Plasma Endotoxin Concentrations Research Articles

Evaluation of pre-operative high dose corticosteroids in elective colorectal surgery and effects on gut barrier function: A phase 2 clinical trial

BackgroundPerioperative inflammation is a predictor of surgical complications and cancer prognosis in surgical oncology. Multimodal protocols are ongoing in order to find ways to control inflammation. A preoperative flash high-dose of corticosteroids has been suggested as a way to control perioperative inflammation, but its safety in colorectal surgery needs to be established prior to a phase 3 trial. The physiologic effects of such a dose should also be explored. MethodsProspective bicentric phase 2 single-arm study with a biological ancillary study. Patients were administered 20 mg/kg of methyl-prednisone before colorectal surgery. Primary outcome was major post-operative complications defined as a grade >II according to the Dindo-Clavien classification. Ancillary outcome was plasma endotoxin concentration and activity. ResultsSixty-seven patients were included. Twelve (17.9 % [90 %CI:10.9 %-29.6 %]) patients developed major post-operative complications. No homeostatic disturbances troubles were observed. Severe postoperative hyperglycemia concerned 3 (4 %) patients which were all non-diabetic. The concentrations of endotoxin (mass) and its activity lowered between the pre-operative time point and the day after surgery. ConclusionPre-operative single flash of high dose methylprednisolone (20 mg/kg) before elective colorectal surgery seemed safe. Our results suggest that corticosteroids could promote gut barrier integrity, reducing endotoxemia in patients with colorectal surgery. Further studies (in particular a large randomized controlled trial) are needed to confirm our findings and explore a potential benefit of corticosteroid in this population. ClinicalTrials.gov03437746

Kynurenine pathway alteration in acute pancreatitis and its role as a biomarker of infected necrosis

IntroductionInfected pancreatic necrosis (IPN) is a major cause of mortality in acute pancreatitis (AP). Currently, no specific strategies are available to predict the development of IPN. Earlier we reported that persistent down-regulation of HLA-DR increases risk of developing IPN. Altered kynurenine pathway (KP) metabolites showed poor prognosis in sepsis. Here we evaluated the role of HLA-DR and KP in IPN. MethodsPatients with ANP and healthy controls were enrolled. Demographic and clinical parameters were recorded. Circulating interleukin (IL)-8, 6, 1β, 10, Tumor necrosis factor-α were quantified using flowcytometry. Plasma procalcitonin, endotoxin, and KP (tryptophan, kynurenine) concentrations were estimated using ELISA. qRT-PCR was conducted to evaluate mRNA expression of HLA-DR, IL-10, Toll like receptor-4 (TLR-4), and kynurenine-3-monooxygenase (KMO) genes on peripheral blood mononuclear cells. Plasma metabolites were quantified using gas chromatography mass spectrometry (GC-MS/MS). Standard statistical methods were used to compare study groups. Metaboanalyst was used to analyse/visualize the metabolomics data. ResultsWe recruited 56 patients in Cohort-1 (IPN:26,Non-IPN:30), 78 in Cohort-2 (IPN:57,Non-IPN:21), 26 healthy controls. Increased cytokines, endotoxin, and procalcitonin were observed in patients with IPN compared to Non-IPN. HLA-DR and KMO gene expressions were significantly down-regulated in IPN groups, showed positive correlation with one another but negatively correlated with IL-6 and endotoxin concentrations. Increased IDO and decreased plasma tryptophan were observed in IPN patients. Metabolome analysis showed significant reduction in several essential amino acids including tryptophan in IPN patients. Tryptophan, at a concentration of 9 mg/ml showed an AUC of 91.9 (95%CI 86.5–97.4) in discriminating IPN. ConclusionHLA-DR downregulation and KP alteration are related to IPN. The KP metabolite plasma tryptophan can act as a potential biomarker for IPN.

Associations between systemic inflammation and intestinal permeability with Onodera's prognostic nutritional index in critically ill patients.

