Sulfated polysaccharides from Undaria pinnatifida improved high fat diet-induced metabolic syndrome, gut microbiota dysbiosis and inflammation in BALB/c mice.

Undaria pinnatifida was shown to reduce serum lipids and fat accumulation and produce beneficial effect on type 2 diabetes, but its effect on intestinal micro-ecology remains unclear. This study showed that sulfated polysaccharides from U. pinnatifida (UPSP) reduced weight gain, fat accumulation and metabolic disorders in mice fed with high fat diet (HFD). UPSP not only alleviated HFD-induced microbiota dysbiosis indicated as increased abundances of some Bacteroidales members that had positive correlations with the improvement of physiological indexes, but also maintained gut barrier integrity and reduced metabolic endotoxemia. A dose-effect relationship was observed between the dose of UPSP and its effect on some physiological indexes, gut microbiota community and nutrient utilization. The in vitro result showed that the use of Bacteroides species within Bacteroidales on UPSP was species-dependent, and the dose of UPSP affected the growth properties of some Bacteroides species. It implied that UPSP can be considered as prebiotic agent to prevent gut dysbiosis and obesity-related diseases in obese individuals.

Lactobacillus rhamnosus GG and Oat Beta-Glucan Regulated Fatty Acid Profiles along the Gut-Liver-Brain Axis of Mice Fed with High Fat Diet and Demonstrated Antioxidant and Anti-Inflammatory Potentials.

SCOPE: This study takes a novel approach to investigate the anti-inflammatory and antioxidant effects of prebiotic oat beta-glucan (OAT) and the probiotic Lactobacillus rhamnosus GG (LGG) against high-fat diets (HFD) by examining the fatty acid profiles in the gut-liver-brain axis. METHOD AND RESULTS: HFD-fed C57BL/6N mice are supplemented with OAT and/or LGG for 17 weeks. Thereafter, mass spectrometry-based targeted lipidomics is employed to quantify short-chain fatty acids (SCFA), polyunsaturated fatty acids (PUFA), and oxidized PUFA products in the tissues. Acetate levels are suppressed by HFD in all tissues but reversed in the brain and liver by supplementation with LGG, OAT, or LGG + OAT, and in cecum content by LGG. The n-6/n-3 polyunsaturated fatty acid (PUFA) ratio is elevated by HFD in all tissues but is lowered by LGG and OAT in the cecum and the brain, and by LGG + OAT in the brain, suggesting the anti-inflammatory property of LGG and OAT. LGG and OAT synergistically, but not individually attenuate the increase in non-enzymatic oxidized products, indicating their synbiotic antioxidant property. CONCLUSION: The regulation of the fatty acid profiles by LGG and OAT, although incomplete, but demonstrates their anti-inflammatory and antioxidant potentials in the gut-liver-brain axis against HFD.

Inhibitory Effects of Carrageenans on Endotoxin-Induced Inflammation.

The inhibitory effects of carrageenans (CRGs) on lipopolysaccharide (LPS) induced inflammation in a mouse model of endotoxemia and in complex therapy of patients with enteric infections of Salmonella etiology were studied. The atomic force microscopy (AFM) examination of LPS and its mixture with CRGs showed that the LPS morphology is significantly changed under the action of κ- and κ/ß-CRGs. CRGs were able to increase the synthesis of anti-inflammatory interleukin 10 (IL-10) in vitro, and, at low concentrations, their activity in the mixture with LPS was higher. The protective effect of CRGs against Escherichia coli LPS was studied in vivo by monitoring the biochemical and pathomorphological parameters. The κ- and κ/ß-CRGs and food supplement "Carrageenan-FE" increased the nonspecific resistance of mice to E. coli LPS at the expense of the inhibition of processes of thymus involution, adrenals hypertrophy, thyroid atrophy, hypercorticoidism, glycogenolysis, and lactate acidosis. The estimation of the therapeutic action of food supplement Carrageenan-FE in complex therapy of patients with enteric infections of Salmonella etiology is given. Carrageenan-FE restores the system of hemostasis and corrects some biochemical indicators and parameters in the immune systems of patients. These results allow us to hope for the practical application of CRGs for lowering the endotoxemia level in patients under the development of the infectious process caused by Gram-negative bacteria.

