The Effect of L-Carnitine on Mortality Rate in Septic Patients: A Systematic Review and Meta-Analysis on Randomized Clinical Trials.

BACKGROUND: Recent clinical trial studies have reported that L-carnitine supplementation can reduce the mortality rate in patients with sepsis, but there are no definitive results in this context. The current systematic review and meta-analysis aimed to evaluate the effect of L-carnitine supplementation on 28-day and one-year mortality in septic patients. METHODS: A systematic search conducted on Pubmed, Scopus and Cochrane Library databases up to June 2019 without any language restriction. The publications were reviewed based on the Cochrane handbook and preferred reporting items for systematic reviews and meta-analyses (PRISMA). To compare the effects of L-carnitine with placebo, Risk Ratio (RR) with 95% confidence intervals (CI) were pooled according to the random effects model. RESULTS: Across five enrolled clinical trials, we found that L-carnitine supplementation reduce one-year mortality in septic patients with SOFA> 12 (RR: 0.68; 95% CI: 0.49 to 0.96; P= 0.03) but had no significant effect on reducing 28-day mortality ((RR: 0.93; 95% CI: 0.68 to 1.28; P= 0.65) compared to placebo. Finally, we observed that based on current trials, L-carnitine supplementation may not have clinically a significant effect on mortality rate. CONCLUSION: L-carnitine patients with higher SOFA score can reduce the mortality rate. However, the number of trials, study duration and using a dosage of L-carnitine are limited in this context and further large prospective trials are required to clarify the effect of L-carnitine on mortality rate in septic patients.

The impact of maternal protein restriction during perinatal life on the response to a septic insult in adult rats.

Although abundant evidence exists that adverse events during pregnancy lead to chronic conditions, there is limited information on the impact of acute insults such as sepsis. This study tested the hypothesis that impaired fetal development leads to altered organ responses to a septic insult in both male and female adult offspring. Fetal growth restricted (FGR) rats were generated using a maternal protein-restricted diet. Male and female FGR and control diet rats were housed until 150-160 d of age when they were exposed either a saline (control) or a fecal slurry intraperitoneal (Sepsis) injection. After 6 h, livers and lungs were analyzed for inflammation and, additionally, the amounts and function of pulmonary surfactant were measured. The results showed increases in the steady-state mRNA levels of inflammatory cytokines in the liver in response to the septic insult in both males and females; these responses were not different between FGR and control diet groups. In the lungs, cytokines were not detectable in any of the experimental groups. A significant decrease in the relative amount of surfactant was observed in male FGR offspring, but this was not observed in control males or in female animals. Overall, it is concluded that FGR induced by maternal protein restriction does not impact liver and lung inflammatory response to sepsis in either male or female adult rats. An altered septic response in male FGR offspring with respect to surfactant may imply a contribution to lung dysfunction.

Soluble dietary fiber protects intestinal mucosal barrier by improving intestinal flora in a murine model of sepsis.

The study investigated the effect of soluble dietary fiber supplementation on gut microbiota, mucosal barrier function, inflammatory markers, and survival in a murine model of sepsis established by cecal ligation and puncture (CLP). The expression of muc2 was down-regulated in septic mice. However, muc2 expression was significantly increased in the septic mice that received soluble dietary fiber. Survival was also improved in the septic mice treated with dietary fiber. The survival benefit was associated with decreased serum concentrations of pro-inflammatory cytokines and reduced neutrophil infiltration in the gut. Furthermore, the mucus thickness, inflammatory response, and degree of gut injury were remarkably alleviated in septic mice treated with soluble dietary fiber, while it was aggravated in septic mice treated with antibiotics in addition to the soluble fiber. Bacterial 16S ribosomal RNA gene sequencing also showed that fiber supplementation caused an increase in the relative abundance of probiotics, commonly associated with metabolic health. Administration of antibiotics to mice fed fiber diet negated the enrichment of probiotics as well as the survival benefit, following cecal ligation and puncture. Dietary supplementation with cellulose offers a microbe-mediated survival advantage in a murine model of sepsis. Improved understanding of the connection between diet, microbiota, and systemic illness may yield new therapeutic strategies for patients with sepsis.