BackgroundMalnutrition is a serious condition in critically ill patients. The aim of this study is to evaluate the relationships between the Onodera’s prognostic nutritional index (OPNI) and intestinal permeability and between OPNI and systemic inflammation in critically ill patients. MethodsThis was a cross-sectional study conducted in the general intensive care unit (ICU) of a university-affiliated hospital. A total of 162 patients admitted between May 2018 and December 2019, was included in the study. The OPNI was calculated at admission and categorized as ≤40 or >40. We assessed plasma endotoxin and zonulin concentrations as markers of intestinal permeability as well as serum interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hs-CRP) as markers of systemic inflammation upon admission under stringent conditions. The relationships between these markers and OPNI were assessed after adjusting for potential confounders through estimation of a binary logistic regression model. ResultsMedian (interquartile range) hs-CRP, IL-6 zonulin, and endotoxin were significantly greater in the low OPNI subgroup than in the high OPNI subgroup (all P<0.05). Multivariate analyses showed significant association between serum IL-6 (odds ratio [OR], 0.88; 95% confidence interval [CI], 0.64–0.96), serum hs-CRP (OR, 0.77; 95% CI, 0.53–0.92), plasma endotoxin (OR, 0.81; 95% CI, 0.72–0.93), and plasma zonulin (OR, 0.83; 95% CI, 0.75–0.98) levels with OPNI in the overall population. ConclusionsOur results provide evidence that higher plasma endotoxin, zonulin, IL-6, and hs-CRP levels are associated with progressively lower OPNI in mixed ICU populations, particularly in surgical ICU patients.

Enhancing dietary cation-anion difference reshaped the distribution of endotoxin across different biofluids and influenced inflammatory response in dairy cows exposed to heat stress

The objective of the present study was to investigate the alterations of lipopolysaccharide (LPS) endotoxin across four different biofluids (i.e., rumen fluid, blood plasma, milk, and urine) and LPS-related inflammation responses in Holstein dairy cows under heat stress through the regulation of dietary cation-anion difference (DCAD). Eight lactating Holstein dairy cows were randomly assigned in a 2 × 2 crossover design to either a control DCAD diet (CON: 33.5 mEq/100 g DM) or a high DCAD diet (HDCAD: 50.8 mEq/100 g DM), and each experimental period lasted for 21 days. Samples of rumen fluid, blood plasma, milk, and urine were collected on the last day of each period and the concentrations of LPS endotoxin in those samples were measured afterwards. In addition, the concentrations of pro-inflammatory indicators related to LPS in the blood serum were also determined. Heat stress was more severe in period I, during which a higher (P < 0.0001) temperature humidity index (THI) was recorded compared to period II. The increase of DCAD by supplementing NaHCO3 and K2CO3 enhanced (P < 0.01) the levels of endotoxin in the urine during period I, whilst lowered (P < 0.01) the endotoxin concentration in plasma during period II. Raising DCAD also decreased (P < 0.01) the levels of lipopolysaccharide binding protein (LBP) and serum amyloid A (SAA) in the serum during period I. The interaction between treatment and period occurred for the concentrations of LPS across four biofluids and a few inflammatory mediators in the serum. Increasing DCAD differently altered the LPS concentrations in rumen liquid (P < 0.01) and milk (P < 0.01), as well as the interleukin (IL)-2 level in serum (P < 0.05) dependent on the period. This study implies that elevating DCAD modified the distribution of LPS endotoxin across different biofluids and affected inflammation response in Holstein cows under heat stress, and it necessitates further investigations to reveal the underlying mechanisms.

Heat Stress Directly Affects Intestinal Integrity in Broiler Chickens.

A study using pair-feeding technique was conducted to determine whether heat exposure directly or indirectly (via reduced feed intake) increases intestinal mucosal damage and permeability to endotoxin in broiler chickens. Male broiler chickens (Ross 308), 27-d-old, were subjected to one of the three treatments (n=8): 1) thermo-neutral conditions (24°C) with ad libitum feed intake, 2) heat stress conditions (33°C) with ad libitum feed intake, or 3) pair-feeding under thermo-neutral conditions, with the feed intake identical to that of heat-stressed chickens. Using these groups, two experiments were performed to evaluate temporal changes in the intestinal morphology in response to each treatment. In experiment 1, chickens were sacrificed after 24 h of exposure to the treatment conditions, while in experiment 2, chickens were sacrificed after 12 or 72 h of exposure to the treatment conditions. In experiment 1, exposure to heat stress conditions for 24 h significantly decreased both the villus height to crypt depth ratio and number of proliferating cell nuclear antigen (PCNA)-positive cells in the duodenum and increased the plasma endotoxin concentration. These findings were not observed in pair-fed chickens. In experiment 2, intestinal integrity and function were unaffected by 12 h of heat stress. On the other hand, chickens exposed to heat stress for 72 h exhibited significantly damaged intestinal morphology in the duodenum as well as increased plasma endotoxin concentration; these negative effects were not observed in pair-fed chickens. These findings suggest that the intestinal morphology and permeability changes observed in chickens that are heat-stressed for 24–72 h are due to the heat stress conditions and not due to reduced feed intake.