Effect of Prebiotic Complex on Gut Microbiota and Endotoxemia in Female Rats with Modeled Heart Failure.

We studied the levels endotoxin and microbial markers in the blood of female rats with experimental heart failure and the effects of preliminary treatment with a prebiotic complex based on fermented wheat bran and inactivated Saccharomyces cerevisiae culture on these parameters. The concentrations of endotoxin, markers of lactobacilli, and opportunistic microorganisms were found to increase in rats with experimental heart failure and significantly decreased against the background of treatment with prebiotic complex. The dynamics of markers of bifidobacteria, eubacteria, and propionibacteria were reciprocal. The observed effect of the prebiotic complex effect on gut microbiota in rats with experimental heart failure suggests that this complex can be used for the correction of intestinal dysbiosis and endotoxemia in this clinical condition.

Prebiotic UG1601 mitigates constipation-related events in association with gut microbiota: A randomized placebo-controlled intervention study.

BACKGROUND: Constipation is a common functional gastrointestinal disorder and its etiology is multifactorial. Growing evidence suggests that intestinal dysbiosis is associated with the development of constipation. Prebiotics are subjected to bacterial fermentation in the gut to produce short-chain fatty acids (SCFAs), which can help relieve constipation symptoms. The prebiotic UG1601 consists of inulin, lactitol, and aloe vera gel, which are known laxatives, but randomized, controlled clinical trials that examine the effects of this supplement on gut microbiota composition are lacking. AIM: To assess the efficacy of the prebiotic UG1601 in suppressing constipation-related adverse events in subjects with mild constipation. METHODS: Adults with a stool frequency of less than thrice a week were randomized to receive either prebiotics or a placebo supplement for 4 wk. All participants provided their fecal and blood samples at baseline and at the end of intervention. Gastrointestinal symptoms and stool frequency were evaluated. The concentrations of serum endotoxemia markers and fecal SCFAs were determined. The relative abundance of SCFA-producing bacteria and the gut microbial community in the responders and non-responders in the prebiotics supplementation group were evaluated. RESULTS: There were no significant differences in gastrointestinal symptoms between groups, although the prebiotic group showed greater symptom improvement. However, after prebiotic usage, serum cluster of differentiation (CD) 14 and lipopolysaccharide (LPS) concentrations were significantly decreased (CD14, P = 0.012; LPS, P < 0.001). The change in LPS concentration was significantly larger in the prebiotic group than in the placebo group (P < 0.001). Fecal SCFAs concentrations did not differ between groups, while the relative abundance of Roseburia hominis, a major butyrate producer, was significantly increased in the prebiotic group (P = 0.045). The abundances of the phylum Firmicutes and the family Lachnospiraceae (phylum Firmicutes, class Clostridia) (P = 0.009) were decreased in the responders within the prebiotic group. In addition, the proportions of the phylum Firmicutes, the class Clostridia, and the order Clostridiales were inversely correlated with several fecal SCFAs (P < 0.05). CONCLUSION: Alterations in gut microbiota composition, including a decrease in the phylum Firmicutes and an increase in butyrate-producing bacteria, following prebiotic UG1601 supplementation might help alleviate symptom scores and endotoxemia.

Metabolic and Inflammatory Effects of an ω-3 Fatty Acid-Based Eucaloric Ketogenic Diet in Mice With Endotoxemia.

