including safety and efficacy parameters, were performed on day 0 and after the last study infusion (day 29). Lipid peroxidation was determined by measurement of thiobarbituric acid reactive substances (TBARS). Results: There were no significant differences in laboratory safety parameters, including liver enzymes, between the groups on day 29. The mean ± standard deviation changes in the total bilirubin concentration between the initial and final values (day 29 to day 0) were significantly different between groups: SMOFlipid group ?1.5 ± 2.4 µmol/L vs SOE group 2.3 ± 3.5 µmol/L, P < .01; 95% confidence interval [CI], ?6.2 to ?1.4). In plasma and red blood cell (RBC) phospholipids, the ω‐3 FAs C20:5ω‐3 (eicosapentaenoic acid) and + C22:6ω‐3 (docosahexaenoic acid) increased significantly in the SMOFlipid group on day 29. The ω‐3:ω‐6 FA ratio was significantly elevated with SMOFlipid 20% compared with SOE group (plasma, day 29: 0.15 ± 0.06 vs 0.07 ± 0.02, P < .01, 95% CI, 0.04–0.11; and RBC, day 29: 0.23 ± 0.07 vs 0.14 ± 0.04, P < .01, 95% CI, 0.04–0.13). Plasma α‐tocopherol concentration increased significantly more with SMOFlipid 20% (15.7 ± 15.9 vs 5.4 ± 15.2 µmol/L, P < .05; 95% CI, ?2.1 to 22.6). The low‐density lipoprotein–TBARS concentrations were not significantly different between both groups, indicating that lipid peroxidation did not differ between groups. Conclusions: SMOFlipid 20%, which contains 15% fish oil, was safe and well tolerated, decreased plasma bilirubin, and increased ω‐3 FA and α‐tocopherol status without changing lipid peroxidation.     

Nutrition Modulation of Cardiotoxicity and Anticancer Efficacy Related to Doxorubicin Chemotherapy by Glutamine and ω‐3 Polyunsaturated Fatty Acids

Background: Doxorubicin (DOX) has been one of the most effective antitumor agents against a broad spectrum of malignancies. However, DOX‐induced cardiotoxicity forms the major cumulative dose‐limiting factor. Glutamine and ω‐3 polyunsaturated fatty acids (PUFAs) are putatively cardioprotective during various stresses and/or have potential chemosensitizing effects during cancer chemotherapy. Methods: Antitumor activity and cardiotoxicity of DOX treatment were evaluated simultaneously in a MatBIII mammary adenocarcinoma tumor‐bearing rat model treated with DOX (cumulative dose 12 mg/kg). Single or combined treatment of parenteral glutamine (0.35 g/kg) and ω‐3 PUFAs (0.19 g/kg eicosapentaenoic acid and 0.18 g/kg docosahexaenoic acid) was administered every other day, starting 6 days before chemotherapy initiation until the end of study (day 50). Results: Glutamine alone significantly prevented DOX‐related deterioration of cardiac function, reduced serum cardiac troponin I levels, and diminished cardiac lipid peroxidation while not affecting tumor inhibition kinetics. Single ω‐3 PUFA treatment significantly enhanced antitumor activity of DOX associated with intensified tumoral oxidative stress and enhanced tumoral DOX concentration while not potentiating cardiac dysfunction or increasing cardiac oxidative stress. Intriguingly, providing glutamine and ω‐3 PUFAs together did not consistently confer a greater benefit; conversely, individual benefits on cardiotoxicity and chemosensitization were mostly attenuated or completely lost when combined. Conclusions: Our data demonstrate an interesting differentiality or even dichotomy in the response of tumor and host to single parenteral glutamine and ω‐3 PUFA treatments. The intriguing glutamine × ω‐3 PUFA interaction observed draws into question the common assumption that there are additive benefits of combinations of nutrients that are beneficial on an individual basis.     

