Lipopolysaccharide-binding Protein Plasma Levels Research Articles

Calorie restriction ameliorates hyperglycemia, modulates the disordered gut microbiota, and mitigates metabolic endotoxemia and inflammation in type 2 diabetic rats.

The effects of calorie restriction (CR) on gut microbiota and the mechanism of CR ameliorating hyperglycemia in streptozotocin (STZ)-induced T2DM model rats were explored. High-fat diet and STZ injection were applied to induce T2DM model rats. Rats were divided into the following three groups: the control-diet ad libitum group, the T2DM model group fed with ad libitum diet, and the T2DM group fed with 30% restriction diet. 16S rRNA sequencing was used to determine the bacterial communities. Lipopolysaccharide (LPS)-binding protein (LBP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were measured. Glucose tolerance and insulin sensitivity were improved by CR, as well as the levels of fasting and random plasma glucose. Besides, CR not only modulated the overall structure of gut microbiota but also had selective enrichment in anti-inflammatory bacteria such as Lachnospiraceae_NK4A136_group, Ruminococcaceae_9, Allobaculum, Alistipes, and Oscillibacter, and decreased pro-inflammatory pathogenic bacteria such as Bacteroides, Lachnoclostridium, and Bifidobacterium. Tax4Fun indicated that CR could regulate related functional pathways such as lipopolysaccharide biosynthesis, and the plasma levels of LBP, IL-6, and TNF-α were markedly reduced by CR, suggesting the mechanism of CR ameliorating hyperglycemia may associate with the modulation of disordered gut microbiota and the reduction of metabolic endotoxemia and inflammation. CR could ameliorate hyperglycemia, the mechanism of which may associate with the alteration of the overall structure of gut microbiota, restoration of disordered microbiota function, and the downregulation of metabolic endotoxemia and inflammation in diabetic rats.

Respiratory dysfunction three months after severe COVID‐19 is associated with gut microbiota alterations

BackgroundAlthough coronavirus disease 2019 (COVID‐19) is primarily a respiratory infection, mounting evidence suggests that the gastrointestinal tract is involved in the disease, with gut barrier dysfunction and gut microbiota alterations being related to disease severity. Whether these alterations persist and are related to long‐term respiratory dysfunction remains unknown.MethodsPlasma was collected during hospital admission and after 3 months from the NOR‐Solidarity trial (n = 181) and analyzed for markers of gut barrier dysfunction and inflammation. At the 3‐month follow‐up, pulmonary function was assessed by measuring the diffusing capacity of the lungs for carbon monoxide (DLCO). Rectal swabs for gut microbiota analyses were collected (n = 97) and analyzed by sequencing the 16S rRNA gene.ResultsGut microbiota diversity was reduced in COVID‐19 patients with respiratory dysfunction, defined as DLCO below the lower limit of normal 3 months after hospitalization. These patients also had an altered global gut microbiota composition, with reduced relative abundance of 20 bacterial taxa and increased abundance of five taxa, including Veillonella, potentially linked to fibrosis. During hospitalization, increased plasma levels of lipopolysaccharide‐binding protein (LBP) were strongly associated with respiratory failure, defined as pO2/fiO2 (P/F ratio) <26.6 kPa. LBP levels remained elevated during and after hospitalization and were associated with low‐grade inflammation and respiratory dysfunction after 3 months.ConclusionRespiratory dysfunction after COVID‐19 is associated with altered gut microbiota and persistently elevated LBP levels. Our results should be regarded as hypothesis generating, pointing to a potential gut–lung axis that should be further investigated in relation to long‐term pulmonary dysfunction and long COVID.

Hypertension promotes microbial translocation and dysbiotic shifts in the fecal microbiome of nonhuman primates.