Effect of antibiotic-free, low-protein diets with specific amino acid compositions on growth and intestinal flora in weaned pigs.

This study investigated the effects of modulation of the amino acid profile on growth performance and gut health in weaned pigs fed an antibiotic-free, low-protein diet. In experiment 1, 5 treatments were included: a control diet with antibiotics; a low-protein diet with antibiotics; a low-protein diet without antibiotics (LP); a LP diet with 10% more dietary essential amino acids (LP110); and an LP110 diet with 12% more dietary Met + Cys, Thr and Trp. The intestinal digestive enzyme activity and morphology were improved with the increase in dietary essential amino acid levels, while the growth performance was decreased, indicating that the dietary amino acid level was too high. In experiment 2, all 5 treatments of experiment 1 were included, plus a LP diet with 5% more dietary essential amino acids (LP105) and an LP105 diet with 6% more dietary Met + Cys, Thr and Trp. The LP105 treatment showed optimal feed efficiency, a reduced plasma endotoxin concentration, and an increased fecal lactate concentration and increased abundances of Prevotellaceae and Roseburia bacteria. Our results demonstrate that the optimal amino acid profile in an antibiotic-free, low-protein diet can efficiently improve growth performance and gut health and modulate the fecal microbial structure in weaned pigs.

Dietary administration of resistant starch improved caecal barrier function by enhancing intestinal morphology and modulating microbiota composition in meat duck.

Resistant starch (RS) was recently approved to exert a powerful influence on gut health, but the effect of RS on the caecal barrier function in meat ducks has not been well defined. Thus, the effect of raw potato starch (RPS), a widely adopted RS material, on microbial composition and barrier function of caecum for meat ducks was determined. A total of 360 Cherry Valley male ducks of 1-d-old were randomly divided and fed diets with 0 (control), 12, or 24 % RPS for 35d. Diets supplemented with RPS significantly elevated villus height and villus height:crypt depth ratio in the caecum. The 16S rRNA sequence analysis indicated that the diet with 12 % RPS had a higher relative abundance of Firmicutes and the butyrate-producing bacteria Faecalibacterium, Subdoligranulum, and Erysipelatoclostridium were enriched in all diets. Lactobacillus and Bifidobacterium were significantly increased in the 24 % RPS diet v. the control diet. When compared with the control diet, the diet with 12 % RPS was also found to notably increase acetate, propionate and butyrate contents and up-regulated barrier-related genes including claudin-1, zonula occludens-1, mucin-2 and proglucagon in the caecum. Furthermore, the addition of 12 % RPS significantly reduced plasma TNF-α, IL-1β and endotoxin concentrations. These data revealed that diets supplemented with 12 % RPS partially improved caecal barrier function in meat ducks by enhancing intestinal morphology and barrier markers expression, modulating the microbiota composition and attenuating inflammatory markers.

Anti-Inflammatory Activity of Isomaltodextrin in a C57BL/6NCrl Mouse Model with Lipopolysaccharide-Induced Low-Grade Chronic Inflammation.