ω‐3 Fatty Acids Reduce Chemotherapy‐Induced Hematological Toxicity by Bone Marrow Stimulation in Mice

Background: ω‐3 Fatty acids exert several benefits during chemotherapy, such as preventing intestinal mucosal damage and improving response to chemotherapy. However, little is known about the effect of ω‐3 fatty acids on chemotherapy‐induced hematological toxicities. Methods: Mice that had consumed either an ω‐3–rich or an ω–3‐poor diet for 2 weeks were intraperitoneally administered cisplatin. The resultant changes in blood cell count, bone marrow cell count, and cytokine levels in bone marrow supernatant were analyzed. The effect of ω‐3 fatty acids on human peripheral blood mononuclear cells (PBMCs) exposed to cisplatin was also examined. Results: Although peripheral blood cell counts decreased after cisplatin treatment in both groups of mice, the decrease in white blood cell count was significantly lower in mice that consumed the ω‐3–rich diet. The decrease in bone marrow cells after cisplatin treatment was also reduced in mice that consumed the ω‐3–rich diet. Levels of stem cell factor (SCF) and fibroblast growth factor 1 (FGF‐1) were significantly higher in bone marrow supernatants from mice that consumed the ω‐3–rich diet. The rate of apoptosis in PBMCs (after exposure to cisplatin) cultured in medium containing ω‐3 fatty acids was significantly lower than in PBMCs cultured in control medium. Conclusion: ω‐3–Rich diets reduced chemotherapy‐induced leukopenia in mice. This may be the result of increased numbers of bone marrow cells due to higher levels of SCF and FGF‐1 in the bone marrow.     

Th17 cell accumulation is decreased during chronic experimental colitis by (n-3) PUFA in Fat-1 mice

During colon inflammation, Th17 cells and immunosuppressive regulatory T cells (Treg) are thought to play promotive and preventative roles, respectively. Dietary (n-3) PUFA favorably modulate intestinal inflammation in part by downregulating T-cell activation and functionality. We used the Fat-1 mouse, a genetic model that synthesizes long-chain (n-3) PUFA de novo, to test the hypothesis that (n-3) PUFA protect against colonic inflammation by modulating the polarization of Treg and Th17 cells during colitis. Male and female wild-type (WT) and Fat-1 mice were administered dextran sodium sulfate (DSS) in the drinking water (2.5%) to induce acute (5 d DSS) or chronic (3 cycles DSS) colitis and the percentage of Treg and Th17 cells residing locally [colonic lamina propria (cLP)] and systemically (spleen) was determined by flow cytometry. The percentage of Treg in either tissue site was unaffected by genotype (P > 0.05); however, during chronic colitis, the percentage of Th17 cells residing in both the spleen and cLP was lower in Fat-1 mice compared to WT mice (P < 0.05). Colonic mucosal mRNA expression of critical Th17 cell cytokines and chemokine receptors (IL-17F, IL-21, and CCR6) were lower, whereas expression of the Th17 cell suppressive cytokine, IL-27, was greater in Fat-1 mice compared to WT mice during chronic colitis (P < 0.05). Moreover, colon histological scores were improved in Fat-1 mice (P < 0.05). Collectively, these results demonstrate for the first time, to our knowledge, that (n-3) PUFA can modulate the colonic mucosal microenvironment to suppress Th17 cell accumulation and inflammatory damage following the induction of chronic colitis.     

Effects of ω‐3 Fish Oil Lipid Emulsion Combined With Parenteral Nutrition on Patients Undergoing Liver Transplantation

Background: The effect of parenteral nutrition (PN) support supplemented with ω‐3 fatty acids was investigated in a randomized, controlled clinical trial at the Affiliated Drum Tower Hospital, Medical School of Nanjing University. Materials and Methods: Ninety‐eight patients with the diagnosis of end‐stage liver disease or hepatic cellular carcinoma were admitted for orthotopic liver transplantation at the Affiliated Drum Tower Hospital. The patients were randomly divided into 3 groups: diet group (n = 32), PN group (n = 33), and polyunsaturated fatty acid (PUFA) group (n = 33). Patients in the PN and PUFA groups received isocaloric and isonitrogenous PN for 7 days after surgery. Venous heparin blood samples were obtained for assay on days 2 and 9 after surgery. A pathological test was performed after reperfusion of the donor liver and on day 9. Results: Alanine aminotransferase levels were improved significantly by PUFA treatment compared with traditional PN support (P < .05). Compared with the results on day 9 in the PN group, a significant difference was seen in the extent of increase of the prognostic nutrition index and prealbumin in the PUFA group. The pathological results also showed that ω‐3 fatty acid supplementation reduced hepatic cell injury. PUFA therapy also decreased the incidence of infectious morbidities and shortened the posttransplant hospital stay significantly. Conclusion: Posttransplant PN support can greatly improve metabolism of protein and nutrition states of patients. ω‐3 fatty acid–supplemented PN significantly reduces injury of the transplanted liver, decreases the incidence of infectious morbidities, and shortens posttransplant hospital stay.     

