Lipid Emulsion Formulation of Parenteral Nutrition Affects Intestinal Microbiota and Host Responses in Neonatal Piglets

Background: Total parenteral nutrition (TPN) is a cause of intestinal microbial dysbiosis and impaired gut barrier function. This may contribute to life‐threatening parenteral nutrition–associated liver disease and sepsis in infants. We compared the effects of a lipid emulsion containing long‐chain ω‐3 polyunsaturated fatty acids (PUFAs; SMOFlipid) and a predominantly ω‐6 PUFA emulsion (Intralipid) on microbial composition and host response at the mucosal surface. Materials and Methods: Neonatal piglets were provided isocaloric, isonitrogenous TPN for 14 days versus sow‐fed (SF) controls. Equivalent lipid doses (10 g/kg/d) were given of either SMOFlipid (ML; n = 10) or Intralipid (SO; n = 9). Ileal segments and mucosal scrapings were used to characterize microbial composition by 16S rRNA gene sequencing and quantitative gene expression of tight junction proteins, mucins, antimicrobial peptides, and inflammatory cytokines. Results: The microbial composition of TPN piglets differed from SF, while ML and SO differed from each other (analysis of molecular variance; P < .05); ML piglets were more similar to SF, as indicated by UniFrac distance (P < .05). SO piglets showed a specific and dramatic increase in Parabacteroides (P < .05), while ML showed an increase in Enterobacteriaceae (P < .05). Gene expression of mucin, claudin 1, β‐defensin 2, and interleukin 8 were higher in TPN; overall increases were significantly less in ML versus SO (P < .05). Conclusion: The formulation of parenteral lipid is associated with differences in the gut microbiota and host response of TPN‐fed neonatal piglets. Inclusion of ω‐3 long‐chain PUFAs appears to improve host‐microbial interactions at the mucosal surface, although mechanisms are yet to be defined.     

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.     

Effect of Parenteral Fish Oil Lipid Emulsion in Parenteral Nutrition Supplementation Combined With Enteral Nutrition Support in Patients Undergoing Pancreaticoduodenectomy

Background: The effect of parenteral fish oil lipid emulsion in parenteral nutrition (PN) supplementation combined with enteral nutrition (EN) support on pancreaticoduodenectomy (PD) was investigated with a randomized controlled clinical trial at the Affiliated Drum Tower Hospital. Materials and Methods: Seventy‐six patients who underwent PD in the Department of Hepatobiliary Surgery were randomly divided into 2 groups: the polyunsaturated fatty acid (PUFA) group (n = 38) and control group (n = 38). Patients in the PUFA group received parenteral fish oil lipid emulsion supplementation combined with early EN support for 5 days after PD. Venous blood samples were obtained for assay on the day before surgery and on day 6 after surgery. Results: Compared with the results of the control group, a significant difference was seen in the extent of the decrease in total protein and prealbumin in the PUFA group (P < .05). Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) were significantly decreased on day 6 in the PUFA group (P < .01), and a significant difference was seen in the extent of decrease in ALT, AST, and LDH in the PUFA group (P < .05). The ratio of infectious complications in the PUFA group was significantly decreased, as well as the postoperative hospital stay (P < .05), and there was no hospital mortality in this study. Conclusion: Parenteral fish oil lipid emulsion in PN supplementation combined with EN support can greatly improve the nutrition state and liver function of patients, decrease the incidence of infectious morbidities, and shorten the postoperative hospital stay.     

Parenteral Soy Oil and Fish Oil Emulsions

Background: Parenteral nutrition (PN)–associated liver disease (PNALD) remains a significant cause of morbidity and mortality for neonates dependent on PN. Total fat emulsion dose and composition, particularly the large amount of ω‐6 long‐chain polyunsaturated fatty acids in plant oils, have been proposed as risk factors for PNALD. We hypothesized restriction of the dose of emulsion would prevent PNALD, regardless of the composition, but growth could be compromised. Methods: Using a neonatal piglet model, we compared conventional soy oil emulsion (Intralipid), dosed high (SO10, n = 8: 10 g/kg/d) and low (SO5, n = 6: 5 g/kg/d), with fish oil (Omegaven), dosed low (FO5, n = 8: 5 g/kg/d). Piglets were given isonitrogenous PN for 14 days. The normal range for all parameters was determined by measurement in equivalent aged sow‐reared piglets. Results: Bile flow was lower with high‐dose Intralipid, outside the normal range, while higher for the other groups (SO10, 5.4 µg/g; SO5, 8.6 µg/g; FO5, 13.4 µg/g; P = .010; normal range, 6.5–12.2 µg/g). Total body weight was low in all treatment groups (SO10, 4.4 kg; SO5, 4.5 kg; FO5, 5.0 kg; P = .038; normal range, 5.2–7.3 kg). Brain weight was not different between groups (SO10, 40.3 g; SO5, 36.0 g; FO5, 36.6 g; P = .122; normal range, 41.8–51.4 g). Corrected for body weight, brain weight was lowest in the fish oil group (SO10, 9.3 g/kg; SO5, 8.0 g/kg; FO5, 7.3 g/kg; P < .001; normal range, 5.9–9.0 g/kg). Conclusion: Low‐dose fat emulsions reduce the risk of developing PNALD. Further investigation of the risk to brain development in neonates exposed to dose restriction, particularly with fish oil, is required.     

