Omega-3 (n-3) Fatty Acid-Statin Interaction: Evidence for a Novel Therapeutic Strategy for Atherosclerotic Cardiovascular Disease.

Managing atherosclerotic cardiovascular disease (ASCVD) often involves a combination of lifestyle modifications and medications aiming to decrease the risk of cardiovascular outcomes, such as myocardial infarction and stroke. The aim of this article is to discuss possible omega-3 (n-3) fatty acid-statin interactions in the prevention and treatment of ASCVD and to provide evidence to consider for clinical practice, highlighting novel insights in this field. Statins and n-3 fatty acids (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) are commonly used to control cardiovascular risk factors in order to treat ASCVD. Statins are an important lipid-lowering therapy, primarily targeting low-density lipoprotein cholesterol (LDL-C) levels, while n-3 fatty acids address triglyceride (TG) concentrations. Both statins and n-3 fatty acids have pleiotropic actions which overlap, including improving endothelial function, modulation of inflammation, and stabilizing atherosclerotic plaques. Thus, both statins and n-3 fatty acids potentially mitigate the residual cardiovascular risk that remains beyond lipid lowering, such as persistent inflammation. EPA and DHA are both substrates for the synthesis of so-called specialized pro-resolving mediators (SPMs), a relatively recently recognized feature of their ability to combat inflammation. Interestingly, statins seem to have the ability to promote the production of some SPMs, suggesting a largely unrecognized interaction between statins and n-3 fatty acids with relevance to the control of inflammation. Although n-3 fatty acids are the major substrates for the production of SPMs, these signaling molecules may have additional therapeutic benefits beyond those provided by the precursor n-3 fatty acids themselves. In this article, we discuss the accumulating evidence that supports SPMs as a novel therapeutic tool and the possible statin-n-3 fatty acid interactions relevant to the prevention and treatment of ASCVD.

Dietary n-3 polyunsaturated fatty acids alter the number, fatty acid profile and coagulatory activity of circulating and platelet-derived extracellular vesicles: a randomized, controlled crossover trial.

BACKGROUND: Extracellular vesicles (EVs) are proposed to play a role in the development of cardiovascular diseases (CVDs) and are considered emerging markers of CVDs. n-3 PUFAs are abundant in oily fish and fish oil and are reported to reduce CVD risk, but there has been little research to date examining the effects of n-3 PUFAs on the generation and function of EVs. OBJECTIVES: We aimed to investigate the effects of fish oil supplementation on the number, generation, and function of EVs in subjects with moderate risk of CVDs. METHODS: A total of 40 participants with moderate risk of CVDs were supplemented with capsules containing either fish oil (1.9 g/d n-3 PUFAs) or control oil (high-oleic safflower oil) for 12 wk in a randomized, double-blind, placebo-controlled crossover intervention study. The effects of fish oil supplementation on conventional CVD and thrombogenic risk markers were measured, along with the number and fatty acid composition of circulating and platelet-derived EVs (PDEVs). PDEV proteome profiles were evaluated, and their impact on coagulation was assessed using assays including fibrin clot formation, thrombin generation, fibrinolysis, and ex vivo thrombus formation. RESULTS: n-3 PUFAs decreased the numbers of circulating EVs by 27%, doubled their n-3 PUFA content, and reduced their capacity to support thrombin generation by >20% in subjects at moderate risk of CVDs. EVs derived from n-3 PUFA-enriched platelets in vitro also resulted in lower thrombin generation, but did not alter thrombus formation in a whole blood ex vivo assay. CONCLUSIONS: Dietary n-3 PUFAs alter the number, composition, and function of EVs, reducing their coagulatory activity. This study provides clear evidence that EVs support thrombin generation and that this EV-dependent thrombin generation is reduced by n-3 PUFAs, which has implications for prevention and treatment of thrombosis. CLINICAL TRIAL REGISTRY: This trial was registered at clinicaltrials.gov as NCT03203512.

Combining proteins with n-3 PUFAs (EPA + DHA) and their inflammation pro-resolution mediators for preservation of skeletal muscle mass.