ω‐3 Fatty Acids Prevent Hepatic Steatosis,Independent of PPAR‐α Activity,in a Murine Model of Parenteral Nutrition–Associated Liver Disease

Objectives: ω‐3 Fatty acids (FAs), natural ligands for the peroxisome proliferator‐activated receptor–α (PPAR‐α), attenuate parenteral nutrition–associated liver disease (PNALD). However, the mechanisms underlying the protective role of ω‐3 FAs are still unknown. The aim of this study was to determine the effects of ω‐3 FAs on hepatic triglyceride (TG) accumulation in a murine model of PNALD and to investigate the role of PPAR‐α and microsomal triglyceride transfer protein (MTP) in this experimental setting. Methods: 129S1/SvImJ wild‐type or 129S4/SvJaePparatm/Gonz/J PPAR‐α knockout mice were fed chow and water (controls); oral, fat‐free PN solution only (PN‐O); PN‐O plus intraperitoneal (IP) ω‐6 FA‐predominant supplements (PN–ω‐6); or PN‐O plus IP ω‐3 FA (PN–ω‐3). Control and PN‐O groups received sham IP injections of 0.9% NaCl. Hepatic histology, TG and cholesterol, MTP activity, and PPAR‐α messenger RNA were assessed after 19 days. Results: In all experimental groups, PN feeding increased hepatic TG and MTP activity compared with controls. Both PN‐O and PN–ω‐6 groups accumulated significantly greater amounts of TG when compared with PN–ω‐3 mice. Studies in PPAR‐α null animals showed that PN feeding increases hepatic TG as in wild‐type mice. PPAR‐α null mice in the PN‐O and PN–ω‐6 groups demonstrated variable degrees of hepatic steatosis, whereas no evidence of hepatic fat accumulation was found after 19 days of oral PN plus IP ω‐3 FAs. Conclusions: PN induces TG accumulation (steatosis) in wild‐type and PPAR‐α null mice. In PN‐fed wild‐type and PPAR‐α null mice given IP ω‐3 FAs, reduced hepatic TG accumulation and absent steatosis are found. Prevention of steatosis by ω‐3 FAs results from PPAR‐α–independent pathways.     

Rapid Incorporation of ω‐3 Fatty Acids Into Colonic Tissue After Oral Supplementation in Patients With Colorectal Cancer

Background: The purpose of the study was to examine whether a preoperative supplement with ω‐3 fatty acids (FAs) leads to their incorporation into colonic tissue in patients scheduled for colorectal cancer surgery. This would be of interest because ω‐3 FAs have potential beneficial (local) immunological effects that might benefit these patients. Methods: In a randomized, double‐blind, prospective, placebo‐controlled, single‐center intervention trial, patients referred for elective colorectal cancer surgery received either an ω‐3 FA–enriched oral nutrition supplement (ONS) (200 mL twice daily) providing 2.0 g of eicosapentaenoic acid (EPA) and 1.0 g of docosahexaenoic acid (DHA) per day or a standard ONS for 7 days before surgery. Tissue samples from healthy colonic tissue (mucosa and muscular layer) were obtained during surgery, and tissue fatty acid composition was analyzed by gas chromatography. Results: EPA was significantly higher in colonic mucosa (P = .001) and in the colonic muscular layer (P = .004) in the ω‐3 FA group compared with controls. Patients in the ω‐3 FA group also tended to have higher docosapentaenoic acid and DHA levels in colonic tissue. Conclusions: EPA is incorporated rapidly into colonic mucosa and colonic muscular layer in patients given 3 g of ω‐3 FA daily for 7 days before surgery for colorectal cancer. This may lead to potential beneficially effects on (local) immune function, which might benefit these patients.     