Impact of Providing a Combination Lipid Emulsion Compared With a Standard Soybean Oil Lipid Emulsion in Children Receiving Parenteral Nutrition

Background: Soybean oil lipid emulsion may compromise immune function and promote hepatic damage due to its composition of long‐chain fatty acids, phytosterols, high proportion of ω‐6 fatty acids, and low α‐tocopherol levels. Combination lipid emulsions have been developed using medium‐chain triglyceride oil, fish oil, and/or olive oil, which provide adequate essential fatty acids, a smaller concentration of ω‐6 fatty acids, and lower levels of phytosterols. The purpose of this systematic review is to determine if combination lipid emulsions have a more favorable impact on bilirubin levels, triglyceride levels, and incidence of infection compared with soybean oil lipid emulsions in children receiving parenteral nutrition. Methods: This study comprises a systematic review of published studies. Data were sufficient and homogeneous to conduct a meta‐analysis for total bilirubin and infection. Results: Nine studies met the inclusion criteria. Meta‐analysis showed that combination lipid emulsion decreased total bilirubin by a mean difference of 2.09 mg/dL (95% confidence interval, –4.42 to 0.24) compared with soybean oil lipid emulsion, although the result was not statistically significant (P = .08). Meta‐analysis revealed no statistically significant difference in incidence of infection between the combination lipid emulsion and the soybean oil lipid emulsion groups (P = .846). None of the 4 studies that included triglyceride as an outcome detected a significant difference in triglyceride levels between the combination lipid emulsion and soybean oil lipid emulsion groups. Conclusion: There is inadequate evidence that combination lipid emulsions offer any benefit regarding bilirubin levels, triglyceride levels, or incidence of infection compared with soybean oil lipid emulsions.     

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.     

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.     

Supplemental Parenteral Vitamin E Into Conventional Soybean Lipid Emulsion Does Not Prevent Parenteral Nutrition–Associated Liver Disease in Full‐Term Neonatal Piglets

Background: Parenteral nutrition–associated liver disease (PNALD) continues to cause morbidity and mortality for neonates with intestinal failure. Lipid peroxidation is one potential etiological factor. This study was designed to test if supplementing vitamin E into conventional soy‐based lipid would reduce the risk of PNALD. Methods: Sixteen piglets, aged 2–5 days and weighing 1.8–2.5 kg, were randomized to parenteral nutrition (PN) with soy lipid (SO, n = 8) or the same lipid plus α‐tocopherol, the most bioactive form of vitamin E (SO+E, n = 8). After 17 days, bile flow, liver chemistry, gene expression associated with bile acid metabolism, and bile acid composition were assessed. C‐reactive protein (CRP) and oxidative stress markers, including plasma 8‐isoprostane, were measured. All results were compared with a sow‐reared control group (CON). Results: Comparing PN‐treated groups, SO vs SO+E mean bile flow (5.91 vs 5.54 µL/g liver; P = .83), serum bile acid concentration (39.2 vs 26.6 µmol/L; P = .12), and total bilirubin (35.2 vs 26.9 µmol/L; P = .56) were not different. Gene expression related to bile acid metabolism and bile composition was not different between PN groups. There was no difference in CRP (41.8 vs 36.8 µg/mL; P = .22) or in plasma 8‐isoprostane (27.9 vs 26.1 pg/mL; P = .77). Conclusions: In term neonatal piglets, supplemental vitamin E did not prevent cholestasis. Additional vitamin E was not associated with reduced inflammation or oxidative stress. The benefit of supplementing vitamin E into conventional lipid, vs adding fish oil, to prevent early onset of PNALD requires further clarification.     

