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Intestinal permeability and systemic infections in critically ill patients: Effect of glutamine
Abstract
This article provides a critical review of the evidence indicating that an increase in intestinal permeability is associated with the installation of bacteremia, sepsis, and the multiple organ failure syndrome and that glutamine in pharmacologic doses reduces the acute increase of intestinal permeability and the infection frequency in critically ill patients.
All studies published until December 2004 about intestinal permeability, bacterial translocation, and glutamine were located by search of PubMed and Web of Science. The reference lists of review articles and primary publications were also examined to identify references not detected in the computer search.
Clinical and experimental studies investigating the correlation between intestinal permeability, bacterial translocation, and frequency of infections, associated or not with the effect of glutamine administration.
Information regarding patient population, experimental design, glutamine doses and routes of administration, nutritional therapy prescribed, methods used to assess intestinal permeability, metabolic variables, and the frequency of infections were obtained from the primary literature.
Intestinal permeability is increased in critically ill patients. The results have not always been consistent, but the studies whose results support the association between intestinal permeability and systemic infections have had better design and more appropriate controls. The administration of glutamine by the intravenous or oral route and at the doses recommended before or immediately after surgery, burns, or the administration of parenteral nutrition has a protective effect that prevents or reduces the intensity of the increase in intestinal permeability. Glutamine reduces the frequency of systemic infections and may also reduce the translocation of intestinal bacteria and toxins, but this has not been demonstrated.
Glutamine administration improves the prognosis of critically ill patients presumably by maintaining the physiologic intestinal barrier and by reducing the frequency of infections.
... Demographic, clinical and nutritional data were documented. Potential diarrhea predictors were determined based on previous studies [3,5,7] and our own experience, including gender (male/female), age (years), Glasgow Coma Scale (GCS) score (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15), acute physiology and chronic health evaluation II (APACHE II) score (0-71), hypertension (yes/ no), diabetes (yes/no), body mass index (BMI), fasting time, daily nutrient solution, high-fat energy (yes/no), EN duration, serum albumin, use of antibiotics, prokinetic and potassium drugs (yes/no). GCS was divided into two groups: 3-5 and 6-8. ...
... The longer the duration of EN, the more likely diarrhea occurs [14]. The specific mechanism is still unclear, and it may be because EN can cause intestinal mucosal atrophy and a decline in absorption function [14,15]. However, further basic research and pathological studies are required to define the mechanisms. ...
Background
Severe traumatic brain injury (STBI) is one of the major causes of death and disability worldwide. The incidence and risk factors of enteral nutrition (EN)-associated diarrhea in older patients with STBI remain unclear.
Methods
A cohort of adult STBI patients were retrospectively studied. The patients were stratified into an older group (≥ 65years) and a young group (< 65 years). All patients received EN for at least 48 h. Demographic, clinical and nutritional data were collected for analysis. We utilize multiple logistic regression models to evaluate predictors of diarrhea.
Results
Among 292 patients with STBI aged 60.38 ± 14.89 years (mean ± standard deviation), 114 cases developed diarrhea, with an incidence of 39.04%. Older patients had a higher incidence of diarrhea than young patients (46.77% vs 33.33%, p = 0.020). Three variables were found to be significantly associated with diarrhea in young STBI patients. In contrast, five variables were significantly associated with this complication in older STBI patients, including acute physiology and chronic health evaluation II score (adjusted OR 1.134, 95% CI 1.019–1.272, p = 0.025), high-fat energy (adjusted OR 1.221, 95% CI 1.055–1.789, p = 0.025), EN duration (adjusted OR 1.105, 95% CI 1.005–1.223, p = 0.044), antibiotics total defined daily dose (DDDs) (adjusted OR 1.076, 95% CI 1.029–1.211, p = 0.039) and tube feeding of potassium (adjusted OR 2.525, 95% CI 1.031–6.450, p = 0.046).
Conclusions
Enteral nutrition-associated diarrhea was prevalent among STBI patients. Older STBI patients had a higher incidence of diarrhea and more risk factors than young patients. Early management of modifiable risk factors may help reduce the incidence of diarrhea.