BACKGROUND: Dietary strategies can aid in the management of critically ill patients. Very-low-carbohydrate diets have been shown to improve glucose control and the inflammatory response. We aimed to determine the effects of a eucaloric ketogenic diet (EKD) enriched with ω-3 fatty acids (O3KD) on glucose levels and inflammation in mice with endotoxemia. METHODS: Adult mice were fed 1 of 3 diets (control diet [CD], EKD, or O3KD). After 4 weeks, each group received saline or Escherichia coli lipopolysaccharide (LPS) (5 mg/kg) intraperitoneally during the postprandial (PPP) or postabsorptive (PAP) periods. Blood glucose was measured at 0, 15, 30, 60, 90, 120, 180, and 240 minutes. Serum tumor necrosis factor (TNF)-α and interleukin (IL) 6 were measured by enzyme-linked immunosorbent assay. Distribution of serum fatty acids was determined by gas liquid chromatography. Hepatic expression of genes involved in inflammation, as well as glucose and lipid metabolism, were determined by quantitative polymerase chain reaction. RESULTS: During the PPP, glucose curves were comparable among the experimental groups. During the PAP, EKD showed a more pronounced increase in glucose levels at the first hour after LPS challenge compared with the CD-LPS group. During the PAP, IL6 was lower in O3KD-LPS compared with CD-LPS and EKD-LPS groups. These differences disappeared in the PPP. Similarly, TNF-α was lower in the O3KD-LPS group compared with the EKD-LPS group. The O3KD significantly increased the serum levels of the ω-3 eicosapentaenoic and docosahexaenoic acids and decreased the ω-6 arachidonic acid. CONCLUSION: An O3KD leads to reduced inflammation and maintains glucose homeostasis in mice with endotoxemia.

Improvement of Lipoprotein Profile and Metabolic Endotoxemia by a Lifestyle Intervention That Modifies the Gut Microbiota in Subjects With Metabolic Syndrome.

Background Metabolic syndrome (MetS) is a serious health problem over the world; thus, the aim of the present work was to develop a lifestyle intervention to decrease the dysbiosis of gut microbiota and reduce the biochemical abnormalities of MetS. Methods and Results The prevalence of MetS was evaluated in 1065 subjects of Mexico City, Mexico, and the gut microbiota in a subsample. Subjects with MetS were selected for a pragmatic study based on a lifestyle intervention with a low-saturated-fat diet, reduced-energy intake, with functional foods and physical activity, and a second group was selected for a randomized control-placebo study to assess the gut microbiota after the dietary intervention. Prevalence of MetS was 53%, and the higher the body mass index, the higher the gut microbiota dysbiosis. The higher the Homeostatic Model Assessment for Insulin Resistance, the lower the high-density lipoprotein cholesterol concentration. The pragmatic study revealed that after 15 days on a low-saturated-fat diet, there was a 24% reduction in serum triglycerides; and after a 75-day lifestyle intervention, MetS was reduced by 44.8%, with a reduction in low-density lipoprotein cholesterol, small low-density lipoprotein particles, glucose intolerance, lipopolysaccharide, and branched-chain amino acid. The randomized control-placebo study showed that after the lifestyle intervention, there was a decrease in the dysbiosis of the gut microbiota associated with a reduction in the Prevotella/ Bacteroides ratio and an increase in the abundance of Akkermansia muciniphila and Faecalibacterium prausnitzii. Conclusions A lifestyle intervention significantly decreased MetS components, small low-density lipoprotein particle concentration, gut microbiota dysbiosis, and metabolic endotoxemia, reducing the risk of atherosclerosis. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT03611140.

Bovine α-lactalbumin hydrolysates ameliorate obesity-associated endotoxemia and inflammation in high-fat diet-fed mice through modulation of gut microbiota.