The optimal feeding strategy for critically ill patients is still debated, but feeding must be adapted to individual patient needs. Critically ill patients are at risk of muscle catabolism, leading to loss of muscle mass and its consequent clinical impacts. Timing of introduction of feeding and protein targets have been explored in recent trials. These suggest that "moderate" protein provision (maximum 1.2 g/kg/day) is best during the initial stages of illness. Unresolved inflammation may be a key factor in driving muscle catabolism. The omega-3 (n-3) fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are substrates for synthesis of mediators termed specialized pro-resolving mediators or SPMs that actively resolve inflammation. There is evidence from other settings that high-dose oral EPA + DHA increases muscle protein synthesis, decreases muscle protein breakdown, and maintains muscle mass. SPMs may be responsible for some of these effects, especially upon muscle protein breakdown. Given these findings, provision of EPA and DHA as part of medical nutritional therapy in critically ill patients at risk of loss of muscle mass seems to be a strategy to prevent the persistence of inflammation and the related anabolic resistance and muscle loss.

Omega-3 fatty acid supplementation affects tryptophan metabolism during a 12-week endurance training in amateur runners: a randomized controlled trial.

The effects of long-term omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation during endurance training on tryptophan (Trp) metabolism and mental state of healthy individuals have not been evaluated so far. Concentrations of plasma Trp, its metabolites and IL-6 were assessed in 26 male runners before and after a 12-week training program combined with supplementation of n-3 PUFAs (O-3 + TRAIN group) or medium chain triglycerides (MCTs; TRAIN group). After the 12-week program participants' mood before and after stress induction was also assessed. The effects of the same supplementation protocol were evaluated also in 14 inactive subjects (O-3 + SEDEN group). Concentrations of 3-hydroxykynurenine (3-HK) and picolinic acid (PA) significantly increased only in the O-3 + TRAIN group (p = 0.01; [Formula: see text] = 0.22 and p = 0.01; [Formula: see text]= 0.26). Favorable, but not statistically significant changes in the concentrations of kynurenic acid (KYNA) (p = 0.06; [Formula: see text]= 0.14), xanthurenic acid (XA) (p = 0.07; [Formula: see text]= 0.13) and 3-hydroxyanthranilic acid (3-HAA) (p = 0.06; [Formula: see text]= 0.15) and in the ratio of neurotoxic to neuroprotective metabolites were seen also only in the O-3 + TRAIN group. No changes in mood and IL-6 concentrations were observed in either group. Supplementation with n-3 PUFAs during endurance training has beneficial effects on Trp's neuroprotective metabolites.Trial registry: This study was registered at ClinicalTrials.gov with identifier NCT05520437 (14/07/2021 first trial registration and 2018/31/N/NZ7/02962 second trial registration).

The impact of fish oil and/or probiotics on serum fatty acids and the interaction with low-grade inflammation in pregnant women with overweight and obesity: secondary analysis of a randomised controlled trial.

N-3 long-chain PUFA (LC-PUFA) and probiotics are generally considered to induce health benefits. The objective was to investigate (1) the impact of fish oil and/or probiotics on serum fatty acids (sFA), (2) the interaction of sFA with low-grade inflammation and (3) the relation of sFA to the onset of gestational diabetes mellitus (GDM). Pregnant women with overweight/obesity were allocated into intervention groups with fish oil + placebo, probiotics + placebo, fish oil + probiotics or placebo + placebo in early pregnancy (fish oil: 1·9 g DHA and 0·22 g EPA, probiotics: Lacticaseibacillus rhamnosus HN001 and Bifidobacterium animalis ssp. lactis 420, 1010 CFU, each daily). Blood samples were collected in early (n 431) and late pregnancy (n 361) for analysis of fatty acids in serum phosphatidylcholine (PC), cholesteryl esters (CE), TAG and NEFA with GC and high-sensitivity C-reactive protein and GlycA by immunoassay and NMR spectroscopy, respectively. GDM was diagnosed according to 2 h 75 g oral glucose tolerance test. EPA in PC, CE and TAG and DHA in PC, CE, TAG and NEFA were higher in fish oil and fish oil + probiotics groups compared with placebo. EPA in serum NEFA was lower in women receiving probiotics compared with women not receiving. Low-grade inflammation was inversely associated with n-3 LC-PUFA, which were related to an increased risk of GDM. Fish oil and fish oil + probiotics consumption increase serum n-3 LC-PUFA in pregnant women with overweight/obesity. Although these fatty acids were inversely related to inflammatory markers, n-3 LC-PUFA were linked with an increased risk for GDM.