... Animal studies have confirmed that burnt mice suffer from impaired intestinal mucosal barrier function and abnormal fecal microbiota within 5 min of being burned [37]. De Souza et al. [38] found that the intestinal function of patients with sepsis was abnormal upon diagnosis. With the widespread application of broad-spectrum antibiotics in critically ill patients treated in the ICU, a large number of sensitive flora have been removed, while non-dominant flora such as opportunistic pathogens has proliferated in large numbers, and many bacterial colonization targets on the intestinal mucosa have been exposed, thus leaving colonization space for pathogenic bacteria. ...
... Our study also showed that, both the Alpha diversity and Beta diversity of fecal microbiota in patients of the Clinical Improvement (CI) group (n = 21) and the Death or DAMA group (n = 10) were no significant differences between these two groups, this may be related to the fact that our fecal specimens were collected only once within 24 h of the patient's admission to the hospital and were not collected dynamically. Studies have shown that the diversity of the fecal microbiota and the structural composition of the flora change significantly over time in patients with sepsis after admission to the ICU [24,37,38,59], especially after various interventions such as medications in the ICU, and that the clinical outcomes of patients may be different. However, this was not further observed because of the timing of our sampling. ...
Background
To analyze the characteristics of fecal microbiota disturbance in the intensive care unit (ICU) patients with sepsis and the correlation with related clinical indicators.
Methods
This study included 31 patients with sepsis admitted to the emergency ICU ward between September 2019 and December 2021. They were divided into Group without septic shock (ND_NS group, 7 cases) and Group with septic shock (ND_S group, 24 cases) according to the presence or absence of septic shock. Furthermore, we divided these 31 sepsis patients into Clinical Improvement group (21 cases) and Death or DAMA group (10 cases) based on clinical outcome, 15 cases of Physical Examiner recruited in the same period were included as control group: ND_HC group (15 cases). The fecal samples of the patients with sepsis within 24 h of admission and random fecal samples of the control group were collected and analyzed by 16S rDNA gene sequencing used for the analysis of fecal microbiota. At the same time, the relevant clinical data of these patients with sepsis were also collected for analysis.
Results
There were 15 cases with drug-resistant bacteria in the ND_S group and only 2 cases in the ND_NS group (P = 0.015). There were significant differences in APACHE II score, length of ICU stay, lactate level, and oxygenation index of patients between the Death or DAMA group and Clinical Improvement group (all P < 0.05). For phylum level, the abundance of Firmicutes, Actinobacteria, and Bacteroidetes decreased in the ND group compared with the ND_HC group, while the abundance of Proteobacteria increased (P < 0.05). For genus level, the relative abundance of Escherichia-Shigella and Klebsiella were significantly increased in the ND group compared with the ND_HC group (P < 0.05). The top six genera in relative abundance in the ND_S group were Escherichia-Shigella, Enterococcus, Bifidobacterium, Lactobacillus, Akkermansia, and Klebsiella. Compared with the Clinical Improvement group, the relative abundance of Escherichia-Shigella and Klebsiella in the Death or DAMA group showed an increasing trend with no significant significance, while the relative abundance of Enterococcus and Faecalibacterium decreased in the Death or DAMA group (P < 0.05). Alpha diversity analysis showed that compared with the ND_HC group, the alpha diversity of the fecal microbiota in the ND group decreased. There were significant differences in the Observed_species index, Chao1 index, and ACE index of patients between the ND_HC group and ND group (all P < 0.05). Moreover, compared with the ND_NS group, the Alpha diversity of the ND_S group was more abundant. PCoA analysis showed significant differences in microbial community structure between the ND group and ND_HC group (P = 0.001). There also were significant differences in microbial community structure between the ND_S group and ND_NS group (P = 0.008). LEfSe analysis showed that compared with the ND_HC group, there were significant differences in the species of the ND group, including Enterobacteriaceae, Escherichia-Shigella, Enterococcus, Elizabethkingia, and Family_XIII_AD3011_group.
Conclusions
ICU patients with sepsis suffered intestinal microecological disturbances with significantly decreased abundance of fecal microbiota, diversity, and beneficial symbiotic bacteria. For these patients, the ratio of pathogenic bacteria, including Escherichia-Shigella and Klebsiella increased and became the main bacterial genus in some samples. Moreover, the increasing trend of these two pathogenic bacteria may be correlated with the development of septic shock and the risk of death in patients with sepsis.