Why a d-ß-hydroxybutyrate monoester?

Much of the world's prominent and burdensome chronic diseases, such as diabetes, Alzheimer's, and heart disease, are caused by impaired metabolism. By acting as both an efficient fuel and a powerful signalling molecule, the natural ketone body, d-ß-hydroxybutyrate (ßHB), may help circumvent the metabolic malfunctions that aggravate some diseases. Historically, dietary interventions that elevate ßHB production by the liver, such as high-fat diets and partial starvation, have been used to treat chronic disease with varying degrees of success, owing to the potential downsides of such diets. The recent development of an ingestible ßHB monoester provides a new tool to quickly and accurately raise blood ketone concentration, opening a myriad of potential health applications. The ßHB monoester is a salt-free ßHB precursor that yields only the biologically active d-isoform of the metabolite, the pharmacokinetics of which have been studied, as has safety for human consumption in athletes and healthy volunteers. This review describes fundamental concepts of endogenous and exogenous ketone body metabolism, the differences between the ßHB monoester and other exogenous ketones and summarises the disease-specific biochemical and physiological rationales behind its clinical use in diabetes, neurodegenerative diseases, heart failure, sepsis related muscle atrophy, migraine, and epilepsy. We also address the limitations of using the ßHB monoester as an adjunctive nutritional therapy and areas of uncertainty that could guide future research.

Early enteral feeding in preterm infants.

Early enteral feeding is a potentially modifiable risk factor for necrotising enterocolitis (NEC) and late onset sepsis (LOS), however enteral feeding practices for preterm infants are highly variable. High-quality evidence is increasingly available to guide early feeding in preterm infants. Meta-analyses of randomised trials indicate that early trophic feeding within 48 h after birth and introduction of progressive enteral feeding before 4 days of life at an advancement rate above 24 ml/kg/day can be achieved in clinically stable very preterm and very low birthweight (VLBW) infants, without higher mortality or incidence of NEC. This finding may not be generalisable to high risk infants such as those born small for gestational age (SGA) or following absent/reversed end diastolic flow velocity (AREDFV) detected antenatally on placental Doppler studies, due to the small number of such infants in existing trials. Trials targeting such high-risk preterm infants have demonstrated that progressive enteral feeding started in the first 4 days is safe and does not lead to higher NEC or mortality; however, there is a paucity of data to guide feeding advancement in such infants. There is little trial evidence to support bolus or continuous gavage feeding as being superior in clinically stable preterm infants. Trials that examine enteral feeding are commonly unblinded for technical and practical reasons, which increases the risk of bias in such trials, specifically when considering potentially subjective outcome such as NEC and LOS; future clinical trials should focus on objective, primary outcome measures such as all-cause mortality, long term growth and neurodevelopment. Alternatively, important short-term outcomes such as NEC could be used with blinded assessment.

Probiotics and Human Milk Oligosaccharides in Premature Infants.

Intestinal dysbiosis precedes and is a likely causative factor in necrotizing enterocolitis (NEC) and many cases of late-onset sepsis. Randomized controlled trials and observational cohort studies demonstrate decreased risk of NEC, sepsis, and death with the administration of probiotic microbes and decreased risk of NEC and sepsis with feeding of human milk. Animal studies suggest promising mechanisms by which probiotic microbes and human milk oligosaccharides alter the composition of the intestinal microbiota and may prevent disease in premature infants. Inclusion of parents in discussions of the risks and benefits of human milk and probiotics for premature infants is essential.

Resting Energy Expenditure and Oxygen Consumption in Critically Ill Patients With vs Without Sepsis.