Accumulating evidence indicates a link between gut barrier dysfunction and hypertension. However, it is unclear whether hypertension causes gut barrier dysfunction or vice versa and whether the gut microbiome plays a role. To understand this relationship, we first cross-sectionally examined 153 nonhuman primates [NHPs; Chlorocebus aethiops sabaeus; mean age, 16 ± 0.4 yr; 129 (84.3%) females] for cardiometabolic risk factors and gut barrier function biomarkers. This analysis identified blood pressure and age as specific factors that independently associated with microbial translocation. We then longitudinally tracked male, age-matched spontaneously hypertensive NHPs (Macaca mulatta) to normotensives (n = 16), mean age of 5.8 ± 0.5 yr, to confirm hypertension-related gut barrier dysfunction and to explore the role of microbiome by comparing groups at baseline, 12, and 27 mo. Collectively, hypertensive animals in both studies showed evidence of gut barrier dysfunction (i.e., microbial translocation), as indicated by higher plasma levels of lipopolysaccharide-binding protein (LBP)-1, when compared with normotensive animals. Furthermore, plasma LBP-1 levels were correlated with diastolic blood pressure, independent of age and other health markers, suggesting specificity of the effect of hypertension on microbial translocation. In over 2 yr of longitudinal assessment, hypertensive animals had escalating plasma levels of LBP-1 and greater bacterial gene expression in mesenteric lymph nodes compared with normotensive animals, confirming microbes translocated across the intestinal barrier. Concomitantly, we identified distinct shifts in the gut microbial signature of hypertensive versus normotensive animals at 12 and 27 mo. These results suggest that hypertension contributes to microbial translocation in the gut and eventually unhealthy shifts in the gut microbiome, possibly contributing to poor health outcomes, providing further impetus for the management of hypertension.NEW & NOTEWORTHY Hypertension specifically had detrimental effects on microbial translocation when age and metabolic syndrome criteria were evaluated as drivers of cardiovascular disease in a relevant nonhuman primate model. Intestinal barrier function exponentially decayed over time with chronic hypertension, and microbial translocation was confirmed by detection of more microbial genes in regional draining lymph nodes. Chronic hypertension resulted in fecal microbial dysbiosis and elevations of the biomarker NT-proBNP. This study provides insights on the barrier dysfunction, dysbiosis, and hypertension in controlled studies of nonhuman primates. Our study includes a longitudinal component comparing naturally occurring hypertensive to normotensive primates to confirm microbial translocation and dysbiotic microbiome development. Hypertension is an underappreciated driver of subclinical endotoxemia that can drive chronic inflammatory diseases.

Plasma Lipopolysaccharide-Binding Protein Reflects Risk and Progression of Parkinson’s Disease

Lipopolysaccharide-binding protein (LBP) presents bacterial endotoxin, lipopolysaccharides, to cellular surface pattern receptors for immune responses in the gut-brain axis of Parkinson's disease (PD). We investigated whether plasma LBP levels were associated with PD severity and progression. This study included 397 participants (248 PD patients and 149 controls). We measured participants' plasma levels of LBP and pro-inflammatory cytokines, including TNF-α, IL-6, andIL-17A. PD patients underwent motor and cognition evaluations at baseline and at a mean follow-up interval of 4.7±2.3 years. We assessed the progression of motor and cognition symptoms based on changes in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III motor score and Mini-Mental State Examination (MMSE) score, respectively. Plasma LBP levels were lower in PD patients than controls (9.08±2.91 vs. 10.10±3.00μg/ml, p < 0.01). A multiple logistic regression model with adjustment for age, sex, and plasma cytokine levels revealed that reduced plasma LBP levels were associated with increased PD risk (odds ratio 0.816, [95% CI 0.717-0.929], p = 0.002). Among PD patients, LBP levels were correlated with MDS-UPDRS part III motor score after adjustment for confounders (coefficient = 0.636, p = 0.017), but not with MMSE score. Adjusted Cox regression analysis showed that higher plasma LBP levels associated with faster motor progression (adjusted hazard ratio 1.084 [95% CI 1.011-1.163], p = 0.024) during follow-up. Our results demonstrated that plasma LBP levels reflect risk, motor symptom severity and progression in patients with PD.

Lipopolysaccharide binding protein and sCD14 as risk markers of stroke-associated pneumonia

To determine the utility of lipopolysaccharide binding protein (LBP) and soluble CD14 (sCD14) as risk markers of stroke-associated pneumonia (SAP). We included 331 stroke patients. The plasma levels of LBP (median: 19.4 vs 15.3 μg/mL, P < 0.01) and sCD14 (median: 1.5 vs 1.4 μg/mL, P = 0.04) were elevated in SAP. In multivariate analysis, a higher level of LBP (OR: 1.09, 95%CI: 1.05–1.13), but not sCD14 (OR: 2.16, 0.94–4.97), was associated with SAP. The addition of LBP or sCD14 to the clinical model did not improve its discriminatory ability. Our results suggest the modest value of studied biomarkers for SAP prediction.