Athletes Can Benefit from Increased Intake of EPA and DHA-Evaluating the Evidence.

Fatty fish, which include mackerel, herring, salmon and sardines, and certain species of algae (e.g., Schizochytrium sp., Crytthecodiniumcohnii and Phaeodactylumtricornutum) are the only naturally rich sources of the omega-3 polyunsaturated fatty acids (n-3 PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). EPA and DHA are the most biologically active members of the n-3 PUFA family. Limited dietary sources and fluctuating content of EPA and DHA in fish raise concerns about the status of EPA and DHA among athletes, as confirmed in a number of studies. The beneficial effects of EPA and DHA include controlling inflammation, supporting nervous system function, maintaining muscle mass after injury and improving training adaptation. Due to their inadequate intake and beneficial health-promoting effects, athletes might wish to consider using supplements that provide EPA and DHA. Here, we provide an overview of the effects of EPA and DHA that are relevant to athletes and discuss the pros and cons of supplements as a source of EPA and DHA for athletes.

Eicosapentaenoic acid-rich oil supplementation activates PPAR-γ and delays skin wound healing in type 1 diabetic mice.

Delayed wound healing is a devastating complication of diabetes and supplementation with fish oil, a source of anti-inflammatory omega-3 (ω-3) fatty acids including eicosapentaenoic acid (EPA), seems an appealing treatment strategy. However, some studies have shown that ω-3 fatty acids may have a deleterious effect on skin repair and the effects of oral administration of EPA on wound healing in diabetes are unclear. We used streptozotocin-induced diabetes as a mouse model to investigate the effects of oral administration of an EPA-rich oil on wound closure and quality of new tissue formed. Gas chromatography analysis of serum and skin showed that EPA-rich oil increased the incorporation of ω-3 and decreased ω-6 fatty acids, resulting in reduction of the ω-6/ω-3 ratio. On the tenth day after wounding, EPA increased production of IL-10 by neutrophils in the wound, reduced collagen deposition, and ultimately delayed wound closure and impaired quality of the healed tissue. This effect was PPAR-γ-dependent. EPA and IL-10 reduced collagen production by fibroblasts in vitro. In vivo, topical PPAR-γ-blockade reversed the deleterious effects of EPA on wound closure and on collagen organization in diabetic mice. We also observed a reduction in IL-10 production by neutrophils in diabetic mice treated topically with the PPAR-γ blocker. These results show that oral supplementation with EPA-rich oil impairs skin wound healing in diabetes, acting on inflammatory and non-inflammatory cells.

The role of omega-3 polyunsaturated fatty acids in the intensive care unit.

PURPOSE OF REVIEW: This review provides an update on the actions of omega-3 polyunsaturated fatty acids (PUFAs) and presents the most recent findings from trials in patients in the intensive care unit (ICU) setting including relevant meta-analyses. Many specialized pro-resolving mediators (SPMs) are produced from bioactive omega-3 PUFAs and may explain many of the beneficial effects of omega-3 PUFAs, although other mechanisms of action of omega-3 PUFAs are being uncovered. RECENT FINDINGS: SPMs resolve inflammation, promote healing and support antiinfection activities of the immune system. Since publication of the ESPEN guidelines, numerous studies further support the use of omega-3 PUFAs. Recent meta-analyses favor the inclusion of omega-3 PUFAs in nutrition support of patients with acute respiratory distress syndrome or sepsis. Recent trials indicate that omega-3 PUFAs may protect against delirium and liver dysfunction in patients in the ICU, although effects on muscle loss are unclear and require further investigation. Critical illness may alter omega-3 PUFA turnover. There has been significant discussion about the potential for omega-3 PUFAs and SPMs in treatment of coronavirus disease 2019. SUMMARY: Evidence for benefits of omega-3 PUFAs in the ICU setting has strengthened through new trials and meta-analyses. Nevertheless, better quality trials are still needed. SPMs may explain many of the benefits of omega-3 PUFAs.