Effect of an Olive Oil–Based Lipid Emulsion Compared With a Soybean Oil–Based Lipid Emulsion on Liver Chemistry and Bile Acid Composition in Preterm Infants Receiving Parenteral Nutrition

Background: The pathogenesis of parenteral nutrition (PN)–associated liver dysfunction is multifactorial. Lipid emulsions may be one of the putative mechanisms. Our aim was to comparatively assess the effect of parenteral olive oil– and soybean oil–based lipid emulsions on liver chemistry and bile acid composition in preterm infants. Methods: We performed a double‐blind, randomized clinical study in which 103 preterm infants were randomly assigned to PN using either soybean oil–based lipid emulsion (SO; n = 51) or olive oil (OO)–based lipid emulsion (OO; n = 52). The primary end point was liver chemistry. The secondary end point was the plasma bile acid composition. Results: One hundred infants completed this study. In the SO group, the serum direct bilirubin was significantly higher after PN for 7 days compared with the OO group. Bile acids increased over time in both treatment groups. However, specific differences in the change in bile acid composition over time were noted between groups. Conclusions: Differences in direct bilirubin and bile acid composition were observed over time between the 2 groups. Considering the long‐term use of lipid emulsions in higher risk babies, these findings might be useful for understanding the pathogenesis of PN‐associated liver dysfunction.     

Evolution of Lipid Profile,Liver Function,and Pattern of Plasma Fatty Acids According to the Type of Lipid Emulsion Administered in Parenteral Nutrition in the Early Postoperative Period After Digestive Surgery

Background: The metabolic effects of intravenous lipid emulsions (ILEs) used in parenteral nutrition (PN) depend on their fatty acid composition. Methods: Subjects in this prospective and randomized double‐blind study were 28 adult patients post digestive surgery. PN was started after surgery and lasts for 5 days. Randomly, patients receive 1 of 4 different ILEs: medium‐chain triglycerides/long‐chain triglycerides (soybean oil; MCT/LCT), olive/soybean oil (oleic), long‐chain triglycerides (soybean oil; LCT), and structured lipid. On days 0 and 6, serum liver function tests were analyzed for cholesterol, triglycerides, lipoproteins, and serum fatty acids. Results: No differences were found in the 4 groups according to their gender, age, body mass index, diagnosis, baseline white blood cell, C‐reactive protein, glucose levels, and other study parameters. Differential significant changes were not observed in any of the hepatic function parameters or plasmatic lipid levels between the groups. A significant decrease was observed in cis monounsaturated fatty acids (MUFAs) and a significant increase in ω‐6 polyunsaturated fatty acids (PUFAs) andω ‐3 PUFA values in LCT and structured groups compared with MCT/LCT and oleic groups, and a tendency for a decrease in trans fatty acids in the oleic and structured groups was found. Conclusions: All ILEs administered were safe and well tolerated. The changes in serum fatty acids reflected the pattern of fatty acids administered with different ILEs. The group receiving the olive oil emulsion achieved a fatty acid composition of serum lipids that could offer major therapeutic or biological advantages.     

Parenteral Fish Oil as Monotherapy Improves Lipid Profiles in Children With Parenteral Nutrition–Associated Liver Disease

Background: Parenteral nutrition (PN) is a life‐saving therapy but has been associated with dyslipidemia. Because fish oil has been shown to have positive effects on lipid profiles, the authors hypothesize that a parenteral fish oil lipid emulsion will improve lipid profiles in children who are PN dependent. Methods: The authors examined the lipid profiles of a unique cohort of 10 children who were exclusively administered a fish oil–based lipid emulsion while on PN for a median duration of 14 weeks. Longitudinal data analysis with a generalized estimating equations approach was used to determine the sterol and bilirubin levels based on duration of the fish oil–based lipid emulsion. Results: After 14 weeks of fish oil monotherapy, children had a 24% increase in high‐density lipoprotein. Compared to baseline, serum low‐density lipoprotein, very low‐density lipoprotein, total cholesterol, and triglyceride levels all significantly decreased by 22%, 41%, 17%, and 46%, respectively. Eight children had their bilirubin improved with a decreased direct bilirubin from 6.9 mg/dL (range, 4.4‐10.7) at baseline to 2.3 mg/dL (range, 1.3‐4.0) after 14 weeks, and a decrease in total bilirubin from 8.7 mg/dL (range, 5.5‐13.7) to 3.8 mg/dL (range, 2.2‐6.5). Conclusion: A fish oil–based lipid emulsion used as monotherapy in children who exclusively depended on PN for survival was associated with significant improvement in all major lipid panels as well as improvement of hyperbilirubinemia. Parenteral fish oil may be the preferred lipid source in children with dyslipidemia.     