The purpose of this study was to identify the anti-inflammatory activity and mechanism of isomaltodextrin (IMD) in a C57BL/6NCrl mouse model with lipopolysaccharide (LPS)-induced systemic low-grade chronic inflammation and the effect on inflammation-induced potential risk of metabolic disorders. Pre-treatment of IMD decreased the production of pro-inflammatory mediators, TNF-α and MCP-1, and stimulated the production of the anti-inflammatory mediator, adiponectin by increasing the protein expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) in the white adipose tissues. IMD administration reduced plasma concentrations of endotoxin, decreased macrophage infiltration into adipocytes, and increased expression of mucin 2, mucin 4, and the tight junction protein claudin 4. These results suggest that IMD administration exerted an anti-inflammatory effect on mice with LPS-induced inflammation, potentially by decreasing circulating endotoxin, suppressing pro-inflammatory mediators and macrophage infiltration, or by improving mucus or tight junction integrity. IMD exerted protein expression of insulin receptor subset-1 (IRS-1). IMD alleviated the disturbance of gut microflora in LPS-treated mice, as the number of B. bifidum, L. casei, and B. fragilis increased, and E. coli and C. difficile decreased, when compared to LPS-treated mice. The analysis of short chain fatty acids (SCFAs) further supported that the concentrations of acetic and butyric acids were positively correlated with IMD, as well as the number of beneficial bacteria. This study provides evidence that IMD possesses anti-inflammatory properties and exerts beneficial functions to prevent systemic low-grade chronic inflammation and reduces the risk of developing insulin resistance and associated metabolic diseases.

Association of intestinal permeability with admission vitamin D deficiency in patients who are critically ill

Emerging data have led to the hypothesis that vitamin D plays a role in promoting epithelial barrier dysfunction. Therefore, intestinal permeability becomes a significant determiner in the future of patients...

Microbial Mechanistic Insights into the Role of Sweet Potato Vine on Improving Health in Chinese Meishan Gilt Model.

Simple SummarySweet potato vine as a source of fiber had been used in China for many years. We investigated the effects of fresh sweet potato vine on intestinal and plasma metabolites as well as colon microbial composition in Chinese Meishan gilts. Results suggest that sweet potato vine promoted intestinal muscle development, decreased gut permeability, endotoxin and pro-inflammatory cytokines concentrations, and increased butyrate production as well as beneficial flora, thus improving gut health.This study explored the impact of fresh sweet potato vine on the growth as well as the metabolites and colon microbial composition in Chinese Meishan gilt. Twenty Meishan gilts (body weight 30 ± 0.18 kg, n = 10 per treatment) were randomly assigned to a control (CON) or sweet potato vine (SPV) supplementation diet treatment. Gilts were housed in individual stalls. In the SPV treatment, 2 kg fresh sweet potato vine was used instead of 0.18 kg basal diet which provided the same amount of digestive energy and crude protein with the exception of crude fiber (CON, 51.00 g/d vs. SPV, 73.94 g/d) in terms of dry matter intake. Gilts were slaughtered and samples were collected on day 19 after the third estrus cycle. The SPV treatment tended to increase slaughter weight of gilts (p = 0.07); it also increased (p < 0.05) gastrointestinal tract weight and intestinal muscle layer thickness. SPV treatment also decreased (p < 0.05) carcass yield and subcutaneous adipose tissue. The concentration of zonulin and endotoxin in plasma was decreased (p < 0.05) as the gilt consumed the SPV diet. Colonic fecal concentrations of endotoxin, lipocalin-2, and tumor necrosis factor-α (TNF-α) were decreased (p < 0.05), and interleukin-10 (IL-10) was increased (p < 0.05) in the SPV treatment. Butyric acid and acetate concentration in colonic content as well as acetate concentration in caecal content were increased (p < 0.05) in the SPV treatment. Furthermore, the expression of carnitine palmityl transferase (CPT-1) and peroxisome proliferator-activated receptor-α (PPAR-α) in gilt liver in SPV treatment was increased (p < 0.05) in comparison with CON treatment. Meanwhile, the composition of the colon microbes was also altered by SPV; representative changes included an increase in Lactobacillus, Bacteroides, Roseburia, and Lachnospira. These results indicate that gilt fed with sweet potato vine had decreased gut permeability, endotoxin and pro-inflammatory cytokines concentrations; colonic fecal microbiota was also changed, which may be further beneficial to the intestinal health of Chinese Meishan gilt.

Physiological and Pathophysiological Consequences of a 25-Day Ultra-Endurance Exercise Challenge.