Pros and Cons of Long-Chain Omega-3 Polyunsaturated Fatty Acids in Cardiovascular Health.

The long-chain omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are found in seafood, supplements, and concentrated pharmaceutical preparations. Prospective cohort studies demonstrate an association between higher intakes of EPA+DHA or higher levels of EPA and DHA in the body and lower risk of developing cardiovascular disease (CVD), especially coronary heart disease and myocardial infarction, and of cardiovascular mortality in the general population. The cardioprotective effect of EPA and DHA is due to the beneficial modulation of a number of risk factors for CVD. Some large trials support the use of EPA+DHA (or EPA alone) in high-risk patients, although the evidence is inconsistent. This review presents key studies of EPA and DHA in the primary and secondary prevention of CVD, briefly describes potential mechanisms of action, and discusses recently published RCTs and meta-analyses. Potential adverse aspects of long-chain omega-3 fatty acids in relation to CVD are discussed.

Influence of Dietary n-3 Long Chain Polyunsaturated Fatty Acid Intake on Oxylipins in Erythrocytes of Women with Rheumatoid Arthritis.

Oxylipins derived from n-3 fatty acids are suggested as the link between these fatty acids and reduced inflammation. The aim of the present study was to explore the effect of a randomized controlled cross-over intervention on oxylipin patterns in erythrocytes. Twenty-three women with rheumatoid arthritis completed 2 × 11-weeks exchanging one cooked meal per day, 5 days a week, for a meal including 75 g blue mussels (source for n-3 fatty acids) or 75 g meat. Erythrocyte oxylipins were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results were analyzed with multivariate data analysis. Orthogonal projections to latent structures (OPLS) with effect projections and with discriminant analysis were performed to compare the two diets' effects on oxylipins. Wilcoxon signed rank test was used to test pre and post values for each dietary period as well as post blue-mussel vs. post meat. The blue-mussel diet led to significant changes in a few oxylipins from the precursor fatty acids arachidonic acid and dihomo-É£-linolenic acid. Despite significant changes in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and free EPA in erythrocytes in the mussel group, no concurrent changes in their oxylipins were seen. Further research is needed to study the link between n-3 fatty-acid intake, blood oxylipins, and inflammation.

Effects of 12 Wk of Omega-3 Fatty Acid Supplementation in Long-Distance Runners.

PURPOSE: This study aimed to investigate the effects of 12 wk of omega-3 fatty acid supplementation during endurance training on omega-3 index (O3I) and indicators of running performance in amateur long-distance runners. METHODS: Twenty-six amateur male long-distance runners ≥29 yr old supplemented omega-3 fatty acid capsules (OMEGA group, n = 14; 2234 mg of eicosapentaenoic acid and 916 mg of docosahexaenoic acid daily) or medium-chain triglycerides capsules as placebo (medium-chain triglyceride [MCT] group, n = 12; 4000 mg of MCT daily) during 12 wk of endurance training. Before and after intervention, blood samples were collected for O3I assessment, and an incremental test to exhaustion and a 1500-m run trial were performed. RESULTS: O3I was significantly increased in the OMEGA group (from 5.8% to 11.6%, P < 0.0001). A significant increase in V̇O 2peak was observed in the OMEGA group (from 53.6 ± 4.4 to 56.0 ± 3.7 mL·kg -1 ⋅min -1 , P = 0.0219) without such change in MCT group (from 54.7 ± 6.8 to 56.4 ± 5.9 mL·kg -1 ⋅min -1 , P = 0.1308). A positive correlation between the change in O3I and the change in running economy was observed when data of participants from both groups were combined (-0.1808 ± 1.917, P = 0.0020), without such an effect in OMEGA group alone ( P = 0.1741). No effect of omega-3 supplementation on 1500-m run results was observed. CONCLUSIONS: Twelve weeks of omega-3 fatty acid supplementation at a dose of 2234 mg of eicosapentaenoic acid and 916 mg of docosahexaenoic acid daily during endurance training resulted in the improvement of O3I and running economy and increased V̇O 2peak without improvement in the 1500-m run trial time in amateur runners.