BACKGROUND: Septic shock is one of the main causes of mortality in intensive care units worldwide. Nutritional support can affect the survival of patients with sepsis. OBJECTIVE: To evaluate whether resting energy expenditure, respiratory quotient, and oxygen consumption and carbon dioxide production (measured by indirect calorimetry) differ between critically ill patients with vs without sepsis. METHODS: A total of 205 patients receiving mechanical ventilation were evaluated consecutively within the first 48 hours of admission. Demographic and clinical data were collected, including age, body mass index, oxygen consumption, carbon dioxide production, respiratory quotient, and resting energy expenditure, with the clinical data measured or estimated via indirect calorimetry. RESULTS: Of the 205 patients, 114 (56%) had no sepsis and 91 (44%) had sepsis. The median values of the studied variables in the no sepsis and sepsis groups, respectively, were as follows: age, 53 vs 58 years (P = .07); body mass index, 25 vs 26 (P = .14); Acute Physiology and Chronic Health Evaluation II score, 24 vs 25 (P = .04); death risk, 47% vs 63% (P = .04); oxygen consumption, 211 vs 202 mL/min (P = .72); and resting energy expenditure, 1434 vs 1430 kcal/d (P = .73). Analysis of receiver operating characteristic curves showed no significant differences between patients with and without sepsis for any of the indirect calorimetry variables. CONCLUSION: In clinical practice, patients with sepsis do not seem to require an increased energy supply. Additional studies are needed to confirm this conclusion.

Western diet regulates immune status and the response to LPS-driven sepsis independent of diet-associated microbiome.

Sepsis is a deleterious immune response to infection that leads to organ failure and is the 11th most common cause of death worldwide. Despite plaguing humanity for thousands of years, the host factors that regulate this immunological response and subsequent sepsis severity and outcome are not fully understood. Here we describe how the Western diet (WD), a diet high in fat and sucrose and low in fiber, found rampant in industrialized countries, leads to worse disease and poorer outcomes in an LPS-driven sepsis model in WD-fed mice compared with mice fed standard fiber-rich chow (SC). We find that WD-fed mice have higher baseline inflammation (metaflammation) and signs of sepsis-associated immunoparalysis compared with SC-fed mice. WD mice also have an increased frequency of neutrophils, some with an "aged" phenotype, in the blood during sepsis compared with SC mice. Importantly, we found that the WD-dependent increase in sepsis severity and higher mortality is independent of the microbiome, suggesting that the diet may be directly regulating the innate immune system through an unknown mechanism. Strikingly, we could predict LPS-driven sepsis outcome by tracking specific WD-dependent disease factors (e.g., hypothermia and frequency of neutrophils in the blood) during disease progression and recovery. We conclude that the WD is reprogramming the basal immune status and acute response to LPS-driven sepsis and that this correlates with alternative disease paths that lead to more severe disease and poorer outcomes.

Nutrient pattern analysis in critically ill patients using Omics technology (NAChO) - Study protocol for a prospective observational study.

INTRODUCTION: Intensive care unit-acquired weakness (ICU-AW) is often observed in critically ill patients with prolonged intensive care unit (ICU) stay. We hypothesized that evolving metabolic abnormalities during prolonged ICU stay are reflected by changing nutrient patterns in blood, urine and skeletal muscle, and that these patterns differ in patients with/without ICU-AW and between patients with/without sepsis. METHODS: In a prospective single-center observational trial, we aim to recruit 100 critically ill patients (ICU length of stay ≥ 5 days) with severe sepsis/septic shock ("sepsis group", n = 50) or severe head trauma/intracerebral hemorrhage ("CNS group", n = 50). Patients will be sub-grouped for presence or absence of ICU-AW as determined by the Medical Research Council sum score. Blood and urine samples will be collected and subjected to comprehensive nutrient analysis at different time points by targeted quantitative mass spectrometric methods. In addition, changes in muscular tissue (biopsy, when available), muscular architecture (ultrasound), electrophysiology, body composition analyses (bioimpedance, cerebral magnetic resonance imaging), along with clinical status will be assessed. Patients will be followed-up for 180 and 360 days including assessment of quality of life. DISCUSSION: Key objective of this trial is to assess changes in nutrient pattern in blood and urine over time in critically ill patients with/without ICU-AW by using quantitative nutrient analysis techniques. Peer-reviewed published NAChO data will allow for a better understanding of metabolic changes in critically ill patients on standard liquid enteral nutrition and will likely open up new avenues for future therapeutic and nutritional interventions.

Survey of Nutrition Practice in Patients with Severe Sepsis among Canadian Registered Dietitians.