Rapid Enrichment of Cell Phospholipids in Long‐Chain Polyunsaturated ω‐3 Fatty Acids After a Bolus Intravenous Injection of a Medium‐Chain Triacylglycerol

The present review aims at highlighting the use of a recently developed medium‐chain triacylglycerol:fish oil (MCT:FO) emulsion for the rapid and sustained enrichment of long‐chain polyunsaturated ω‐3 fatty acids in cell phospholipids. Preclinical in vitro, in vivo, and ex vivo experiments are briefly considered with emphasis on the changes in the fatty acid pattern of cell phospholipids in several organs, the partial correction of liver steatosis, and the cardiovascular modification of cationic and functional variables observed in ω‐3‐depleted rats examined 60–120 minutes after a bolus intravenous (IV) injection (1.0 mL) of the MCT:FO emulsion. The clinical findings collected in healthy male volunteers before or after the bolus IV injection (50.0 mL) of either the MCT:FO emulsion or a control medium‐chain triacylglycerol:long‐chain triacylglycerol emulsion are also reviewed, with emphasis on the rapid (within 60 minutes) and sustained (up to 2–3 days) enrichment of platelet and white blood cell phospholipids in long‐chain polyunsaturated ω‐3 fatty acids and hemostatic safety of the present procedure proposed as a tool for the rapid prevention or correction of metabolic and functional disturbances in humans with a relative deficiency in such ω‐3 fatty acids.     

Pretreatment With an Intravenous Lipid Emulsion Increases Plasma Eicosapentanoic Acid and Downregulates Leukotriene B4, Procalcitonin,and Lymphocyte Concentrations After Open Heart Surgery in Infants

Background: The effect of providing a lipid emulsion containing medium‐chain triglyceride (MCT), soybean oil, and fish oil in critically ill infants is not widely studied. This study investigated lipid emulsion effects on plasma phospholipids and immune biomarkers. Materials and Methods: Thirty‐two infants undergoing cardiopulmonary bypass (CPB) and dependent on parenteral nutrition (PN) were randomized to receive either soybean oil (control, n = 16) or a 50:40:10 mixture of MCT, soybean oil, and fish oil (treatment, n = 16). PN was administered for 3 days preoperatively and 10 days postoperatively. Fatty acids, procalcitonin (PCT), leukotriene B₄ (LTB₄), and lymphocytes were quantified at baseline, before surgery, and days 1, 7 and 10 after surgery. Results: PCT was significantly lower in the treatment vs control group 1 day postoperatively (P = .01). The treatment group exhibited a lower ω‐6 to ω‐3 ratio (P = .0001) and a higher ω‐3 concentration at all postoperative study periods (P = .001). Treatment resulted in higher (P < .05) plasma phospholipid eicosapentaenoic acid (EPA) on days 7 and 10, while α‐linolenic acid, arachidonic acid, and docosahexaenoic acid remained constant. An increase in plasma phospholipid EPA concentration was associated with a decrease in plasma phospholipid LTB₄ concentration (P < .05). On postoperative day 10, treatment infants with high Pediatric Risk of Mortality III scores exhibited a 45% lower lymphocyte concentration (P < .05). Conclusion: These findings suggest that treating infants undergoing CPB with a lipid emulsion containing ω‐3 improves fatty acid status and results in a lower inflammatory response after surgery. Overall, this alternative ω‐3–enriched lipid emulsion may benefit clinical outcomes of critically ill infants after cardiac surgery.     

Restoration of Mannose‐Binding Lectin Complement Activity Is Associated With Improved Outcome in Patients With Advanced Pancreatic Cancer Treated With Gemcitabine and Intravenous ω‐3 Fish Oil

Background: Pancreatic cancer has an extremely poor clinical outcome. Surrogate biomarkers for outcome are scarce. There is mixed evidence for the association of high mannose‐binding lectin (MBL) complement activity with cancer outcomes, including reduced survival and increased infectious complications. ω‐3–rich fatty acids (ω‐3FA) attenuate production of proinflammatory cytokines and potentially manipulate complement activity. Materials and Methods: As part of a single‐arm phase II trial in a university hospital, patients with advanced pancreatic adenocarcinoma were treated with weekly ω‐3FA–rich intravenous infusion (Lipidem [B. Braun Melsungen AG, Melsungen, Germany]: up to 100 g/wk) plus gemcitabine chemotherapy until withdrawal or tumor progression. Primary outcome measure was objective response rate. Changes in complement activity, which were a secondary outcome measure, were analyzed and relation to clinical outcome determined. Results: Twenty‐three patients were assessable for time to progression (TTP), overall survival (OS), and complement activity. No hypoactivity in alternative and classical pathways was demonstrated. Baseline MBL was low in 10 of 23 patients (43.5%). There was no difference in OS or TTP between low‐ and high‐baseline MBL patients. Of these 10 patients, 5 were classified as MBL responders. MBL responders had a tendency toward improved OS over nonresponders (8.9 vs 4.4 months, P = .07). MBL responders had significantly improved TTP over nonresponders (10.6 vs 5.3 months, P = .03). Conclusion: MBL restoration had an association with improved outcome in the cohort of patients with low MBL activity at baseline. The independent contribution of ω‐3FA to this effect warrants further investigation in the form of randomized clinical trials.     