Increased Plasma L-Arginine Levels and L-Arginine/ADMA Ratios after Twelve Weeks of Omega-3 Fatty Acid Supplementation in Amateur Male Endurance Runners.

It is not fully understood how supplementation with omega-3 fatty acids affects the metabolism of amino acids required for the bioavailability/synthesis of NO, i.e., L-arginine (L-arg), asymmetric dimethylarginine (ADMA), their metabolites, and the L-arg/ADMA ratio and their impact on running economy (RE) in runners. Thus, 26 male amateur endurance runners completed a twelve-week study in which they were divided into two supplemented groups: the OMEGA group (n = 14; 2234 mg and 916 mg of eicosapentaenoic and docosahexaenoic acid daily) or the MCT group (n = 12; 4000 mg of medium-chain triglycerides daily). At the same time, all participants followed an endurance training program. Before and after the 12-week intervention, blood was collected from participants at two time points (at rest and immediately post-exercise) to determine EPA and DHA in red blood cells (RBCs) and plasma levels of L-arg, ADMA, and their metabolites. RBC EPA and DHA significantly increased in the OMEGA group (p < 0.001), which was related to the resting increase in L-arg (p = 0.001) and in the L-arg/ADMA ratio (p = 0.005) with no changes in the MCT group. No differences were found in post-exercise amino acid levels. A total of 12 weeks of omega-3 fatty acid supplementation at a dose of 2234 mg of EPA and 916 mg of DHA daily increased levels of L-arg and the L-arg/ADMA ratio, which indirectly indicates increased bioavailability/NO synthesis. However, these changes were not associated with improved RE in male amateur endurance runners.

Models predict change in plasma triglyceride concentrations and long-chain n-3 polyunsaturated fatty acid proportions in healthy participants after fish oil intervention.

Introduction: Substantial response heterogeneity is commonly seen in dietary intervention trials. In larger datasets, this variability can be exploited to identify predictors, for example genetic and/or phenotypic baseline characteristics, associated with response in an outcome of interest. Objective: Using data from a placebo-controlled crossover study (the FINGEN study), supplementing with two doses of long chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs), the primary goal of this analysis was to develop models to predict change in concentrations of plasma triglycerides (TG), and in the plasma phosphatidylcholine (PC) LC n-3 PUFAs eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA), after fish oil (FO) supplementation. A secondary goal was to establish if clustering of data prior to FO supplementation would lead to identification of groups of participants who responded differentially. Methods: To generate models for the outcomes of interest, variable selection methods (forward and backward stepwise selection, LASSO and the Boruta algorithm) were applied to identify suitable predictors. The final model was chosen based on the lowest validation set root mean squared error (RMSE) after applying each method across multiple imputed datasets. Unsupervised clustering of data prior to FO supplementation was implemented using k-medoids and hierarchical clustering, with cluster membership compared with changes in plasma TG and plasma PC EPA + DHA. Results: Models for predicting response showed a greater TG-lowering after 1.8 g/day EPA + DHA with lower pre-intervention levels of plasma insulin, LDL cholesterol, C20:3n-6 and saturated fat consumption, but higher pre-intervention levels of plasma TG, and serum IL-10 and VCAM-1. Models also showed greater increases in plasma PC EPA + DHA with age and female sex. There were no statistically significant differences in PC EPA + DHA and TG responses between baseline clusters. Conclusion: Our models established new predictors of response in TG (plasma insulin, LDL cholesterol, C20:3n-6, saturated fat consumption, TG, IL-10 and VCAM-1) and in PC EPA + DHA (age and sex) upon intervention with fish oil. We demonstrate how application of statistical methods can provide new insights for precision nutrition, by predicting participants who are most likely to respond beneficially to nutritional interventions.

Improved Oxygen Uptake Efficiency Parameters Are Not Correlated with VO2peak or Running Economy and Are Not Affected by Omega-3 Fatty Acid Supplementation in Endurance Runners.