PURPOSE: The purpose of this study was to determine the opinions and reported nutrition practices of Canadian Registered Dietitians (RDs) with regard to feeding patients with severe sepsis. METHODS: In 2017, surveys were sent to 112 eligible Canadian RDs in 10 provinces who were practicing in an intensive care environment. The survey included embedded branching logic questions developed to address major facets of sepsis, critical illness, and nutrition. The survey instrument assimilated all data in an anonymous manner, so respondents could not be linked to their answers. RESULTS: Of the 64 RDs who responded (57% response rate), the majority practiced in adult intensive care (81%), within an academic center (59%), and in a mixed unit (73%). A wide variability of Canadian RDs' opinions and practice was reported in determining energy requirements, enteral nutrition (EN) practice, EN with vasoactive agents, parenteral nutrition (PN), and supplemental micronutrients. CONCLUSIONS: Practice variability of Canadian RDs likely reflects gaps in both evidence and guidelines for severe sepsis. Further research efforts are needed to customize nutritional requirements in the patient with evolving sepsis, EN with patients at high risk for gastrointestinal dysfunction, optimizing PN, and the role of micronutrients.

Early enteral nutrition is associated with reduced in-hospital mortality from sepsis in patients with sarcopenia.

PURPOSE: To determine whether the association of early enteral nutrition (EEN) with mortality from sepsis differs between patients with and without sarcopenia. MATERIALS AND METHODS: We retrospectively reviewed septic patients treated at our centre between January 2010 and August 2017. The skeletal muscle area (SMA) at the level of the third lumbar vertebra was measured with CT on admission, and sarcopenia was defined as SMA < 80% of the predicted value. Patients were divided into two subgroups (sarcopenic and non-sarcopenic patients), and in-hospital mortality was compared in patients treated with and without EEN within each subgroup. We used logistic regression to examine factors associated with in-hospital mortality in each subgroup. RESULTS: EEN was administered to 35/91 sarcopenic patients and 43/100 non-sarcopenic patients. In-hospital mortality did not differ between non-sarcopenic patients with EEN and those without EEN (16% vs 16%, P = 0.947), but was significantly lower in sarcopenic patients with EEN than in those without EEN (9% vs 34%, P = 0.005). Logistic regression showed that EEN was independently associated with reduced in-hospital mortality in sarcopenic patients (OR 0.18, 95% CI 0.05-0.71, P = 0.014), but not in non-sarcopenic patients. CONCLUSIONS: EEN may be more beneficial in sarcopenic patients.

Alterations in energy substrate metabolism in mice with different degrees of sepsis.

BACKGROUND: Nutritional management is crucial during the acute phase of severe illnesses. However, the appropriate nutritional requirements for patients with sepsis are poorly understood. We investigated alterations in carbohydrate, fat, and protein metabolism in mice with different degrees of sepsis. MATERIALS AND METHODS: C57BL/6 mice were divided into three groups: control mice group, administered with saline, and low- and high-dose lipopolysaccharide (LPS) groups, intraperitoneally administered with 1 and 5 mg of LPS/kg, respectively. Rectal temperature, food intake, body weight, and spontaneous motor activity were measured. Indirect calorimetry was performed using a respiratory gas analysis for 120 h, after which carbohydrate oxidation and fatty acid oxidation were calculated. Urinary nitrogen excretion was measured to evaluate protein metabolism. The substrate utilization ratio was recalculated. Plasma and liver carbohydrate and lipid levels were evaluated at 24, 72, and 120 h after LPS administration. RESULTS: Biological reactions decreased significantly in the low- and high-LPS groups. Fatty acid oxidation and protein oxidation increased significantly 24 h after LPS administration, whereas carbohydrate oxidation decreased significantly. Energy substrate metabolism changed from glucose to predominantly lipid metabolism depending on the degree of sepsis, and protein metabolism was low. Plasma lipid levels decreased, whereas liver lipid levels increased at 24 h, suggesting that lipids were transported to the liver as the energy source. CONCLUSIONS: Our findings revealed that energy substrate metabolism changed depending on the degree of sepsis. Therefore, in nutritional management, such metabolic alterations must be considered, and further studies on the optimum nutritional intervention during severe sepsis are necessary.