Heat-killed Lactobacillus plantarum L-137 attenuates obesity and associated metabolic abnormalities in C57BL/6 J mice on a high-fat diet.

Heat-killed Lactobacillus plantarum L-137 (HK L-137) has anti-allergic, antitumor, and antiviral effects in mice, as well as an anti-inflammatory effect in rats with metabolic syndrome through regulation of immunity. To evaluate the influence of HK L-137 on chronic inflammation in mice with diet-induced obesity, C57BL/6 J mice were fed a normal diet (16% of energy as fat) or a high-fat diet (62% of energy as fat) with or without 0.002% HK L-137 for 4 to 20 weeks. It was found that HK L-137 supplementation alleviated weight gain and elevation of plasma glucose, cholesterol, alanine aminotransferase, and aspartate transaminase levels in mice with diet-induced obesity. Expression of several inflammation-related genes, including F4/80, CD11c, and IL-1β, in the epididymal adipose tissue of these mice was significantly downregulated by HK L-137. In addition, plasma levels of lipopolysaccharide-binding protein, a marker of endotoxemia, tended to be decreased by administration of HK L-137. These findings suggest that HK L-137 supplementation ameliorates obesity-induced metabolic abnormalities and adipose tissue inflammation, possibly through improvement of intestinal permeability.

Markers of microbial translocation during pregnancy: differences among HIV+ women of African and European provenance.

Microbial translocation (MT) markers are indicators of HIV-related immune activation, but reference values are mostly derived from European or North American populations and could be substantially different in populations living in developing countries. Here we evaluate possible differences in MT markers levels in HIV+ pregnant women of different geographical provenance. This study is nested within an observational study of pregnant women with HIV in Italy. Women were dichotomized on the basis of provenance in two groups of European (n = 14) and African (n = 26) origin. Soluble CD14, lipopolysaccharide-binding protein (LBP) and intestinal-fatty acid binding protein (I-FABP) were measured in plasma samples collected between the first and second trimester of pregnancy. Demographic and viroimmunological characteristics were similar between groups, although European women were more commonly smokers and HCV-coinfected. Irrespective of origin, LBP plasma levels were positively correlated with I-FABP (r = 0.467, p = 0.004) and sCD14 levels (r = 0.312 p = 0.060). Significantly higher levels of sCD14 (1885 vs. 1208 ng/mL, p = 0.005) LBP (28.5 vs. 25.3 µg/mL, p = 0.050) and I-FABP (573.4 vs. 358.2 pg/mL, p = 0.002) were observed in European compared with African women. A multivariable linear regression analysis, adjusted for smoking and HCV coinfection confirmed the association between sCD14 levels and women provenance (p = 0.03). Our observations indicate significant differences in soluble markers among women of different provenance. In the design and analysis of studies evaluating MT markers, population-specific reference values should be considered.