Dietary Fish Oil Aggravates Paracetamol‐Induced Liver Injury in Mice

Background: Paracetamol (APAP) hepatotoxicity remains the leading cause of drug‐induced liver failure. Fish oil, which contains ω‐3 fatty acids, has demonstrated therapeutic efficacy in several models of liver disease. Evidence for its use in APAP intoxication, however, is conflicting. The effects of fish oil supplementation on APAP‐induced liver failure were investigated. Methods: Ten C57BL6/J mice were fed a diet based on menhaden fish oil (MEN) or soybean oil (SOY) for 3 weeks followed by APAP intoxication. In a second experiment, the prefeeding period was reduced to 5 days. In a third experiment, 10 mice received the study diets for 3 weeks, after which they received chronic, low‐dose APAP administration for another 4 weeks. Finally, 10 mice received oral parenteral nutrition supplemented with either intravenous (IV) soybean‐based or fish oil–based lipid emulsion for 19 days, followed by APAP intoxication. Results: The extent of hepatocellular necrosis (3.8 ± 0.2 vs 2.8 ± 0.2; P = .021) and serum alanine aminotransferase values (2807 ± 785 vs 554 ± 141 IU/L; P = .048) were significantly elevated in mice fed a MEN diet compared with SOY‐diet fed controls. Long‐term, low‐dose APAP administration did not lead to liver injury irrespective of study diet. Pretreatment with soybean‐ or fish oil–based IV lipid emulsions followed by APAP intoxication demonstrated no significant differences in hepatic injury between groups. Conclusion: Within therapeutic ranges, APAP is harmless to the liver irrespective of dietary fat composition. IV use of fish oil did not increase APAP‐induced hepatotoxicity, but animals fed a fish oil–based diet were more susceptible, rather than resistant, to APAP‐induced hepatotoxicity.     

CLA and n-3 PUFA differentially modulate clinical activity and colonic PPAR-responsive gene expression in a pig model of experimental IBD

BACKGROUND AND AIMS: Conjugated linoleic acid (CLA) and n-3 polyunsaturated fatty acids (PUFA) have been proposed as important pharmaco-nutrients for modulating mucosal immunity and therapeutic responses in patients with inflammatory bowel disease (IBD). We evaluated the ability of CLA and n-3 PUFA alone or in combination to modulate IBD in a pig model of dextran sodium sulfate (DSS)-induced colitis. METHODS: Sixty-four, 15-day-old pigs were used to evaluate the effect of CLA, n-3 PUFA and a 50:50 mixture of CLA and n-3 PUFA on growth, clinical activity and colonic PPAR-responsive gene expression. Diets were formulated to contain: 1.33% soybean oil (control); 1.33% CLA; 1.33% fish oil; or 1.33% of a 50:50 mixture of CLA and fish oil. Intestinal inflammation was induced by an intragastric challenge with DSS on day 42 of dietary supplementation. The colonic expression of peroxisome proliferator-activated receptor-gamma (PPAR-gamma), PPAR gamma- and delta-responsive genes, keratinocyte growth factor (KGF) and tumor necrosis factor (TNF-alpha) were assayed by quantitative RT-PCR. RESULTS: The onset of IBD was delayed, colitis less severe and growth suppression attenuated in pigs fed CLA, which correlated with induction of colonic PPAR gamma and its responsive gene PPAR gamma-coactivator-1alpha (PGC1-alpha) and downregulation of TNF-alpha. However, dietary supplementation with n-3 PUFA alone or in combination with CLA resulted in an early onset of disease (i.e., day 2) and faster recovery on days 6 and 7, which correlated with a marked induction of the PPAR delta-responsive gene uncoupling protein 3 (UCP3). CLA and n-3 PUFA acted synergistically to upregulate colonic KGF expression in DSS-challenged pigs but n-3 PUFA blocked CLA-induced PPAR gamma activation. CONCLUSION: Dietary CLA-supplementation upregulated colonic PPAR gamma expression and contributed to delaying the onset of experimental IBD, whereas n-3 PUFA failed to protect from IBD, although it accelerated colonic regeneration and clinical remission by activating PPAR delta.