... The investigation of alternative therapeutic possibilities, such as nutraceuticals, is an appealing area since conventional therapies for these disorders sometimes include medicines that have possible negative effects. The influence of nutraceuticals on gastrointestinal health has been the subject of increased study in recent years, with particular attention paid to their anti-inflammatory, antibacterial, and mucoprotective qualities (De-Souza et al., 2019) [11] . This investigation fits in with the larger idea of precision nutrition, which customizes dietary therapies to meet the requirements and circumstances of each person. ...
... The gastrointestinal mucosa, which is the vital lining of the digestive system, is greatly protected and maintained by nutraceuticals. De-Souza et al. (De-Souza et al., 2019) [11] have shown that compounds such as glutamine, an amino acid included in a variety of meals and supplements, are essential for maintaining the integrity of the gut lining and fostering mucosal repair. The significance of glutamine in reducing intestinal mucosal damage and enhancing the general well-being of the gastrointestinal system is highlighted by research conducted by Déchelotte et al. (Déchelotte et al., 2013) [10] . ...
The potential therapeutic function of nutraceuticals in the treatment of gastrointestinal tract disorders has garnered increasing attention in the area of gastroenterology. The purpose of this article is to provide readers an overview of the complex field of nutritional supplements in relation to gastrointestinal disorders. Through a review of the scientific literature written by different authors, we are able to identify the changing viewpoints and contributions that support the investigation of nutritional supplementation as supplementary or alternative therapies to conventional medical treatments for gastrointestinal illnesses. Nutraceutical interventions offer a complementary approach to conventional treatments, providing patients and healthcare practitioners with additional tools for managing and improving gastrointestinal health.
... Notably, the depletion of microbial pathways associated with the glutamate metabolism was associated with CD severity status. Indeed, several studies have highlighted the critical role of glutamate in maintaining mucosal integrity (DeMarco et al., 2003;De-Souza and Greene, 2005), possibly by preventing disruption of tight junctions via transactivation of the epidermal growth factor receptor, which mediates intestinal epithelial cell proliferation (Basuroy et al., 2005). ...
Introduction
Crohn’s disease (CD) results from alterations in the gut microbiota and the immune system. However, the exact metabolic dysfunctions of the gut microbiota during CD are still unclear. Here, we investigated metagenomic functions using PICRUSt2 during the course of CD to better understand microbiota-related disease mechanisms and provide new insights for novel therapeutic strategies.
Methods
We performed 16S rRNA-based microbial profiling of 567 faecal samples collected from a cohort of 383 CD patients, including 291 remissions (CR), 177 mild-moderate (CM) and 99 severe (CS) disease states. Gene and pathway composition was assessed using PICRUSt2 analyses of 16S data.
Results
As expected, changes in alpha and beta diversity, in interaction networks and increases in Proteobacteria abundance were associated with disease severity. However, microbial function was more consistently disrupted than composition from CR, to CM and then to CS. Major shifts in oxidative stress pathways and reduced carbohydrate and amino acid metabolism in favour of nutrient transport were identified in CS compared to CR. Virulence factors involved in host invasion, host evasion and inflammation were also increased in CS.
Conclusions
This functional metagenomic information provides new insights into community-wide microbial processes and pathways associated with CD pathogenesis. This study paves the way for new advanced strategies to rebalance gut microbiota and/or eliminate oxidative stress, and biofilm to downregulate gut inflammation.
... Critically ill patients are susceptible to intestinal mucosal disturbances and increased intra-abdominal pressure due to impaired intestinal motility, facilitating intestinal bacterial translocation and promoting consequent enterobacterial infections [10]. Laxatives may alleviate bacterial and toxin accumulation by promoting the passage of intestinal contents [11]. ...