Low-Grade Inflammation in Hemophilia

We previously showed that impaired clotting in hemophilia leads to a deficit in macrophage differentiation, which negatively affects critical regenerative macrophage functions such as clot infiltration and red blood cell phagocytosis. These data provide a functional basis for the delayed wound healing as well as protracted joint inflammation commonly observed in hemophiliacs and suggest that altered macrophage function is linked to the activation of the innate immune system. We, therefore, hypothesize that hemophiliacs suffer from chronic low-grade inflammation, which in turn can affect joint health, tissue regeneration and age-related ailments such as cardiovascular disease. For this study, we collected citrated blood from 48 adult male patients with hemophilia A or B with an average age of 36 years and a body mass index (BMI) of 27.7 kg/m2. The majority of patients had a residual FVIII/FIX activity &lt; 1% (77%) and received prophylactic treatment (60%) with a recombinant or plasmatic coagulation factor concentrate. Approximately one-half of the patients had target joints or other bleeding events in the last 3 months and one-third of the patients had contracted HBV, HCV or HIV. For controls, we randomly recruited male blood donors (n = 60; age, 35.8 years; BMI, 27.0) from our blood donation center. To assess inflammation in hemophiliacs, we analyzed platelet-poor plasma from our main collective and a BMI-adjusted cohort using commercially available ELISA kits. The results showed a significant increase of two acute-phase proteins, C-reactive protein and leptin in hemophilia patients compared to healthy controls. Further analysis demonstrated that C-reactive protein and leptin expression inversely correlated with the residual clotting activity as both parameters were high in patients with severe Hemophilia A or B and comparatively low in patients with moderate to mild hemophilia. Of note, there was neither an increase of C-reactive protein or leptin in hemophilia patients with recent bleeding (&lt; 3 month), arthropathy, chronic viral infection nor a decrease in patients with coagulation factor activity &gt; 10% due to prophylactic treatment or recent replacement. Therefore, these data suggest a basic link between clotting deficiencies and chronic low-grade inflammation. Low-grade inflammation is maintained by adipokines, which originate from the adipose tissue and are modulated by a process known as adipose tissue inflammation. In addition to the upregulation of the pro-inflammatory leptin, we detected a significant down-regulation of the anti-inflammatory adiponectin in the plasma of hemophilia patients resulting in a markedly decreased adiponectin/leptin ratio. To enquire if the adipose tissue inflammation in hemophilia originates from gram-negative gut bacteria that translocate into the blood circulation, we also detected elevated plasma levels of lipopolysaccharide-binding protein and hepcidin in hemophilia patients. Together, these data support the concept that low-grade inflammation in hemophilia originates from lipopolysaccharide, which in turn causes adipose tissue inflammation. To test the hypothesis that low-grade inflammation in hemophilia is caused by decreased clotting activity, we collected blood from hemophilia B patients before and after transition from a conventional standard-half-life factor IX concentrate to a prophylactic therapy with an elongated half-life (EHL) FIX (Albutrepennonacog alfa, Idelvion®). Following up on the enhanced factor replacement after &gt; 6 months, we observed a return of hepcidin plasma levels back to baseline values in healthy controls. The decreased hepcidin values from EHL FXI therapy correlated with healing of target joints suggesting that EHL FIX not only controls bleeding but also inflammation. Together, our data demonstrate a specific link between hemophilia and low-grade inflammation that appears to involve increased lipopolysaccharide levels in the blood circulation and subsequent adipose tissue inflammation. In addition, we present evidence that low-grade inflammation is the result of the underlying clotting deficit and that sustained normalization of the clotting deficit with EHL factors ameliorates inflammation. Disclosures Eichler: Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Pilch:CSL Behring: Other: Grants (investigator initiated), Speakers Bureau; ASPIRE Award/Pfizer: Other: Grants (investigator initiated); Bayer: Consultancy, Speakers Bureau; Roche: Consultancy.

Brazilian propolis extract reduces intestinal barrier defects and inflammation in a colitic mouse model

Brazilian propolis is rich in cinnamic acid derivatives and reportedly reduces intestinal inflammation in rodents; however, the underlying mechanisms remain unclear. We hypothesized that the regulation of tight junction (TJ) barrier, Th17 cell differentiation, and/or, macrophage activation by cinnamic acid derivatives were involved in the propolis-mediated anti-inflammatory effect. Mice were orally administered 2% dextran sodium sulfate (DSS) in combination with either the feeding control or a diet containing 0.3% ethanol extract of Brazilian propolis for 9 days. DSS administration induced acute colitis in mice, whereas the propolis extract mitigated DSS-induced weight loss; colon shortening; increased plasma levels of lipopolysaccharide-binding protein; reduced expression of TJ proteins, such as zonula occludens, junctional adhesion molecule-A, occludin, and claudins; and increased expression of inflammatory cytokines, such as tumor necrosis factor (TNF) α, interleukin (IL) 6, and IL-17a. Cinnamic acid derivatives, such as artepillin C and caffeic acid phenethyl ester, present in the propolis extract suppressed the IL-17 production from cultured murine splenocytes through decreased retinoic acid-related orphan receptor gT expression. Baccharin, drupanin, and culifolin, which are also present in Brazilian propolis, reduced the TNF-α and/or IL-6 production by suppressing inflammatory signaling in murine RAW 264.7 macrophages. Taken together, the regulation of Th17 differentiation and macrophage activation by cinnamic acid derivatives, at least in part, contribute to the anti-inflammatory effect mediated by Brazilian propolis.