Gut microbiota has been identified as an important factor in the link between nutrient excess and obesity. The aim of this study was to confirm whether bovine α-lactalbumin hydrolysates (LAH) can ameliorate high-fat diet (HFD)-induced endotoxemia and systematic inflammation by modulating the structure of gut microbiota in mice. The results showed that LAH changed the overall structure of gut microbiota in HFD-induced obese mice. LAH increased the Bacteroidetes/Firmicutes ratios and the relative abundance of S24-7, Lachnospiraceae and Blautia. Spearman's correlation analysis revealed significant correlations between the alteration of gut microbiota and obesity-related indexes. LAH decreased the HFD-induced protein expression of G protein-coupled receptor 43 (GPR43) and 41 (GPR41) in the colon tissue. Besides, LAH inhibited the destruction of the gut barrier through the up-regulation of tight junction protein (zonulin/zonula occludens (ZO)-1 and occludin) expression and the decrease of toll-like receptor 4 (TLR4) protein expression in the colon tissue. LAH also significantly reduced the concentration of tumour cell necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in both serum and colon and decreased the level of lipopolysaccharides (LPS) in serum and feces, leading to reduced systematic inflammation and metabolic endotoxemia. In summary, LAH partly modulated the gut microbial composition and structure, and alleviated the obesity-associated inflammation. These findings shed light on bovine α-lactalbumin hydrolysate as a potential functional food ingredient to prevent obesity-related inflammation.

The Endotoxemia Marker Lipopolysaccharide-Binding Protein is Reduced in Overweight-Obese Subjects Consuming Pomegranate Extract by Modulating the Gut Microbiota: A Randomized Clinical Trial.

SCOPE: Gut microbiota dysbiosis, intestinal barrier failure, obesity, metabolic endotoxemia, and pro-inflammatory status promote cardiovascular risk. However, the modulation of the gut microbiome to prevent endotoxemia in obesity has been scarcely studied. We investigated the association between gut microbiota modulation and plasma lipopolysaccharide-binding protein (LBP), a surrogate marker of endotoxemia, in overweight-obese individuals. METHODS AND RESULTS: In a randomized trial, 49 overweight-obese subjects (body mass index> 27 kg m-2 ) with mild hypelipidemia daily consumed, in a cross-over fashion, two doses (D1 and D2, lasting 3 weeks each) of pomegranate extract (PE) or placebo alternating with 3 weeks of wash-out periods. A significant decrease (p < 0.05) of plasma LBP and a marginal decrease (p = 0.054) of high-sensitivity C-reactive protein were observed, but only after PE-D2 administration (656 mg phenolics). 16S rDNA sequencing analyses revealed the increase of microorganisms important for maintaining normal balance of gut microbiota and gut barrier function, particularly Bacteroides, Faecalibacterium, Butyricicoccus, Odoribacter, and Butyricimonas. PE-D2 also decreased pro-inflammatory microorganisms including Parvimonas, Methanobrevibacter, and Methanosphaera. Remarkably, plasma LBP reduction was significantly associated (p < 0.05) with both Faecalibacterium and Odoribacter increase and Parvimonas decrease. CONCLUSIONS: Consumption of PE decreased endotoxemia in overweight-obese individuals by reshaping the gut microbiota, mainly through the modulation of Faecalibacterium, Odoribacter, and Parvimonas.

Finger millet arabinoxylan protects mice from high-fat diet induced lipid derangements, inflammation, endotoxemia and gut bacterial dysbiosis.

Arabinoxylan (AX), a non-starch polysaccharide extracted from cereals such as wheat, rice and millets, is known to impart various health promoting effects. Our earlier study suggested that finger millet (FM) could ameliorate high fat diet (HFD)-induced metabolic derangements. The present study is aimed to evaluate the effect of FM-AX supplementation, a key bioactive from finger millet, on HFD-induced metabolic and gut bacterial derangements. Male Swiss albino mice were fed with normal chow diet (NPD) or HFD (60%kcal from fat) for 10 weeks. FM-AX was orally supplemented at doses of 0.5 and 1.0g/kg bodyweight on every alternate day for 10 weeks. Glucose tolerance, serum hormones, hepatic lipid accumulation and inflammation, white adipose tissue marker gene expression, adipocyte size and inflammation; metagenomic alterations in cecal bacteria; cecal short chain fatty acids and colonic tight junction gene expressions were studied. FM-AX supplementation prevented HFD-induced weight gain, alerted glucose tolerance and serum lipid profile, hepatic lipid accumulation and inflammation. Hepatic and white adipose tissue gene expressions were beneficially modulated. Further, AX supplementation prevented metagenomic alterations in cecum; improved ileal and colonic health and overall prevented metabolic endotoxemia. Present work suggests that AX from finger millet can be developed as a nutraceutical for the management of HFD- induced obesity.