Objective: To investigate the effects of prophylactic use of stimulant laxatives and/or docusate on the clinical outcomes in critically ill patients who required mechanical ventilation (MV). Methods: A single-center, retrospective, cohort study was conducted. Patients who received MV in the first 24 h after intensive care unit (ICU) admission were enrolled and divided into four groups: non-laxative, stimulant laxatives, docusate, and stimulant laxatives–docusate combination. The primary outcome was in-hospital mortality. The major secondary outcomes included ICU-free days and ventilator-free days at 28 days; the other outcomes were ventilation-associated pneumonia (VAP), enterobacterial infection, diarrhea, and electrolyte disturbances. Inverse probability treatment weighting (IPTW) was used to adjust for confounders. Results: A total of 2129 patients were included in this study, 263 of whom received stimulant laxatives, 253 received docusate, 368 received a combination, and 1245 did not receive any laxative. The prophylactic use of docusate was associated with a decreased risk of in-hospital mortality (OR: 0.59, 95% CI 0.42 to 0.83, p = 0.002) and VAP (OR: 0.62, 95% CI 0.47 to 0.81, p = 0.001). It was also associated with an increase in ICU-free days at 28 days (β: 0.89, 95% CI 0.83 to 0.95, p < 0.001). Importantly, laxatives prophylaxis was not associated with increased risks of diarrhea, electrolyte disturbances, and enterobacterial infections. Conclusions: Prophylactic use of docusate may improve certain prognoses and does not demonstrate any adverse events. However, further research is necessary to determine the optimal regimen and dosage of prophylactic laxatives in this specific population.
... 11 Since the 1990s, immunonutrition supported by specific nutrients, mainly glutamine (Gln), has been recognized to provide the necessary energy, improve the nutritional status of patients with cancer, and increase the number of intestinal lymphocytes, thereby regulating immune function, compared with traditional nutritional support. 12, 13 Immunonutrition attenuates the increased intestinal permeability 14 and bacterial translocation 15 and regulates the inflammatory response, 16 nitrogen balance, and protein synthesis, 17 reducing the incidence of postoperative complications and shortening the LOS. 18,19 In the hypercatabolic situation of surgical stress, the requirement for Gln increases while the production capacity is impaired; consequently, the Gln obtained from dietary intake and endogenous synthesis is insufficient to meet the needs of the body, 20,21 and additional Gln supplementation is therefore required. ...
Purpose
This study investigated the effects of parenteral glutamine (Gln) supplement immunonutrition versus conventional nutritional support on postoperative Clavien–Dindo classification complications and recovery, perioperative nutritional status, and immune, inflammation, and safety indicators in patients with colorectal cancer (CRC).
Patients and Methods
Clinical data were collected for a retrospective cohort study of 178 patients (58 and 120 patients in the observation and control groups, respectively) who underwent radical resection of CRC from January 2019 to December 2021. The incidence of postoperative complications was calculated. Postoperative recovery, nutritional indicators, inflammatory factors indicator, and the safety indicators before operation and at 1, 3, and 7 days after operation were compared. SPSS 29.0 statistical software was used for statistical analysis.
Results
The incidence of postoperative overall complications in the control group and the observation group was 22.50% (27/120) and 17.24% (10/58), respectively, and there was no significant difference between the two groups (P=0.42). The incidence of postoperative complications of Clavien-Dindo grade ≥III in the control group and the observation group was 14.17% (17/120) and 3.45% (2/58), respectively, and the difference between the two groups was statistically significant (P=0.03). Secondary outcomes (first exhaust, defecation, and liquid diet intake times) were significantly recovered earlier in the observation group than those in the control group (P<0.05), while the postoperative hospital stay was significantly shorter(P=0.04). The perioperative nutritional status did not significantly differ between the groups before and after surgery(P>0.05), although significant differences were observed in several inflammatory and safety indicators(P<0.05).
Conclusion
Unlike conventional nutritional support, postoperative parenteral Gln supplementation reduced the incidence of postoperative Clavien–Dindo complications grade ≥III in patients with CRC while increasing intestinal and immune functions, decreasing inflammation, and reducing the length of hospital stay.
... Permeability, in turn, is controlled by TJ proteins between each cell that regulate the paracellular space [23]. A leaky gut is one of the factors contributing to the development of sepsis [24]. Some individuals have a leaky gut where mucosal integrity is invasion-prone [25], and excessive cytokine production and immune cell adhesion contribute to the development of sepsis. ...