Bacteria-related Events and the Immunological Response of Onset and Relapse Adult Crohn's Disease Patients.

Crohn's disease [CD] is a chronic, systemic inflammatory disease characterised by periods of remission and flare-ups. It has been associated with a disturbed gastrointestinal barrier function, an increase in the transport of luminal contents into the tissue, and lower immune tolerance. Peripheral blood samples were collected from healthy controls and 33 adult active flare-up CD patients. We classified patients as onset or relapse flare-up subjects, according to the days of disease evolution. Plasma levels of lipopolysaccharide-binding protein [LBP], fatty acid-binding proteins [FABP], and antibodies against bacterial lysates, interferons [IFN] and interleukin-6 [IL6] were measured by enzyme-linked immunosorbent assay [ELISA] in each group of patients. Onset CD patients had higher plasma levels of LBP [57.32 ± 38.86 vs 30.22 ± 9.80 µg/ml] and IFNα [1.25 ± 0.23 vs 0.95 ± 0.36 log10pg/ml] and lower levels of immunoglobulins G and A [IgG and IgA] antibodies against bacterial lysates than relapse CD patients. We also observed a subgroup of onset patients with the highest levels of LBP. In this subgroup, LBP correlated negatively with C-reactive protein [CRP]. Onset and relapse CD patients had similar levels of FABP6 and FABP2, though LBP and FABP6 correlated positively only in relapse patients. In relapse patients, anti-E coli IgG antibodies correlated positively with systemic IL6 and IFNα levels. Our findings suggest that onset and relapse flare-ups in adult CD patients are related to different systemic immune-related bacterial events. Characterising these differences may provide insights into the aetiology of Crohn's disease, and would help in the selection of appropriate therapies.

Abstract # 1795 Plasma levels of lipopolysaccharide-binding protein in response to psychosocial stress induction: Association with sympathetic nervous system response

Background Numerous studies have linked the gut microbiota with stress- and inflammation-related diseases, such as depression and the metabolic syndrome. It has been hypothesized that higher circulating concentrations of lipopolysaccharide (LPS), an inflammatory cell wall component of (gut residing) Gram-negative bacteria, are caused by stress-induced increases in barrier permeability, allowing the translocation of bacteria and/or LPS across the gut wall. Goal Investigate if acute psychosocial stress increases gut permeability as indicated by plasma concentrations of LPS-binding protein (LBP), a biomarker reflecting plasma exposure to LPS, and explore its relationship to inflammation and the autonomic nervous system response. Methods 12 young adults (5 women and 7 men) underwent a standardized laboratory stress test. Heart rate (HR) was measured continuously, and plasma interleukin (IL)-6 and LBP levels were measured at baseline and after the stressor (+30 min, +90 min). Results Mean IL-6 levels (p = .003), but not LBP levels were significantly increased 30 min after the stressor. After adjusting for sex and BMI, overall LBP concentrations (represented as area under the curve) were positively correlated with HR during the stress test (r = .737, p = .015). Conclusion Acute psychosocial stress does not significantly change LBP plasma levels. However, higher LBP concentrations are associated with higher HR levels after stress induction, suggesting a relationship between microbial presence and increased sympathetic nervous system reactivity.

Lipopolysaccharide-binding protein plasma levels as a biomarker of obesity-related insulin resistance in adolescents.