Low-fat yogurt consumption reduces biomarkers of chronic inflammation and inhibits markers of endotoxin exposure in healthy premenopausal women: a randomised controlled trial.

The anti-inflammatory mechanisms of low-fat dairy product consumption are largely unknown. The objective of this study was to determine whether low-fat yogurt reduces biomarkers of chronic inflammation and endotoxin exposure in women. Premenopausal women (BMI 18·5-27 and 30-40 kg/m2) were randomised to consume 339 g of low-fat yogurt (yogurt non-obese (YN); yogurt obese (YO)) or 324 g of soya pudding (control non-obese; control obese (CO)) daily for 9 weeks (n 30/group). Fasting blood samples were analysed for IL-6, TNF-α/soluble TNF II (sTNF-RII), high-sensitivity C-reactive protein, 2-arachidonoyl glycerol, anandamide, monocyte gene expression, soluble CD14 (sCD14), lipopolysaccharide (LPS), LPS binding protein (LBP), IgM endotoxin-core antibody (IgM EndoCAb), and zonulin. BMI, waist circumference and blood pressure were also determined. After 9-week yogurt consumption, YO and YN had decreased TNF-α/sTNFR-RII. Yogurt consumption increased plasma IgM EndoCAb regardless of obesity status. sCD14 was not affected by diet, but LBP/sCD14 was lowered by yogurt consumption in both YN and YO. Yogurt intervention increased plasma 2-arachidonoylglycerol in YO but not YN. YO peripheral blood mononuclear cells expression of NF-κB inhibitor α and transforming growth factor ß1 increased relative to CO at 9 weeks. Other biomarkers were unchanged by diet. CO and YO gained approximately 0·9 kg in body weight. YO had 3·6 % lower diastolic blood pressure at week 3. Low-fat yogurt for 9 weeks reduced biomarkers of chronic inflammation and endotoxin exposure in premenopausal women compared with a non-dairy control food. This trial was registered as NCT01686204.

Effect of Dietary Lipids on Endotoxemia Influences Postprandial Inflammatory Response.

Metabolic syndrome (MetS) results in postprandial metabolic alterations that predisposes one to a state of chronic low-grade inflammation and increased oxidative stress. We aimed to assess the effect of the consumption of the quantity and quality of dietary fat on fasting and postprandial plasma lipopolysaccharides (LPS). A subgroup of 75 subjects with metabolic syndrome was randomized to receive 1 of 4 diets: HSFA, rich in saturated fat; HMUFA, rich in monounsaturated fat; LFHCC n-3, low-fat, rich in complex carbohydrate diet supplemented with n-3 polyunsaturated fatty acids; LFHCC low-fat, rich in complex carbohydrate diet supplemented with placebo, for 12 weeks each. We administered a fat challenge reflecting the fatty acid composition of the diets at postintervention. We determined the plasma lipoproteins and glucose and gene expression in peripheral blood mononuclear cells (PBMC) and adipose tissue. LPS and LPS binding protein (LBP) plasma levels were determined by ELISA, at fasting and postprandial (4 h after a fat challenge) states. We observed a postprandial increase in LPS levels after the intake of the HSFA meal, whereas we did not find any postprandial changes after the intake of the other three diets. Moreover, we found a positive relationship between the LPS plasma levels and the gene expression of IkBa and MIF1 in PBMC. No statistically significant differences in the LBP plasma levels at fasting or postprandial states were observed. Our results suggest that the consumption of HSFA diet increases the intestinal absorption of LPS which, in turn, increases postprandial endotoxemia levels and the postprandial inflammatory response.

Emulsifying dietary fat modulates postprandial endotoxemia associated with chylomicronemia in obese men: a pilot randomized crossover study.