Cancer patients face increased susceptibility to invasive infections, primarily due to ulcerative lesions on mucosal surfaces and immune suppression resulting from chemotherapy. Pseudomonas aeruginosa (P. aeruginosa) bacteremia is notorious for its rapid progression into fatal sepsis, posing a significant threat to cancer patients, particularly those experiencing chemotherapy-induced neutropenia. This bacterial infection contributes significantly to morbidity and mortality rates among such individuals. Our latest report showed the mutually beneficial effects of postbiotic butyrate on 1,25-dihydroxyvitamin D3 (1,25D3)-controlled innate immunity during Salmonella colitis. Hence, we investigated the impact of butyrate and 1,25D3 on chemotherapy-induced gut-derived P. aeruginosa sepsis in mice. The chemotherapy-induced gut-derived P. aeruginosa sepsis model was established through oral administration of 1 × 10⁷ CFU of the P. aeruginosa wild-type strain PAO1 in C57BL/6 mice undergoing chemotherapy. Throughout the infection process, mice were orally administered butyrate and/or 1,25D3. Our observations revealed that the combined action of butyrate and 1,25D3 led to a reduction in the severity of colitis and the invasion of P. aeruginosa into the liver and spleen of the mice. This reduction was attributed to an enhancement in the expression of defensive cytokines and antimicrobial peptides within the cecum, coupled with decreased levels of zonulin and claudin-2 proteins in the mucosal lining. These effects were notably more pronounced when compared to treatments administered individually. This study unveils a promising alternative therapy that involves combining postbiotics and 1,25D3 for treating chemotherapy-induced gut-derived P. aeruginosa sepsis.
... L-Arginine, a nutritionally functional nonessential amino acid, was found to have the potential to prevent T2DM and enhance insulin sensitivity which might occur by regulating the L-arginine-nitric oxide pathway [68]. L-Glutamine, a major precursor for citrulline synthesis [69], could improve intestinal barrier function [70] and protect mice from non-alcoholic steatohepatitis in western-style diet-fed mice [71]. N2-Acetyl-L-ornithine, can be used to synthesize ornithine [72]. ...
Background
In recent decades, the prevalence of metabolic diseases, particularly diabetes, hyperlipidemia, obesity, and non-alcoholic fatty liver disease (NAFLD), has increased dramatically, causing great public health and economic burdens worldwide. Traditional Chinese medicine (TCM) serves as an effective therapeutic choice. Xiao-Ke-Yin (XKY) is a medicine and food homology TCM formula consisting of nine “medicine and food homology” herbs and is used to ameliorate metabolic diseases, such as insulin resistance, diabetes, hyperlipidemia and NAFLD. However, despite its therapeutic potential in metabolic disorders, the underlying mechanisms of this TCM remain unclear. This study aimed to evaluate the therapeutic effectiveness of XKY on glucolipid metabolism dysfunction and explore the potential mechanisms in db/db mice.
Methods
To verify the effects of XKY, db/db mice were treated with different concentrations of XKY (5.2, 2.6 and 1.3 g/kg/d) and metformin (0.2 g/kg/d, a hypoglycemic positive control) for 6 weeks, respectively. During this study, we detected the body weight (BW) and fasting blood glucose (FBG), oral glucose tolerance test (OGTT), insulin tolerance test (ITT), daily food intake and water intake. At the end of the animal experiment, blood samples, feces, liver and intestinal tissue of mice in all groups were collected. The potential mechanisms were investigated by using hepatic RNA sequencing, 16 S rRNA sequencing of the gut microbiota and metabolomics analysis.
Results
XKY efficiently mitigated hyperglycemia, IR, hyperlipidemia, inflammation and hepatic pathological injury in a dose dependent manner. Mechanistically, hepatic transcriptomic analysis showed that XKY treatment significantly reversed the upregulated cholesterol biosynthesis which was further confirmed by RT-qPCR. Additionally, XKY administration maintained intestinal epithelial homeostasis, modulated gut microbiota dysbiosis, and regulated its metabolites. In particular, XKY decreased secondary bile acid producing bacteria ( Clostridia and Lachnospircaeae ) and lowered fecal secondary bile acid (lithocholic acid (LCA) and deoxycholic acid (DCA)) levels to promote hepatic bile acid synthesis by inhibiting the LCA/DCA-FXR-FGF15 signalling pathway. Furthermore, XKY regulated amino acid metabolism including arginine biosynthesis, alanine, aspartate and glutamate metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, and tryptophan metabolism likely by increasing Bacilli , Lactobacillaceae and Lactobacillus , and decreasing Clostridia , Lachnospircaeae , Tannerellaceae and Parabacteroides abundances.
Conclusion
Taken together, our findings demonstrate that XKY is a promising “medicine food homology” formula for ameliorating glucolipid metabolism and reveal that the therapeutic effects of XKY may due to its downregulation of hepatic cholesterol biosynthesis and modulation of the dysbiosis of the gut microbiota and metabolites.