Background: This case-report characterized the respiratory, cardiovascular, and nutritional/gastrointestinal (GI) responses of a trained individual to a novel ultra-endurance exercise challenge.Case Presentation: A male athlete (age 45 years; O2max 54.0 mL⋅kg-1⋅min-1) summited 100 mountains on foot in 25 consecutive days (all elevations >600 m).Measures: Laboratory measures of pulmonary function (spirometry, whole-body plethysmography, and single-breath rebreathe), respiratory muscle function (maximum static mouth-pressures), and cardiovascular structure and function (echocardiography, electrocardiography, large vessel ultrasound, and flow-mediated dilatation) were made at baseline and 48 h post-challenge. Dietary intake (four-day food diary), self-reported GI symptoms and plasma endotoxin concentrations were assessed at baseline, pre/post mid-point, pre/post end-point, and 48 h post-challenge.Results: The challenge was completed in a total exercise time of 142 h (5.3 ± 2.8 h⋅d-1), with a distance of 1141 km (42.3 ± 43.9 km⋅d-1), and energy expenditure of 80460 kcal (2980 ± 1451 kcal⋅d-1). Relative to baseline, there were post-challenge decreases in pulmonary capacities and expiratory flows (≤34%), maximum expiratory mouth-pressure (19%), and maximum voluntary ventilation (29%). Heart rate variability deteriorated, manifesting as a 48% decrease in the root mean square of successive differences and a 70% increase in the low-frequency/high-frequency ratio. Pre- to post-challenge endotoxin concentrations were elevated by 60%, with a maximum increase of 130% after a given stage, congruent with an increased frequency and severity of GI symptoms.Conclusion: The challenge resulted in pulmonary and autonomic dysfunction, endotoxaemia, and GI distress. The findings extend our understanding of the limits of physiological function and may inform medical best-practice for personnel supporting ultra-endurance events.

Association of intestinal permeability with a NUTRIC score in critically ill patients.

The aim of this study was to investigate the association of intestinal permeability with the Nutrition Risk in Critically Ill (NUTRIC) score and the modified NUTRIC score (mNUTRIC) in intensive care unit (ICU) hospitalized patients. One hundred and fifty ICU hospitalized adult patients admitted between October 2017 and April 2018 who stayed for >24 h in the general ICU were enrolled in the study. Nutrition status was estimated using the NUTRIC score, an ICU-specific nutrition risk assessment tool. The NUTRIC score was calculated using the exact same thresholds and point system as developed previously. Admission plasma endotoxin and zonulin concentrations were measured to assess intestinal permeability. Median plasma endotoxin and zonulin increased with increasing mNUTRIC and NUTRIC categories in the overall study population and in the glutamine-deficient subgroup. Multivariate binary logistic regression analyses showed a significant association between the plasma endotoxin (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.8-3.52) and zonulin (OR, 1.11; 95% CI, 1.03-1.20) levels with NUTRIC category in the overall population and the glutamine-deficient subgroup. Similar results were obtained when using mNUTRIC. Results from the present study provided evidence that higher plasma endotoxin and zonulin levels are associated with a progressively higher NUTRIC score in critically ill patients.

Effects of early enteral bovine colostrum supplementation on intestinal permeability in critically ill patients: A randomized, double-blind, placebo-controlled study.

In this study we sought to investigate the effect of early enteral bovine colostrum supplementation on intestinal permeability in intensive care unit (ICU)-hospitalized patients. A total of 70 ICU-hospitalized adult patients were randomly assigned to receive a bovine colostrum supplement or placebo according to the stratified blocked randomization by age and admission category. Plasma endotoxin and zonulin concentrations were measured on days 5 and 10 of intervention. Out of 70 participants, 32 patients in the colostrum group and 30 patients in the control group were included in the final analysis of the outcomes. Plasma endotoxin concentration decreased significantly in the colostrum group on the 10th day (P < 0.05). Furthermore, plasma levels of zonulin reduced in the colostrum group significantly compared with the placebo group (P < 0.001).The incidence of diarrhea was significantly lower in the colostrum group than in the control group (P = 0.02). Our results provide evidence that bovine colostrum supplementation may have beneficial effects on intestinal permeability and gastrointestinal complications in ICU-hospitalized patients. Further studies are needed to investigate the exact mechanism of action of these effects.

Cortical Inflammation is Increased in a DSS-Induced Colitis Mouse Model.