Peak oxygen uptake (VO2peak) is one of the most reliable parameters of exercise capacity; however, maximum effort is required to achieve this. Therefore, alternative, and repeatable submaximal parameters, such as running economy (RE), are needed. Thus, we evaluated the suitability of oxygen uptake efficiency (OUE), oxygen uptake efficiency plateau (OUEP) and oxygen uptake efficiency at the ventilatory anaerobic threshold (OUE@VAT) as alternatives for VO2peak and RE. Moreover, we evaluated how these parameters are affected by endurance training and supplementation with omega-3 fatty acids. A total of 26 amateur male runners completed a 12-week endurance program combined with omega-3 fatty acid supplementation or medium-chain triglycerides as a placebo. Before and after the intervention, the participants were subjected to a treadmill test to determine VO2peak, RE, OUE, OUEP and OUE@VAT. Blood was collected at the same timepoints to determine eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in erythrocytes. OUE correlated moderately or weakly with VO2peak (R2 = 0.338, p = 0.002) and (R2 = 0.226, p = 0.014) before and after the intervention, respectively. There was a weak or no correlation between OUEP, OUE@VAT, VO2peak and RE despite steeper OUE, increased OUEP and OUE@VAT values in all participants. OUE parameters cannot be treated as alternative parameters for VO2peak or RE and did not show changes following supplementation with omega-3 fatty acids in male amateur endurance runners.

Measuring muscle protein synthesis in humans and the influence of nutritional state.

In 1982 and 2011, Clinical Science published papers that used infusion of stable isotope-labeled amino acids to assess skeletal muscle protein synthesis in the fasted and fed state and before and after a period of increased intake of omega-3 fatty acids, respectively; both of these papers have been highly cited. An overview of the study designs, key findings and novel features, and a consideration of the lasting impact of these two papers is presented. The earlier paper introduced stable isotope tracer approaches in humans that showed consuming a meal will increase whole body oxidation, synthesis, and breakdown of protein, but that protein synthesis is greater than breakdown resulting in net accumulation of protein. The paper also demonstrated that consuming a meal promotes net protein synthesis in skeletal muscle. The later paper introduced the concept that omega-3 polyunsaturated fatty acids are able to improve anabolism by reporting that 8 weeks consumption of high-dose omega-3 fatty acids by healthy young and middle-aged adults increased skeletal muscle protein synthesis during a hyperaminoacidemic-hyperinsulinemic clamp compared with what was seen during the clamp at study entry. Omega-3 fatty acids also increased the phosphorylation of important signaling proteins in muscle, including mammalian target of rapamycin, p70s6k, and Akt, during the clamp. These two papers remain relevant because they offer experimental approaches to study human (patho)physiology in different contexts, they present novel insights into the impact of nutritional state (feeding) and specific nutrients (omega-3 fatty acids) on muscle protein synthesis, and they suggest ways to explore the potential of interventions to help prevent and reverse the age-, disease-, and disuse-associated decline in muscle mass.

Nutrition, Immunosenescence, and Infectious Disease: An Overview of the Scientific Evidence on Micronutrients and on Modulation of the Gut Microbiota.

The immune system is key to host defense against pathogenic organisms. Aging is associated with changes in the immune system, with a decline in protective components (immunosenescence), increasing susceptibility to infectious disease, and a chronic elevation in low-grade inflammation (inflammaging), increasing the risk of multiple noncommunicable diseases. Nutrition is a determinant of immune cell function and of the gut microbiota. In turn, the gut microbiota shapes and controls the immune and inflammatory responses. Many older people show changes in the gut microbiota. Age-related changes in immune competence, low-grade inflammation, and gut dysbiosis may be interlinked and may relate, at least in part, to age-related changes in nutrition. A number of micronutrients (vitamins C, D, and E and zinc and selenium) play roles in supporting the function of many immune cell types. Some trials report that providing these micronutrients as individual supplements can reverse immune deficits in older people and/or in those with insufficient intakes. There is inconsistent evidence that this will reduce the risk or severity of infections including respiratory infections. Probiotic, prebiotic, or synbiotic strategies that modulate the gut microbiota, especially by promoting the colonization of lactobacilli and bifidobacteria, have been demonstrated to modulate some immune and inflammatory biomarkers in older people and, in some cases, to reduce the risk and severity of gastrointestinal and respiratory infections, although, again, the evidence is inconsistent. Further research with well-designed and well-powered trials in at-risk older populations is required to be more certain about the role of micronutrients and of strategies that modify the gut microbiota-host relationship in protecting against infection, especially respiratory infection.