PurposeLipopolysaccharide-binding protein (LBP) is a 65-kDa acute phase protein, derived from the liver, which is present in high concentrations in plasma. Data regarding the association between circulating plasma LBP levels and obesity-related biomarkers in the pediatric population are scarce. We aimed to determine whether there was a difference in plasma LBP levels between overweight/obese and normal-weight adolescents and to assess the correlation of circulating LBP levels with anthropometric measures and obesity-related biomarkers, including insulin resistance, liver enzyme levels, and lipid profiles.MethodsThe study included 87 adolescents aged 12–13 years; 44 were overweight/obese and 43 were of normal-weight. We assessed anthropometric and laboratory measures, including body mass index (BMI), blood pressure, insulin resistance, liver enzyme levels, and lipid profiles. Plasma LBP levels were measured using an enzyme-linked immunosorbent assay.ResultsThe mean age of the participants was 12.9±0.3 years. Circulating plasma LBP levels were significantly increased in overweight/obese participants compared with those in normal-weight participants (7.8±1.9 µg/mL vs. 6.0±1.6 µg/mL, P<0.001). LBP levels were significantly and positively associated with BMI, systolic blood pressure, aspartate aminotransferase, alanine aminotransferase, total cholesterol, low density lipoprotein-cholesterol, fasting glucose and insulin, and insulin resistance as indicated by the homeostatic model assessment of insulin resistance (HOMA-IR) (all P<0.05). In multivariate linear regression analysis, BMI and HOMA-IR were independently and positively associated with plasma LBP levels.ConclusionLBP is an inflammatory biomarker associated with BMI and obesity-related insulin resistance in adolescents. The positive correlation between these parameters suggests a potentially relevant pathophysiological mechanism linking LBP to obesity-related insulin resistance in adolescents.

Lipopolysaccharide-Binding Protein Plasma Levels in Children: Effects of Obstructive Sleep Apnea and Obesity

Obstructive sleep apnea (OSA) has been linked to obesity, inflammation, and metabolic syndrome. The gut microbiota, which serves as reservoir for bacterial lipopolysaccharides (LPS), could be altered by OSA and trigger inflammation. LPS-binding protein (LBP) serves as a surrogate marker of underlying low-grade endotoxemia by LPS from the gut. We hypothesized that systemic LBP levels would be higher in obese children and in those with OSA. Consecutive snoring and nonsnoring children (mean age 6.8 ± 1.3 y) were included after overnight polysomnography, and fasting levels of lipids, insulin glucose, and high-sensitivity C-reactive protein were obtained. Children were subdivided into four subgroups based on the presence of obesity or OSA. Plasma LBP levels were assayed using ELISA. Of 219 participants, nonobese controls had the lowest levels of LBP, and the presence of obesity without OSA was associated with significant LBP increases. Nonobese children with OSA exhibited increased LBP levels, with obese children with OSA demonstrating the highest LBP levels of all four groups. Furthermore, LBP was independently associated with body mass index and with measures of OSA severity as well as with metabolic dysfunction, particularly insulin resistance as indicated by the homeostasis model assessment of insulin resistance. Systemic low-level endotoxemia and resultant systemic inflammation is present in children who are either obese or suffer from OSA and is particularly prominent when both conditions are present. We postulate that disrupted sleep and other factors facilitating obesity such as a high-fat diet may disrupt the gut microbiome and lead to increased systemic LPS levels with resultant inflammation, promoting downstream metabolic dysfunction.

The effect of normovolemic modified ultrafiltration on inflammatory mediators, endotoxins, terminal complement complexes and clinical outcome in high-risk cardiac surgery patients

The clinical benefit of normovolemic modified ultrafiltration (N-MUF) after cardiac surgery is still debated. As we have shown in a previous publication, there is a significant improvement in platelet function, so we were interested in whether ultrafiltration can reduce plasma levels of endotoxins, terminal complement complexes and cytokines after cardiopulmonary bypass (CPB) in adults with increased risk profiles. In this single-center, prospective, randomized trial, fifty high-risk patients (mean logistic EuroSCORE II: 17.5%) who underwent cardiac surgery were randomized. After CPB, Group 1 (n = 25) served as the control and in, Group 2 (n= 25), an N-MUF of 3000 ml was performed, using a BC140plus filter after weaning from CPB. Blood samples were taken after the induction of anesthesia, before CPB, before CPB weaning, 30 minutes after CPB and at 6, 24 and 48 hours postoperatively. Primary outcomes were plasma levels of lipopolysaccharide-binding protein (LBP), terminal complement complex (C5b9) and cytokines (IL-6, IL-10, IL-1beta, TNF-α). Secondary outcomes focused on differences in the clinical outcome. A significant reduction in LBP concentration (preoperatively: 23.8±8.4 pg/ml, postoperatively: 14.2±12.9 pg/ml) and C5b9 (preoperatively: 4.18±2.6 pg/ml, postoperatively: 3.05±2.39 pg/ml) were detected 6 hours after N-MUF. In the N-MUF group, significantly lower concentrations of lactate could be detected in the early postoperative period. Furthermore, postoperative chest tube blood loss was significantly lower in the N-MUF group at 24 and 48 hours. N-MUF leads to a significant reduction of lipopolysaccharide-binding protein and terminal complement complex and was associated with reduced blood loss and postoperative lactate concentrations shortly after surgery.