BACKGROUND: Postprandial hyperlipemia is recognized as a major cardio-metabolic risk factor, recently linked to the co-absorption of pro-inflammatory lipopolysaccharides with dietary lipids. This causes endotoxemia that is involved in the pathophysiology of obesity and insulin resistance, but to date the impact of food formulation is unknown. We tested a novel concept that endotoxin absorption can be modulated by fat emulsified structure in the meal, and potentially differently in obese vs. lean men. METHODS: In a randomized controlled crossover study, eight normal-weight and eight obese age-matched healthy men ingested two isocaloric, isolipidic breakfasts of identical composition including 40 g of milk fat that was emulsified or unemulsified. Plasma- and chylomicron-endotoxemia and chylomicron-triglycerides were measured during 8 h after breakfast ingestion. RESULTS: After emulsion consumption, parallel to an enhanced chylomicronemia, obese subjects presented an early and sharp increase in chylomicron-endotoxemia at 60 min (P time = 0.02), which was higher than (i) after spread fat in obese subjects (P < 0.05) and (ii) after both spread and emulsified fat in normal-weight subjects (P < 0.05). However in obese subjects, the iAUC of plasma endotoxemia over 8 h was lower after emulsion than after spread fat (P < 0.05) whereas in NW subjects such reduction of plasma LPS-iAUC was not observed (P = 0.67). CONCLUSION: This study provides initial evidence that optimizing fat structure in the meal can be part of a dietary strategy to lower the metabolic impact of postprandial endotoxemia in obese men. TRIAL REGISTRATION: Registered at ClinicalTrials.gov # NCT01249378 on July 13, 2010.

Postprandial serum endotoxin in healthy humans is modulated by dietary fat in a randomized, controlled, cross-over study.

BACKGROUND: High-fat diets may contribute to metabolic disease via postprandial changes in serum endotoxin and inflammation. It is unclear how dietary fat composition may alter these parameters. We hypothesized that a meal rich in n-3 (ω3) fatty acids would reduce endotoxemia and associated inflammation but a saturated or n-6 (ω6) fatty acid-rich meal would increase postprandial serum endotoxin concentrations and systemic inflammation in healthy adults. METHODS: Healthy adults (n = 20; mean age 25 ± 3.2 S.D. years) were enrolled in this single-blind, randomized, cross-over study. Participants were randomized to treatment and reported to the laboratory, after an overnight fast, on four occasions separated by at least one week. Participants were blinded to treatment meal and consumed one of four isoenergetic meals that provided: 1) 20 % fat (control; olive oil) or 35 % fat provided from 2) n-3 (ω3) (DHA = 500 mg; fish oil); 3) n-6 (ω6) (7.4 g; grapeseed oil) or 4) saturated fat (16 g; coconut oil). Baseline and postprandial blood samples were collected. Primary outcome was defined as the effect of treatment meal on postprandial endotoxemia. Serum was analyzed for metabolites, inflammatory markers, and endotoxin. Data from all 20 participants were analyzed using repeated-measures ANCOVA. RESULTS: Participant serum endotoxin concentration was increased during the postprandial period after the consumption of the saturated fat meal but decreased after the n-3 meal (p < 0.05). The n-6 meal did not effect a different outcome in participant postprandial serum endotoxin concentration from that of the control meal (p > 0.05). There was no treatment meal effect on participant postprandial serum biomarkers of inflammation. Postprandial serum triacylglycerols were significantly elevated following the n-6 meal compared to the n-3 meal. Non-esterified fatty acids were significantly increased after consumption of the saturated fat meal compared to other treatment meals. CONCLUSIONS: Meal fatty acid composition modulates postprandial serum endotoxin concentration in healthy adults. However, postprandial endotoxin was not associated with systemic inflammation in vivo. TRIAL REGISTRATION: This study was retrospectively registered at clinicaltrials.gov as NCT02521779 on July 28, 2015.

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.

Dietary cocoa reduces metabolic endotoxemia and adipose tissue inflammation in high-fat fed mice.