Impact of a telemedicine eICU cart on sepsis management in a community hospital emergency department.

Introduction Intensivist involvement for patients with sepsis is associated with decreased complications and mortality, and lower hospital resource utilization, but few studies have evaluated outcomes for patients exposed to electronic intensive care unit (eICU) telemedicine sepsis management in the emergency department (ED). In this study, we assess whether eICU cart exposure in the ED improved compliance with components of the 2010 Surviving Sepsis Campaign bundles, length of stay (LOS), disposition and hospital costs. Methods An institutional review board-approved, retrospective cohort study was completed on patients with confirmed sepsis who presented to our ED from July 2010 through February 2013. Results Of 711 patient ED encounters, 314 cases met criteria for analysis (95 exposed and 219 non-exposed). Patient cohorts had similar demographics and comorbid International Classification of Diseases, Ninth Edition (ICD-9) diagnoses. The exposed cohort received antibiotics more quickly (122.3 minutes ±83.3 versus 163.4 minutes ±204.4, p = 0.043) and were more likely to have lactic acid levels drawn within six hours (98.9% vs. 90%, p = 0.019). The exposed cohort had a shortened ED LOS (in days) 0.08 ± 0.28 versus 0.16 ± 0.37, p = 0.036. Hospital LOS, disposition and death were similar in both cohorts. Total hospital costs for the exposed cohort were lower and less variable (US$19,713 ± 16,550 vs. US$24,364 ± 25068), but this was not significant ( p = 0.274). Discussion Our findings suggest that in individuals with confirmed sepsis, ED exposure to a telemedicine-based eICU cart impacted adherence to aspects of the Surviving Sepsis Campaign recommended bundle, but did not impact overall survival and medical costs.

Nitrite administration improves sepsis-induced myocardial and mitochondrial dysfunction by modulating stress signal responses.

PURPOSE: A specific therapeutic strategy in sepsis-induced myocardial dysfunction remains to be determined. Nitrite may have cardioprotective effects against sepsis-induced myocardial dysfunction. This study investigated the cardioprotective effects of nitrite on myocardial function, mitochondrial bioenergetics, and its underlying molecular mechanisms in severe septic rats. METHODS: Sepsis was induced in male Wistar rats by cecal ligation and puncture (CLP). After CLP, we administered normal saline (NS group) or nitrite (nitrite group) subcutaneously. We administered nitrite at different doses (0.1-10 mg/kg) to ascertain the most effective dose and examined cardiac function in an isolated heart experiment 8 h after CLP. We investigated mitochondrial bioenergetics and molecular mechanisms underlying the administration of nitrite in vitro. RESULTS: In isolated heart experiments, the left ventricular developed pressure (96 ± 5 mmHg) at a moderate nitrite dose (1.0 mg/kg) was significantly higher than that in the NS group (75 ± 4 mmHg, P < 0.05). Mitochondrial oxidative phosphorylation in the nitrite group was significantly higher than that in the NS group (P < 0.01). Immunoblotting revealed that nitrite significantly increased the phosphorylation of Akt (P < 0.05) and reduced the nuclear translocation of NF-κB (P < 0.05) compared with the NS group. Nitrite was also shown to improve the rate of survival in severe septic rats (P < 0.001). CONCLUSIONS: Our results showed that a moderate nitrite dose improved septic myocardial dysfunction at organ, cellular, and molecular levels via modulation of stress signal responses, which resulted in an improvement in survival.

A randomized synbiotic trial to prevent sepsis among infants in rural India.

Sepsis in early infancy results in one million annual deaths worldwide, most of them in developing countries. No efficient means of prevention is currently available. Here we report on a randomized, double-blind, placebo-controlled trial of an oral synbiotic preparation (Lactobacillus plantarum plus fructooligosaccharide) in rural Indian newborns. We enrolled 4,556 infants that were at least 2,000 g at birth, at least 35 weeks of gestation, and with no signs of sepsis or other morbidity, and monitored them for 60 days. We show a significant reduction in the primary outcome (combination of sepsis and death) in the treatment arm (risk ratio 0.60, 95% confidence interval 0.48-0.74), with few deaths (4 placebo, 6 synbiotic). Significant reductions were also observed for culture-positive and culture-negative sepsis and lower respiratory tract infections. These findings suggest that a large proportion of neonatal sepsis in developing countries could be effectively prevented using a synbiotic containing L. plantarum ATCC-202195.