Beneficial effect of oral administration of Lactobacillus casei strain Shirota on insulin resistance in diet-induced obesity mice

This study aimed at determining whether oral administration of a probiotic strain, Lactobacillus casei strain Shirota (LcS), can improve insulin resistance, which is the underlying cause of obesity-associated metabolic abnormalities, in diet-induced obesity (DIO) mice. DIO mice were fed a high-fat diet without or with 0·05% LcS for 4 weeks and then subjected to an insulin tolerance test (ITT) or oral glucose tolerance test (OGTT). Oral administration of LcS not only accelerated the reduction in plasma glucose levels during the ITT, but also reduced the elevation of plasma glucose levels during the OGTT. In addition, plasma levels of lipopolysaccharide-binding protein (LBP), which is a marker of endotoxaemia, were augmented in the murine models of obese DIO, ob/ob, db/db and KK-A(y) and compared to those of lean mice. LcS treatment suppressed the elevation of plasma LBP levels in DIO mice, but did not affect intra-abdominal fat weight. LcS improves insulin resistance and glucose intolerance in DIO mice. The reduction in endotoxaemia, but not intra-abdominal fat, may contribute to the beneficial effects of LcS. This study suggests that LcS has the potential to prevent obesity-associated metabolic abnormalities by improving insulin resistance.

Lipopolysaccharide-Binding Protein Plasma Levels and Liver TNF-Alpha Gene Expression in Obese Patients: Evidence for the Potential Role of Endotoxin in the Pathogenesis of Non-Alcoholic Steatohepatitis

Some lines of evidence suggest that endotoxin may induce non-alcoholic steatohepatitis (NASH) in a background of fatty liver. However, a clear association between increased endotoxemia and development of steatohepatitis in obese patients has not been confirmed. We aim to assess the endotoxemic state of patients with non-alcoholic fatty liver disease (NAFLD) and its relationship with the liver expression of TNF-alpha and the presence of NASH. Prospective study comprising 40 patients with morbid obesity who were diagnosed with NAFLD. Blood samples and liver biopsies were collected. Endotoxemia was assessed by the evaluation of circulating level of LPS-binding protein (LBP). Plasma levels of LBP and TNF-alpha were assessed by ELISA. The expression of TNF-alpha in liver tissue was evaluated by real-time PCR. Histological examination was performed to evaluate the presence of steatosis or NASH. Levels of LBP were increased in obese patients with NAFLD. In addition, plasma level of LBP was increased in patients with steatohepatitis (14.2 +/- 3.9 microg/mL) when compared with patients with simple steatosis (11.5 +/- 3.2 microg/mL), P=0.041. The TNF-alpha mRNA expression in liver tissue was significantly higher in patients with NASH. This increment correlated with the rise in plasma levels of LBP (r=0.412, P=0.036). NAFLD patients have elevated plasma levels of LBP and they are further increased in patients with NASH. This increase is related to a rise in TNF-alpha gene expression in the hepatic tissue which supports a role for endotoxemia in the development of steatohepatitis in obese patients.

Impact of Blood Transfusions on Inflammatory Mediator Release in Patients Undergoing Cardiac Surgery