While inflammatory bowel disease (IBD) might be a risk factor in the development of brain dysfunctions, the underlying mechanisms are largely unknown. Here, mice were treated with 5% dextran sodium sulfate (DSS) in drinking water and sacrificed on day 7. The serum level of IL-6 increased, accompanied by elevation of the IL-6 and TNF-α levels in cortical tissue. However, the endotoxin concentration in plasma and brain of mice with DSS-induced colitis showed a rising trend, but with no significant difference. We also found significant activation of microglial cells and reduction in occludin and claudin-5 expression in the brain tissue after DSS-induced colitis. These results suggested that DSS-induced colitis increases systemic inflammation which then results in cortical inflammation via up-regulation of serum cytokines. Here, we provide new information on the impact of colitis on the outcomes of cortical inflammation.

Metabolic Syndrome During Perinatal Period in Sows and the Link With Gut Microbiota and Metabolites.

In humans, the metabolic and immune changes occurring during perinatal period also describe metabolic syndrome. Gut microbiota can cause symptoms of metabolic syndrome in pregnant women. Increased gut permeability is also involved in metabolic disorders in non-pregnant hosts. However, longitudinal studies investigating the changes in metabolic characteristics, gut microbiota, and gut permeability of sows throughout pregnancy and lactation are lacking. The correlation between gut microbiota and metabolic status of sows is also poorly known. The present study was conducted to investigate the temporal variations in sow metabolic characteristics, gut microbiota, gut permeability, and gut inflammation at days 30 (G30) and 109 (G109) of gestation and days 3 (L3) and 14 (L14) of lactation. Results showed that insulin sensitivity was decreased in L3. Circulating concentrations of pro-inflammatory cytokine IL-6 increased in G109 and L3. 16S rRNA gene sequencing of the V3-V4 region showed that gut microbiota changed dramatically across different reproductive stages. The bacterial abundance and alpha diversity in L3 were the lowest. The phyla Proteobacteria and Fusobacteria exhibited the highest relative abundance in L3. Among the genera, Bacteroides, Escherichia_Shigella, and Fusobacterium were highest, but Oscillospira the lowest, in relative abundance in L3. The fecal levels of acetate and total short-chain fatty acids were increased in G109, but fecal butyrate concentrations were markedly decreased in L3. The plasma zonulin concentrations, a biomarker for gut permeability, were increased in G109 and L3. The plasma endotoxin concentrations were increased in L3. Furthermore, levels of fecal lipocalin-2 and pro-inflammatory cytokines IL-6 and TNF-α were increased in G109 and L3. In contrast, fecal levels of anti-inflammatory cytokine IL-10 were significantly decreased in G109 and L3. Additionally, the increased relative abundances of Fusobacterium in L3 were positively correlated with plasma zonulin and fecal endotoxin but negatively correlated with fecal IL-10. These findings indicate that the mother sow exhibits a metabolic syndrome and dramatical changes in gut microbiota during perinatal period, especially in early lactation. Besides, increased gut permeability and plasma endotoxin concentrations caused by negative microbial changes would possibly be the potential mechanisms under which sow’s metabolic disorders and inflammatory status were exacerbated during early lactation.

The Impact of Mild Heat Stress During Prolonged Running On Gastrointestinal Integrity, Gastrointestinal Symptoms, Systemic Endotoxin and Cytokine Profiles.

The study aimed to determine the effects of mild exertional heat stress on intestinal injury, permeability, gastrointestinal symptoms, and systemic endotoxin and cytokine responses. Ten endurance runners completed 2 h of running at 60% V̇O2max in warm (WARM: 30°C) and temperate (TEMP: 22°C) ambient conditions. Rectal temperature (Tre) and gastrointestinal symptoms were recorded every 10 min during exercise. Blood samples were collected pre- and post-exercise, and during recovery to determine plasma intestinal fatty acid-binding protein (I-FABP) and cortisol concentrations, and systemic endotoxin and inflammatory cytokine profiles. Urinary lactulose:L-rhamnose ratio (L/R) was used to measure small intestine permeability. Compared with TEMP, WARM significantly increased Tre from 50 min onwards (38.1±0.3°C vs. 38.4±0.5°C, respectively; p<0.01), gastrointestinal symptoms (p=0.017), post-exercise plasma cortisol (26% vs. 59%, respectively; p<0.001) and I-FABP (127% vs. 184%, respectively; p<0.001) concentrations. Circulatory anti-endotoxin antibodies increased post-exercise (p<0.001) on WARM (20%) and TEMP (28%). No differences were observed for plasma endotoxin concentration (6% vs. 5% increase, respectively) or small intestine permeability (L/R 0.026±0.010 and 0.025±0.015, respectively). Both pro- and anti-inflammatory cytokines increased post-exercise, with inflammatory response cytokines TNF-α (p=0.015) and IL-8 (p=0.044), and compensatory anti-inflammatory cytokines IL-10 (p=0.065), and IL-1ra higher on WARM than TEMP. Findings suggest that exposure to warm ambient conditions during prolonged submaximal running induces transient intestinal epithelial injury, increases gastrointestinal symptoms, and promotes greater perturbations to the systemic cytokine profile compared to running in temperate conditions.