Beneficial Effects of Omega-3 Supplement to the Enteral Feeding in Children With Mild to Moderate Sepsis.

OBJECTIVE: The objective was to investigate the benefits of supplementing enteral feeding with omega-3 fatty acids in children with mild to moderate sepsis and its effects on acute-phase reactants and interleukin 6 (IL-6) level. METHODS: The study was a prospective randomized, double-blind, placebo-controlled study from January 2012 to June 2014, which included 2 groups of children with mild to moderate sepsis tolerating enteral feeding. Group A included 60 children supplemented with omega-3 fatty acids, whereas group B included 60 children who received enteral feeding without omega-3 supplementation. Both groups had complete blood pictures, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), serum albumin, and IL-6 before and after 7 days from supplementation. RESULTS: There was a significant improvement in hemoglobin percentage ( P < .0001), total white blood cell (WBC) count ( P < .0001), and platelet count ( P < .0001) and significant decrease in CRP ( P < .0001), ESR ( P < .0001), IL-6 ( P < .0001), and albumin level ( P < .001) in the supplemented group than the nonsupplemented group. The supplemented group also had a significantly shorter duration of stay in pediatric intensive care unit (PICU; P < .01) and decreased death rate than the nonsupplemented group. CONCLUSION: Children with mild to moderate sepsis showed significant improvement in inflammatory markers and had shorter PICU admission when enteral feeding was supplemented with omega-3 essential fatty acids.

Effects of omega-3 fatty acid nutrition on mortality in septic patients: a meta-analysis of randomized controlled trials.

BACKGROUND: A previous systematic review and meta-analysis reported that omega-3 fatty acids nutrition may reduce mortality in septic patients. As new randomized controlled trials began to accumulate, we conducted an update. METHODS: A PubMed database was searched through Feb 2016, and randomized controlled trials comparing omega-3 fatty acids with control were selected by two reviewers independently. RESULTS: Eleven trials randomly assigning 808 patients were included in the present study. Using a fixed effects model, we found no significant effect of omega-3 fatty acids on overall mortality (risk ratio 0.84; 95 % confidence interval (CI): 0.67 to 1.05, P = 0.12), or infectious complications (risk ratio 0.95; 95 % CI: 0.72 to 1.25, P = 0.70). However, the duration of mechanical ventilation was markedly reduced by omega-3 fatty acids (weighted mean differences (WMD) = -3.82; 95 % CI: -4.61 to -3.04; P < 0.00001). A significant heterogeneity was found when the duration of hospital (I (2) = 93 %; WMD = -2.82; 95 % CI: -9.88 to 4.23, P = 0.43), or intensive care stay (I (2) = 87 %; WMD = -2.70; 95 % CI: -6.40 to 1.00, P = 0.15) were investigated. CONCLUSIONS: Omega-3 fatty acids confer no mortality benefit but are associated with a reduction in mechanical ventilation duration in septic patients. However, low sample size and heterogeneity of the cohorts included in this analysis limits the generalizability of our findings.

Probiotics for prevention of necrotizing enterocolitis and sepsis in preterm infants.

PURPOSE OF REVIEW: Few areas in neonatal medicine have generated as much discussion and controversy as the use of prophylactic probiotics for the prevention of necrotizing enterocolitis. We summarize recent studies from the last 1-2 years. RECENT FINDINGS: Systematic reviews show that probiotics reduce the risk of necrotizing enterocolitis but there are methodological limitations to all the published trials, and the largest trial to date is at odds with the conclusions of the meta-analyses. Trials have used a range of commercially available products with differing species, and administered these at different times to heterogeneous populations of preterm babies. Although there is strong evidence to show that 'probiotics' are likely to represent a major advance for neonatal care, it is increasingly clear that not all species have beneficial effects in preterm infants. This makes interpretation of meta-analyses complex, and the determination of a single 'risk reduction' potentially flawed. SUMMARY: Despite current uncertainties, it is difficult for clinicians to ignore the current data, and increasing numbers now use commercially available products. It remains a matter of concern that many products lack the robust quality control most clinicians and parents would consider important for use in vulnerable populations. Head-to-head trials are needed.