In diet-induced obesity, adipose tissue (AT) is in a chronic state of inflammation predisposing the development of metabolic syndrome. Cocoa (Theobroma cacao) is a polyphenol-rich food with putative anti-inflammatory activities. Here, we examined the impact and underlying mechanisms of action of cocoa on AT inflammation in high fat-fed mice. In the present study, male C57BL/6 J mice were fed a high fat diet (HF), a HF diet with 8% (w/w) unsweetened cocoa powder (HFC), or a low-fat diet (LF) for 18 weeks. Cocoa supplementation decreased AT mRNA levels of tumor necrosis factor-α, interleukin-6, inducible nitric oxide synthase, and EGF-like module-containing mucin-like hormone receptor-like 1 by 40-60% compared to HF group, and this was accompanied by decreased nuclear protein levels of nuclear factor-κB. Cocoa treatment reduced the levels of arachidonic acid in the AT by 33% compared to HF controls. Moreover, cocoa treatment also reduced protein levels of the eicosanoid-generating enzymes, adipose-specific phospholipase A2 and cyclooxygenase-2 by 53% and 55%, respectively, compared to HF-fed mice. Finally, cocoa treatment ameliorated metabolic endotoxemia (40% reduction in plasma endotoxin) and improved gut barrier function (as measured by increased plasma levels of glucagon-like peptide-2). In conclusion, the present study has shown for the first time that long-term cocoa supplementation can reduce AT inflammation in part by modulating eicosanoid metabolism and metabolic endotoxemia.

Omega-3 PUFA supplementation and the response to evoked endotoxemia in healthy volunteers.

SCOPE: Fish oil-derived n-3 PUFA may improve cardiometabolic health through modulation of innate immunity. However, findings in clinical studies are conflicting. We hypothesized that n-3 PUFA supplementation would dose-dependently reduce the systemic inflammatory response to experimental endotoxemia in healthy humans. METHODS AND RESULTS: The Fenofibrate and omega-3 Fatty Acid Modulation of Endotoxemia (FFAME) study was an 8-wk randomized double-blind trial of placebo or n-3 PUFA supplementation (Lovaza 465 mg eicosapentaenoic acid (EPA) + 375 mg docosahexaenoic acid (DHA)) at "low" (1/day, 900 mg) or "high" (4/day, 3600 mg) dose in healthy individuals (N = 60; age 18-45; BMI 18-30; 43% female; 65% European-, 20% African-, 15% Asian-ancestry) before a low-dose endotoxin challenge (LPS 0.6 ng/kg intravenous bolus). The endotoxemia-induced temperature increase was significantly reduced with high-dose (p = 0.03) but not low-dose EPA + DHA compared to placebo. Although there was no statistically significant impact of EPA + DHA on individual inflammatory responses (tumor necrosis factor-α (TNF-α), IL-6, monocyte chemotactic protein (MCP-1), IL-1 receptor agonist (IL-1RA), IL-10, C-reactive protein (CRP), serum amyloid A (SAA)), there was a pattern of lower responses across all biomarkers with high-dose (nine of nine observed), but not low-dose EPA + DHA. CONCLUSION: EPA + DHA at 3600 mg/day, but not 900 mg/day, reduced fever and had a pattern of attenuated LPS induction of plasma inflammatory markers during endotoxemia. Clinically and nutritionally relevant long-chain n-3 PUFA regimens may have specific, dose-dependent, anti-inflammatory actions.

Oligofructose-enriched inulin improves some inflammatory markers and metabolic endotoxemia in women with type 2 diabetes mellitus: a randomized controlled clinical trial.