... Es necesario detectar el origen de la misma y eliminarla, sin embargo, en muchos casos, la fuente no se detecta y puede deberse a traslocación bacteriana. (8,9) Otras causas pudieran ser sepsis punto de partida de catéter venoso central o causas extraabdominales. Es imperativo observar y reconocer tempranamente los signos de sepsis, buscar la causa y tratarla.(10) ...
La falla intestinal (FI) se define como la disminución de la función del intestino por debajo de lo mínimo necesario para la absorción de los macronutrientes y / o agua y electrolitos, de tal manera que se requiere de la suplementación intravenosa (SIV) para mantener la salud y el crecimiento. Desde el punto de vista funcional se clasifica en tres tipos. FI tipo I: condición aguda, de corto duración y generalmente autolimitada, FI tipo II: estado agudo prolongado, a menudo en pacientes metabólicamente inestables, que requieren cuidado multidisciplinario y SIV durante períodos de una semana o meses, acompañada de complicaciones sépticas, metabólicas y nutricionales y FI tipo III: condición crónica, en pacientes metabólicamente estables, que requieren SIV durante meses o años. Su manejo requiere de terapia nutricional y en casos seleccionados cirugía autóloga de reconstrucción.
... Es el sustrato más importante para la generación de amonio a nivel renal y representa el sustrato principal para los enterocitos, colonocitos y células T y B del sistema inmune (13) . La integridad de la mucosa intestinal parece ser protegida y estimulada por cantidades suficientes en las reservas corporales de glutamina (14) . Las reservas corporales de glutamina se disminuyen después de alguna lesión, como trauma, procedimiento quirúrgico, quemaduras, infecciones o evento de pancreatitis, razón por la cual se considera un aminoácido condicionalmente esencial (12) . ...
La desnutrición en el paciente con cáncer que es sometido a un procedimiento quirúrgico es uno de los problemas nutricionales mayormente asociado con desenlaces clínicos adversos, como aumento en el riesgo de las infecciones, mayor riesgo de formación de fístulas e incremento en los días de estancia hospitalaria y en el riesgo de mortalidad. La inmunonutrición (IMN) se refiere al uso de diversos nutrimentos en dosis mucho más altas de los requerimientos diarios, con la finalidad de lograr una modulación en la respuesta del sistema inmune del huésped en el proceso inflamatorio y una mejoría en el estado de nutrición en pacientes quirúrgicos. Es importante conocer el estado actual del uso de la IMN en el paciente con cáncer sometido a una cirugía, con la finalidad de aplicar correctamente la terapia nutricional y disminuir los desenlaces clínicos adversos, así como aumentar la supervivencia. El objetivo de esta revisión es conocer el estado actual del arte de la IMN en el paciente oncológico quirúrgico para llegar, de forma puntual, a recomendaciones en la práctica clínica basadas en la mejor evidencia científica disponible en la actualidad.
... These data are basically similar to the research results of Liu et al. (2013) [4], which indicated that the addition of Gln to a high-concentrate finishing diet can provide a protective effect against diet-caused ruminal inflammation; this may be profitable to improve the immune response of Hu lambs and weaken immunosuppression. Some reports indicated that the administration of Gln was found to be beneficial in decreasing intestinal permeability and increasing the mRNA expression of the tight epithelial junction proteins (such as claudin, occluding, and ZO) in humans [35], rats [36], and broiler chickens [16]. These effects may be due to the use of Gln, which is an energy fuel for lymphocytes and epithelial cells and plays an important role in glucose metabolism, while maintaining the acid-base balance and nitrogen balance [15]. ...
Simple Summary
It has been reported that goats fed a high-concentrate finishing diet had increased the short-chain fatty acid production and concentration; a decreased mean ruminal pH, leading to an increase in the epithelium’s permeability; destruction of the tight junctions between cells; and damage to the barrier function. Glutamine, as a conditionally nonessential amino acid, can maintain the acid base balance of body fluids, promote nitrogen balance, and strengthen the mucosa and the integrity of the tight junction proteins. In this study, we aimed to investigate if Gln (Glutamine) would improve the digestive enzymes’ activity, the ruminal epithelial barrier and fermentation, and immune responses by supplying energy to the mononuclear cells, improving the ruminal epithelium’s morphology and integrity, and mediating the mRNA expression of cytokines and tight junction proteins.