Dietary Omega-3 Fatty Acids Increase Survival and Decrease Bacterial Load in Mice Subjected to Staphylococcus aureus-Induced Sepsis.

Sepsis caused by Staphylococcus aureus is increasing in incidence. With the alarming use of antibiotics,S. aureus is prone to become methicillin resistant. Antibiotics are the only widely used pharmacological treatment for sepsis. Interestingly, mice fed high-fat diet (HFD) rich in polyunsaturated fatty acids have better survival of S. aureus-induced sepsis than mice fed HFD rich in saturated fatty acids (HFD-S). To investigate what component of polyunsaturated fatty acids, i.e., omega-3 or omega-6 fatty acids, exerts beneficial effects on the survival of S. aureus-induced sepsis, mice were fed HFD rich in omega-3 or omega-6 fatty acids for 8 weeks prior to inoculation with S. aureus Further, mice fed HFD-S were treated with omega-3 fatty acid metabolites known as resolvins. Mice fed HFD rich in omega-3 fatty acids had increased survival and decreased bacterial loads compared to those for mice fed HFD-S after S. aureus-induced sepsis. Furthermore, the bacterial load was decreased in resolvin-treated mice fed HFD-S after S. aureus-induced sepsis compared with that in mice treated with vehicle. Dietary omega-3 fatty acids increase the survival of S. aureus-induced sepsis by reversing the deleterious effect of HFD-S on mouse survival.

Short-Term Dietary Restriction Rescues Mice From Lethal Abdominal Sepsis and Endotoxemia and Reduces the Inflammatory/Coagulant Potential of Adipose Tissue.

OBJECTIVES: Visceral adipose tissue is a major site for expression of proinflammatory and procoagulant genes during acute systemic inflammation. In this study, we tested whether the loss of fat mass by dietary restriction would remove the major source of these factors resulting in improved tolerance to sepsis and endotoxemia. DESIGN: Prospective, laboratory controlled experiments. SETTING: Aging and critical care research laboratory in a university hospital. SUBJECTS: Middle-aged (12-month old) male C57BL/6 mice. INTERVENTIONS: Mice were subjected to 40% dietary restriction for 3 weeks followed by induction of abdominal sepsis or endotoxemia by intraperitoneal injection with cecal slurry or lipopolysaccharide, respectively. MEASUREMENTS AND MAIN RESULTS: Compared with freely fed mice, dietary restricted mice exhibited dramatically improved survival (80% vs 0% after sepsis; p < 0.001 and 86% vs 12% after endotoxemia; p = 0.013) and significantly reduced visceral fat-derived messenger RNA expression of interleukin-6, thrombospondin-1, plasminogen activator inhibitor-1, and tissue factor, which positively correlated with fat mass. Plasma levels of interleukin-6 were significantly reduced by dietary restriction and correlated with adipose interleukin-6 messenger RNA levels and fat mass (p < 0.001; R = 0.64 and 0.89). In vitro culture of visceral fat explants from naive dietary restricted mice showed significantly reduced interleukin-6 secretion compared with that from freely fed mice in response to lipopolysaccharide. Analysis of major adipose immune cell populations by flow cytometry demonstrated that macrophages were the only cell population reduced by dietary restriction and that CD11c/CD206 (M2-type) and CD11c/CD206 (double negative) macrophages, in addition to T cells, are the major immune cell populations that produce interleukin-6 in middle-aged mice during systemic inflammation. CONCLUSIONS: Short-term dietary restriction drastically improved the survival outcome of middle-aged mice during both polymicrobial sepsis and sterile endotoxemia. Improved survival was accompanied by a significantly attenuated inflammatory response in adipose tissue, which is likely due to alterations of both fat mass quantity and qualitative changes, including a reduction in macrophage populations.