This study was conducted to investigate whether intraoperative blood transfusions affect the release of proinflammatory mediators in patients undergoing cardiac surgery. Therefore, we measured plasma levels of bactericidal permeability increasing protein (BPI) as a marker of neutrophil activation, interleukin-6 (IL-6), lipopolysaccharide binding protein (LBP), and C-reactive protein (CRP). In addition, these mediators, except CRP, were also measured in packed red cell units (PCs) administered to these patients. Prospective study. Cardiopulmonary surgery department in a university hospital. One hundred fourteen consecutive patients undergoing cardiac surgery. Blood samples were taken at induction of anesthesia, at the start of aortic cross-clamping, at aortic unclamping, and at 0.5, 4, 8, and 18 h thereafter. Thirty-six patients received PC intraoperatively. BPI levels in patients who received transfusions were significantly higher at 0.5 and 4 h after aortic unclamping than in patients without transfusions (p < 0.05), and increased with the number of PC administered. IL-6 levels at 0.5, 4, and 18 h after aortic unclamping were also significantly higher in patients who received transfusions (p < 0.01). BPI was found in all units of packed red cells tested at concentrations up to 15 times preoperative plasma levels in patients. However, PC IL-6 could be detected in none of the samples. Plasma levels of LBP and CRP were similar in both patient groups. LBP was found in very low concentrations in all PC. Patients who received intraoperative transfusions had a worse postoperative performance. Intraoperative PC transfusions do contribute to the inflammatory response after cardiac surgery both by enhancing part of the response and by directly changing plasma concentrations of inflammatory mediators. Furthermore, these data show that intraoperative PC transfusion is associated with a worse postoperative performance.

Plasma lipopolysaccharide binding protein and bactericidal/permeability increasing factor in CRF and HD patients.

The recent characterization of lipopolysaccharide binding protein (LBP) and bactericidal/permeability increasing factor (BPI) have provided the opportunity to examine the natural factors that regulate cytokine production in response to endotoxin in patients on hemodialysis (HD). Whole blood was collected in EDTA from 28 undialyzed patients with chronic renal failure (undialyzed CRF), 36 patients on chronic HD (HD) and 15 healthy controls, and plasma levels of LBP and BPI were measured by a sandwich ELISA. Plasma LBP levels in undialyzed patients with CRF (P = 0.04) and patients on HD (P = 0.01) were significantly higher than those in healthy controls, but not significantly different from each other. Plasma BPI levels in undialyzed patients with CRF and patients on HD were not significantly different from those in healthy controls. There was no correlation between serum creatinine and plasma levels of either LBP or BPI. Peripheral blood mononuclear cells (PBMC) were harvested from healthy volunteers by FLcoll-Hypaque separation, and 0.125 mL of 10 x 10(6)/mL suspensions were incubated with 0.125 mL of test plasma (containing different LBP/BPI ratios) and 0.25 mL of RPMI, containing 1 ng/mL of endotoxin, for 24 h at 37 degrees C. Samples were subjected to three freeze-thaw cycles, and total interleukin-1 receptor antagonist (IL-1Ra) or interleukin-1 alpha (IL-1 alpha) production was measured by a specific non-crossreactive RIA. The results of this study showed: (1) IL-1Ra production by endotoxin-stimulated PBMC incubated with pooled plasma from HD patients with LBP/BPI ratios of 11 x 10(2), 167 x 10(2), 379 x 10(2), and 778 x 10(2), respectively was 1466 +/- 195 pg, 3105 +/- 462 pg, 8179 +/- 1020 pg, and 4770 +/- 1185 pg (P < 0.001); (2) Paired plasma collected before dialysis (predialysis) and at 15 min after the start of dialysis (15 minute) with cellulose membranes showed a negligible change in plasma LBP levels (-3 +/- 5%), but a 6681 +/- 1788% increase in plasma BPI levels. Consequently, compared with predialysis plasma, there was a 35 +/- 6% decrease in endotoxin-stimulated IL-1 alpha production by PBMC incubated with plasma drawn at 15 min (P = 0.001); (3) Compared with the PBMC incubated with predialysis plasma from HD patients, there was a 39 +/- 5%, 53 +/- 5%, and 60 +/- 5% decrease in endotoxin-stimulated IL-1 alpha production in the presence of 1 ng/ mL, 10 ng/mL, or 1 microgram/mL of recombinant BPI, respectively (P < 0.003). These results suggest that the plasma LBP:BPI ratio could influence cytokine production in response to bacterial endotoxin; the high LBP:BPI ratios observed in patients with chronic renal failure probably imparts an increased susceptibility to endotoxin-stimulated cytokine production; and natural or pharmacological increases in plasma BPI levels and the consequent decrease in LBP:BPI ratios could attenuate this susceptibility to endotoxin-stimulated cytokine production.