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.     

Platelet Arachidonic Acid Deficiency May Contribute to Abnormal Platelet Function During Parenteral Fish Oil Monotherapy in a Piglet Model

Background: Fish oil monotherapy has been an advance for treating intestinal failure–associated liver disease (IFALD). However, such patients are at risk of bleeding complications from liver disease and because fish oil can inhibit thrombosis. We have previously reported abnormal platelet function in neonatal piglets given fish oil monotherapy during parenteral nutrition (PN). The purpose of this study was to determine if abnormal fatty acid composition of the platelets could explain the prior observed antiplatelet effect. Methods: Neonatal piglets were assigned to 2 treatments: PN with fish oil monotherapy (FO; n = 4) or PN with soy oil (SO; n = 5). On day 14, plasma was collected and platelets isolated by centrifuging. The fatty acid content in plasma and platelet plug were measured using gas liquid chromatography and compared with controls (CON; n = 5). Results: The arachidonic acid (AA) content in the FO group was on average half that of the SO group, in both the platelets (FO, 3.5% vs SO, 7.6%; P = .021; CON, 4.5%–11%) and the plasma (FO, 3.8% vs SO, 9.2%; P = .002; CON, 6.1%–9.5%). No bleeding complications were observed for any piglets during PN treatment. Conclusions: Using platelet mapping, we have previously shown that neonatal piglets given fish oil monotherapy have abnormal platelet function in the AA pathway. This report demonstrates that such an abnormality can be explained by platelet AA deficiency. Platelet mapping and platelet fatty acid analysis should be undertaken in human infants treated with fish oil monotherapy during PN.     

Dietary ω‐6/ω‐3 Polyunsaturated Fatty Acid Ratios Affect the Homeostasis of Th/Treg Cells in Mice With Dextran Sulfate Sodium–Induced Colitis

Background: This study evaluated the effect of different dietary ω‐6/ω‐3 polyunsaturated fatty acid (PUFA) ratios on modulating helper T (Th) and regulatory T (Treg) lymphocytes in mice with dextran sulfate sodium (DSS)–induced colitis. Methods: There were 3 control and 3 colitis groups. Mice were fed for 24 days with diets with soybean oil (S), a mixture of soybean oil and low fish oil content (LF), or high fish oil content (HF). The ratio of ω‐6/ω‐3 PUFA in the LF diet was 4:1, and that in the HF diet was 2:1. The control groups drank distilled water while colitis groups were provided 2% DSS in drinking water during days 15–19. All mice drank distilled water from days 20–24 for recovery and were sacrificed on day 25. Results: Colitis resulted in higher blood Th1, Th2, and Th17 and lower Treg percentages. Also, plasma haptoglobin and proinflammatory chemokines were elevated in colon lavage fluid. Colitic groups with fish oil had lower inflammatory mediators in the plasma and colon lavage fluid. Furthermore, the percentages of blood Th1, Th2, and Th17 cells were lower, whereas Treg cell percentages were higher than those in the soybean oil group. The colitis group with an ω‐6/ω‐3 PUFA ratio of 2:1 had more pronounced effects than the group with a ratio of 4:1. Conclusions: Diets with an ω‐6/ω‐3 PUFA ratio of 2:1 or 4:1 regulate the Th/Treg balance and attenuate inflammatory mediator production in colitis. Compared with the ω‐6/ω‐3 PUFA ratio of 4:1, the ratio of 2:1 was more effective in reducing inflammatory reactions in DSS‐induced colitis.     

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.     

Characterization of Fatty Acid Profiles in Infants With Intestinal Failure–Associated Liver Disease

Background

The purpose of this study was to characterize fatty acid profiles (FAPs) in parenteral nutrition (PN)‐dependent infants with intestinal failure–associated liver disease (IFALD) receiving soybean oil–based lipid emulsion (SO) doses of ～3 and ～1 g/kg/d.

Methods

Prospectively collected data were retrospectively reviewed. Serum FAPs of patients <1 year old who experienced development of IFALD while receiving standard PN with SO were examined before transitioning to a fish oil–based lipid emulsion for IFALD treatment. Time on SO, dose, gestational age, and weight‐ and length‐for‐age z scores were also reviewed.