OBJECTIVES: Anti-inflammatory therapeutic approaches are considered for the management of type 2 diabetes and for the prevention of its complications. There is limited evidence regarding the effects of prebiotics on inflammation, especially in patients with type 2 diabetes. This trial aims to examine the effects of oligofructose-enriched inulin on glycemic status, inflammation markers, and metabolic endotoxemia in female patients. METHODS: Over a period of 8 wk, 52 women with body mass indices of >25 kg/m(2) but <35 kg/m(2) with type 2 diabetes were randomly assigned to either an intervention group, in which participants were given oligofructose-enriched inulin (n = 27, consuming 10 g/d of oligofructose-enriched inulin), or to a control group, in which participants were given maltodextrin (n = 25, consuming 10 g/d of maltodextrin). Fasting plasma glucose, glycosylated hemoglobin, high-sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-α, interferon-γ, interleukin-10, and plasma lipopolysaccharide were measured before and after the intervention. Data were analyzed with the use of SPSS software version 13. Paired and unpaired Student t tests and analysis of covariance were used to compare quantitative variables. RESULTS: Oligofructose-enriched inulin caused a significant decrease in the levels of fasting plasma glucose (19.2 mg/dL; 9.50%), glycosylated hemoglobin (1.0%; 8.40%), interleukin-6 (1.3 pg/mL; 8.15%), tumor necrosis factor-α (3.0 pg/mL; 19.80%) and plasma lipopolysaccharide (6.0 EU/mL; 21.95%) as compared with maltodextrin (P < 0.05). Decreases in levels of interferon-γ (0.3 pg/mL; 16.50%) and high-sensitivity C-reactive protein (3.9 ng/mL; 31.70%) and an increase in the level of interleukin-10 (0.4 pg/mL, 11.50%) were not significant in the oligofructose-enriched inulin group as compared with the maltodextrin group. CONCLUSIONS: In women with type 2 diabetes and suboptimal daily dietary fiber intake, oligofructose-enriched inulin may help to modulate some inflammatory markers.

Preventive and therapeutic effects of quercetin on lipopolysaccharide-induced oxidative stress and vascular dysfunction in mice.

Quercetin, a dietary antioxidant flavonoid, possesses strong anti-inflammatory and cytoprotective activities. The effects were investigated in an animal model of lipopolysaccharide (LPS)-induced endotoxaemia and vascular dysfunction in vivo. Male ICR mice were injected with LPS (10 mg/kg; i.p.). Quercetin (50 or 100 mg/kg) was intragastrically administered either before or after LPS administration. Fifteen hours after LPS injection, mice were found in endotoxaemic condition, as manifested by hypotension, tachycardia, and blunted vascular responses to vasodilators and vasoconstrictor. The symptoms were accompanied by increased aortic iNOS protein expression, decreased aortic eNOS protein expression, marked suppression of cellular glutathione (GSH) redox status, enhanced aortic superoxide production, increased plasma malodialdehyde and protein carbonyl, and elevated urinary nitrate/nitrite. Treatment with quercetin either before or after LPS preserved the vascular function, as blood pressure, heart rate, vascular responsiveness were restored to near normal values, particularly when quercetin was given as a preventive regimen. The vascular protective effects were associated with upregulation of eNOS expression, reduction of oxidative stress, and maintained blood GSH redox ratio. Overall findings suggest the beneficial effect of quercetin on the prevention and restoration of a failing eNOS system and alleviation of oxidative stress and vascular dysfunction against endotoxin-induced shock in mice.

Gelam honey inhibits lipopolysaccharide-induced endotoxemia in rats through the induction of heme oxygenase-1 and the inhibition of cytokines, nitric oxide, and high-mobility group protein B1.

Malaysian Gelam honey has anti-inflammatory and antibacterial properties, a high antioxidant capacity, and free radical-scavenging activity. Lipopolysaccharide (LPS) stimulates immune cells to sequentially release early pro- and anti-inflammatory cytokines and induces the synthesis of several related enzymes. The aim of this study was to investigate the effect of the intravenous injection of honey in rats with LPS-induced endotoxemia. The results showed that after 4h of treatment, honey reduced cytokine (tumor necrosis factor-α, interleukins 1ß, and 10) and NO levels and increased heme oxygenase-1 levels. After 24h, a decrease in cytokines and NO and an increase in HO-1 were seen in all groups, whereas a reduction in HMGB1 occurred only in the honey-treated groups. These results support the further examination of honey as a natural compound for the treatment of a wide range of inflammatory diseases.