Dynamics of Endotoxin, Inflammatory Variables, and Organ Dysfunction After Treatment With Antibiotics in an Escherichia coli Porcine Intensive Care Sepsis Model.

To investigate the dynamics of antibiotic-induced endotoxin liberation and inflammatory response in vivo in a clinically relevant large animal intensive care sepsis model and whether the addition of an aminoglycoside to a β-lactam antibiotic affects these responses. Prospective, placebo-controlled interventional experimental study. University research unit. Thirty-six healthy pigs administered Escherichia coli as a 3-hour infusion. After 2 hours, during E. coli infusion, the animals were exposed to cefuroxime alone, the combination of cefuroxime and tobramycin, or saline. Plasma endotoxin, interleukin-6, tumor necrosis factor-α, leucocytes, and organ dysfunction were recorded for 4 hours after antibiotic treatment, and differences to the values before treatment were calculated. In vitro experiments were performed to ascertain whether endotoxin is released during antibiotic-induced bacterial killing of this E. coli strain. Despite differences between the treatment arms in vitro, no differences in plasma endotoxin were observed in vivo. Antibiotic-treated animals demonstrated a higher interleukin-6 response (p < 0.001), greater leucocyte activation (p < 0.001), and more pronounced deterioration in pulmonary static compliance (p < 0.01) over time than controls. Animals treated with the combination showed a trend toward less inflammation. Treatment with antibiotics may elicit an increased inflammatory interleukin-6 response that is associated with leucocyte activation and pulmonary organ dysfunction. No observable differences were detected in plasma endotoxin concentrations. The reduction in cefuroxime-induced endotoxin release after the addition of an aminoglycoside in vitro could not be reproduced in this model.

Beneficial Effect of Alcohol Withdrawal on Gut Permeability and Microbial Translocation in Patients with Alcohol Use Disorder.

The human intestinal microbiota exerts beneficial or harmful effects in several disorders. Many factors, including alcohol consumption, may influence its composition and trigger bacterial translocation. Excessive alcohol consumption increases gut permeability and translocation of endotoxin into peripheral circulation. Although plasma endotoxin concentrations have been measured often, quantitative changes following alcohol withdrawal have never been described in subjects with alcohol use disorder (AUD). The aim of this study was to measure microbial translocation (MT) and gut permeability markers in patients with AUD, to compare these markers to healthy controls (HC) and to monitor markers during the first 6weeks of abstinence. Sixty-five patients with AUD and hospitalized for alcohol withdrawal were included. Epidemiological, clinical, biological, and addictological data were gathered. Blood samples were collected at baseline, then 3 and 6weeks after alcohol withdrawal. A hundred healthy volunteers were used as controls. Three markers of MT were monitored in plasma samples: sCD14 and lipopolysaccharide-binding protein (LBP) were quantified using ELISA, and 16S rDNA was quantified using real-time polymerase chain reaction. Zonulin and intestinal fatty acid binding protein (I-FABP) blood levels were also monitored as indirect markers of gut permeability, using ELISA. At baseline, LBP, 16S rDNA, sCD14 and I-FABP markers were significantly higher in patients with AUD than in HC. Six weeks after alcohol withdrawal plasma levels of sCD14 and LBP decreased significantly. Cannabis consumption and body mass index (BMI) before alcohol withdrawal influenced baseline MT levels and the decrease in MT markers after 6weeks. Finally, markers of MT and gut permeability did not correlate with each other before and after alcohol withdrawal. Before alcohol withdrawal, MT markers were higher in patients with AUD than in HC. After 6weeks of abstinence, an improvement in MT markers was observed. Our data suggest that there is a link between MT, its improvement, BMI, and cannabis consumption.