Impact of enteral immunonutrition on infectious complications and immune and inflammatory markers in cancer patients undergoing chemotherapy: A systematic review of randomised controlled trials.

BACKGROUND: There is increasing awareness of the importance of nutritional support in cancer treatment including the interaction with immunity. Immunonutrition is the provision of one or more nutrients (e.g. Vitamins A, D, or E, omega-3 fatty acids, arginine and glutamine) known to modulate immune function when given at levels above those normally encountered in the diet in order to support immune system function or modulate its activity, including control of inflammation. We reviewed the role of oral or enteral immunonutrition versus standard nutrition on infection and infection-related biomarkers in adult cancer patients undergoing chemotherapy. METHODS: A systematic search of oral or enteral immunonutrition versus standard nutrition in adult cancer patients during chemotherapy with or without radiotherapy or haematopoietic stem cell transplant was conducted in MEDLINE, EMBASE and CENTRAL. The search was limited to randomised controlled trials. Our primary outcome was infectious episodes or immune-related biomarkers (e.g. immune cell numbers, inflammatory markers). Secondary outcomes included incidence of malnutrition or cachexia, non-infection related adverse events (AEs), rate of remission, survival, and delays or incomplete cycles of chemotherapy. Risk of bias was assessed using ROB 2.0 and study quality was assessed using CASP for RCTs. RESULTS: The search yielded seven studies involving 521 patients (261 immunonutrition, 260 control) for analysis. All studies enrolled patients with solid tumours (no haematological malignancies). Studies were heterogenous for cancer type (upper gastrointestinal, head and neck, pancreatic and lung), immunonutrient composition (omega-3 fatty acids, vitamin A, E, glutamine, arginine or nucleotides), delivery route (enteral nutrition or oral nutritional supplement) and control used. Intervention period ranged from 4 to 14 weeks. No study reported absolute number of infections. Three studies reported AEs including potential infectious episodes of febrile neutropenia, pneumonitis and mucositis with oral candidiasis. Some studies report a decrease in blood concentrations of CRP and TNF-α with immunonutrition. CONCLUSION: There is currently insufficient evidence to define a role for immunonutrition on infectious episodes during chemotherapy in adult cancer patients. Further well-defined studies that account for degree of malnutrition, dose, timing and duration of immunonutrition in specific well-defined cancer groups using a standardised outcome framework are needed.

Glucose-Dependent Insulinotropic Polypeptide Plasma Level Influences the Effect of n-3 PUFA Supplementation.

Elevated glucose-dependent insulinotropic peptide (GIP) levels in obesity may predict the metabolic benefits of n-3 PUFA supplementation. This placebo-controlled trial aimed to analyze fasting and postprandial GIP response to 3-month n-3 PUFA supplementation (1.8 g/d; DHA:EPA, 5:1) along with caloric restriction (1200-1500 kcal/d) in obese subjects. Compliance was confirmed by the incorporation of DHA and EPA into red blood cells (RBCs). Blood analyses of glucose, insulin, non-esterified fatty acids (NEFAs), GIP and triglycerides were performed at fasting, and during an oral glucose tolerance test and a high fat mixed-meal tolerance test. Fatty acid composition of RBC was assessed by gas chromatography and total plasma fatty acid content and composition was measured by gas-liquid chromatography. The DHA and EPA content in RBCs significantly increased due to n-3 PUFA supplementation vs. placebo (77% vs. -3%, respectively). N-3 PUFA supplementation improved glucose tolerance and decreased circulating NEFA levels (0.750 vs. 0.615 mmol/L), as well as decreasing plasma saturated (1390 vs. 1001 µg/mL) and monounsaturated (1135 vs. 790 µg/mL) fatty acids in patients with relatively high GIP levels. The effects of n-3 PUFAs were associated with the normalization of fasting (47 vs. 36 pg/mL) and postprandial GIP levels. Obese patients with elevated endogenous GIP could be a target group for n-3 PUFA supplementation in order to achieve effects that obese patients without GIP disturbances can achieve with only caloric restriction.