Results

Among the 49 patients analyzed, there were no differences in demographics or anthropometrics between patients who received standard SO (SO‐S) (n = 14, range of dosage 2.06–3.31 g/kg/d) and reduced SO (SO‐R) (n = 35, range of dosage 0.90–1.34 g/kg/d). Patients received SO for a median of 53 days (interquartile range 39, 73) before FAP measurement. Patients who received SO‐R had significantly higher Mead acid and lower α‐linolenic, eicosapentaenoic, linoleic, stearic, total ω‐3, and total ω‐6 fatty acid levels than patients who received SO‐S (P < .01). Triene:tetraene ratios were higher in patients who received SO‐R (P = .0009), and no patients experienced biochemical essential fatty acid deficiency (EFAD).

Conclusion

PN‐dependent infants with IFALD receiving SO‐R have different FAPs than patients receiving SO‐S. No patients in either group had biochemical EFAD.     

Glucagon‐Like Peptide 2 Improves Cholestasis in Parenteral Nutrition–Associated Liver Disease

Background: Parenteral nutrition‐associated liver disease (PNALD) remains a significant cause of morbidity and mortality in neonates with intestinal failure. Although glucagon‐like peptide‐2 (GLP‐2) is being advanced as therapy, the effect of GLP‐2 treatment on PNALD is unknown. We aim to investigate the effect of exogenous GLP‐2 administration on hepatic function in a neonatal piglet model of PNALD. Methods: Neonatal piglets (aged 2–6 days) underwent jugular venous catheterization to receive isonitrogenous, isocaloric parenteral nutrition (PN). Piglets were allocated to 2 groups: group 1 (n = 8) received saline while group 2 (n = 7) received GLP‐2 (at 11 nmol/kg/d). After 17 days, piglets underwent terminal laparotomy, and bile flow was measured. Liver specimens were analyzed histologically and with immunoperoxidase staining. Age‐matched sow‐reared control piglets (group 3, n = 8) were used for comparison. Results: Both groups 1 and 2 receiving PN developed cholestasis relative to sow‐reared controls, as evidenced by a decrease in bile flow and increase in serum total bilirubin. However, group 2 had improved bile flow (1.35 vs 0.73 µL/g; P = .02) and diminished bilirubin (38.0 vs 78.5 µmol/L; P = .008) compared with group 1. Group 2 also had lower serum alanine aminotransferase levels, a marker of liver injury. Histologically, the liver specimens in group 1 had marked hepatocyte pigmentation, which was decreased in group 2 specimens. Conclusions: The exogenous administration of GLP‐2 is associated with the improvement of cholestasis and liver injury. This study introduces a novel role for GLP‐2 in improving PNALD in the setting of prolonged PN duration.     

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.     

Effects on Varying Intravenous Lipid Emulsions on the Small Bowel Epithelium in a Mouse Model of Parenteral Nutrition

Background: Injectable fat emulsions (FEs) are a clinically dependable source of essential fatty acids (FA). ω‐6 FA is associated with an inflammatory response. Medium‐chain triglycerides (MCT, ω‐3 FA), fish oil, and olive oil are reported to decrease the inflammatory response. However, the effect of these lipids on the gastrointestinal tract has not been well studied. To address this, we used a mouse model of parenteral nutrition (PN) and hypothesized that a decrease in intestinal inflammation would be seen when either fish oil and MCT or olive oil were added. Methods: Three FEs were studied in adult C57BL/6 mice via intravenous cannulation: standard soybean‐based FE (SBFE), 80% olive oil ‐supplemented FE (OOFE), or a combination of a soybean oil, MCT, olive oil, and fish oil emulsion (SMOF). PN was given for 7 days, small bowel mucosa‐derived cytokines, animal survival rate, epithelial cell (EC) proliferation and apoptosis rates, intestinal barrier function and mucosal FA composition were analyzed. Results: Compared to the SBFE and SMOF groups, the best survival, highest EC proliferation and lowest EC apoptosis rates were observed in the OOFE group; and associated with the lowest levels of tumor necrosis factor‐α, interleukin‐6, and interleukin‐1β expression. Jejunal FA content showed higher levels of eicosapentaenoic and docosapentaenoic acid in the SMOF group and the highest arachidonic acid in the OOFE group. Conclusion: The study showed that PN containing OOFE had beneficial effects to small bowel health and animal survival. Further investigation may help to enhance bowel integrity in patients restricted to PN.     

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.