A novel method for multiple bowel injuries: a pilot canine experiment

BackgroundIntestinal ligation is the cornerstone for damage control in abdominal emergency, yet it may lead to bowel ischemia. Although intestinal ligation avoids further peritoneal cavity pollution, it may lead to an increased pressure within the bowel segments and rapid bacterial translocation. In this study, we showed that severed intestine could be readily reconnected by using silicon tubes and be secured by using rubber bands in a canine model.MethodsAdult Beagle dogs, subject to multiple intestinal transections and hemorrhagic shock by exsanguination, randomly received conventional ligation vs. silicon tubes reconnecting (n = 5 per group). Intestinal transections were carried out under general anesthesia after 24-h fasting. The abdomen was opened with a midline incision. The small intestine was severed at 50, 100, and 150 cm below the Treitz ligament. Hemorrhagic shock was established by streaming blood from the left carotid artery until the mean arterial pressure reached 40 mmHg in 20 min. Fluid resuscitation and surgery began 30 min after the establishment of hemorrhagic shock. Severed intestines were ligated or connected with silicon tubes. Definitive repair was conducted in subjects surviving for at least 48 h.ResultsOperation time was comparable between the two groups (39.6 ± 8.9 vs. 36.6 ± 7.8 min in ligation and reconnecting groups, respectively; p = 0.56). The time spent in managing each resection was also comparable (4.6 ± 1.1 vs. 3.8 ± 0.84 min; p = 0.24). Blood loss (341.2 ± 28.6 vs. 333.8 ± 34.6 ml; p = 0.48), and fluid resuscitation within the first 24 h (1676 ± 200.6 vs. 1594 ± 156.5 ml; p = 0.46) were similar. One subject in the ligation group was sacrificed at 36-h due to severe vomiting that led to aspiration. Four remaining dogs in the ligation group received definitive surgery, but two out of four had to be sacrificed at 24-h after definitive repair due to imminent death. All five dogs in the reconnecting group survived for at least a week. Radiographic examination confirmed the integrity of the GI tract in the reconnecting group. In both groups, plasma endotoxin concentration increased after damage control surgery, but the increase was much more pronounced in the ligation group. Microscopic examination of the involved segment of the intestine revealed much more severe pathology in the ligation group.ConclusionThe current study showed that the reconnecting resected intestine by using silicon tubes is feasible under emergency. Such a method could decrease short-term mortality and minimize endotoxin translocation.

Markers of intestinal permeability are already altered in early stages of non-alcoholic fatty liver disease: Studies in children.

Background & aimsRecent studies have shown that patients with manifest non-alcoholic fatty liver disease (NAFLD), e.g. steatosis grade 3 or steatohepatitis with or without beginning fibrosis frequently show altered fecal microbiota composition and elevated bacterial endotoxin levels. However, if these alterations are signs of a progressing disease or are already found in initial disease stages has not yet been clarified.MethodsTwenty children with simple steatosis (grade 1) diagnosed by ultrasound and 29 normal weight healthy control children (age <10 years) were included in the study (mean age 7.6 ± 1.1 years). Metabolic parameters, markers of intestinal barrier function and inflammation were determined.ResultsActivity of alanine aminotransferase, concentrations of some markers of inflammation and insulin resistance were significantly higher in plasma of NAFLD children than in controls. When compared to controls, plasma bacterial endotoxin and lipopolysaccharide-binding protein (LBP) levels were significantly higher in NAFLD children (+50% and +24%, respectively), while soluble CD14 serum and D-lactate plasma levels as well as the prevalence of small intestinal bacterial overgrowth did not differ between groups. Plasma endotoxin and LBP levels were positive associated with proinflammatory markers like plasminogen activator inhibitor-1, c-reactive protein, interleukin-6 and leptin while no associations with markers of insulin resistance were found.ConclusionsTaken together, our results indicate that even in juvenile patients with early stages of NAFLD e.g. simple steatosis grade 1, plasma endotoxin concentrations are already elevated further suggesting that intestinal barrier dysfunction might be present already in the initial phases of the disease.