Abstract
The present experiment aimed to research the effects of glutamine (Gln) on the digestive and barrier function of the ruminal epithelium in Hu lambs fed a high-concentrate finishing diet containing some soybean meal and cottonseed meal. Thirty healthy 3-month-old male Hu lambs were randomly divided into three treatments. Lambs were fed a high-concentrate diet and supplemented with 0, 0.5, and 1% Gln on diet for 60 days. The experimental results show that the Gln treatment group had lower pepsin and cellulase enzyme activity, propionate acid concentration, and IL-6, TNF-α, claudin-1, and ZO-1 mRNA expression in the ruminal epithelium (p < 0.05); as well as increases in lipase enzyme activity, the ratio of propionic acid to acetic acid, the IL-10 content in the plasma, and the mRNA expression of IL-2 and IL-10 in the ruminal epithelium, in contrast to the CON (control group) treatment (p < 0.05). Taken together, the findings of this present study support the addition of Gln to improve digestive enzyme activity, the ruminal epithelium’s barrier, and fermentation and immune function by supplying energy to the mononuclear cells, improving the ruminal epithelium’s morphology and integrity, and mediating the mRNA expression of tight junction proteins (TJs) and cytokines.
... Normal intestinal peristalsis prevents excessive proliferation and adhesion of pathogenic intestinal bacteria. Inhibition of intestinal motility can lead to intestinal barrier dysfunction [35] and increase the development of BT. It has been shown that the application of gastrointestinal motility drugs is helpful for prevention and treatment of BT. ...
Background
Bacterial translocation was observed in critical illness and patients with chronic diseases such as liver cirrhosis and chronic kidney disease (CKD). Hypokalemia is a common complication in these diseases. Whether low potassium diet may increase intestinal permeability and result in bacterial translocation lack of evidence. The present study was aimed to investigate the potential effects of LK on intestinal permeability.
Methods
Grade 8-week-old male Bal B/C mice were randomly placed either on a normal potassium (NK) mouse chow or a low potassium (LK) diet for 28 days. Intestinal permeability and expression of tight junction proteins were compared between the two groups.
Results
Compared with the NK group, the mice in LK group had significantly lower serum potassium level, increased levels of plasmas endotoxin and plasma d-lactate. The bacterial translocation was higher and in occurred mainly in mesenteric lymph nodes (MLN), liver and spleen. The pathologic change of small intestine was obvious with thinner villus lamina propria, shorter crypt depth and thinner intestinal wall. Slight increases in the expression of proteins and mRNA levels of both claudin-1 and claudin-2 were observed in LK group.
Conclusions
Low potassium diet could increase intestinal permeability and thereby lead to bacterial translocation, which was suspected to result from impaired intestinal epithelial barrier and biological barrier.
... Glutamine is a non-essential amino acid that plays a key role in intestinal physiology [92]. Short-term glutamine in critically ill patients seems to improve the intestinal barrier [93]. Its supplementation in the formula for malnourished children improved the intestinal barrier function as compared with the unsupplemented formula [94]. ...
Food Allergy is a chronic systemic immuno-inflammatory condition that depends on several factors, but, above all, the gastrointestinal epithelial barrier. The rupture of this intestinal barrier results in a deleterious increase in intestinal permeability allowing the paracellular permeation of molecules greater than 150 Da into the bloodstream, producing an equivalent immune response, decreasing the immune tolerance. Intestinal Hyperpermeability has been linked not only to food allergy but also to Metabolic Syndrome and Non-Alcoholic Fat Liver Disease. Here we review the factors that contribute to producing Intestinal Hyperpermeability, as well the factors that contribute to the restoration of the epithelial barrier, improving the clinical outcome of food-allergic patients. The main factors that increase the Intestinal Hyperpermeability are A) Immune-Inflammatory (food allergy itself and autoimmune conditions); B) Iatrogenic (steroids, non-steroidal anti-inflammatories, antacids, antibiotics, and gastric-bypass surgeries); C) Infectious (rotavirus, HIV, SARS-CO2, Helicobacter pylori, Candida albicans, etc.); and D) Lifestyle-related (alcoholic beverages, food addiction, food overconsumption, consumption of industrialized food with high-fructose content and emulsifiers). The main factors that restore the intestinal barrier and immune tolerances are the intestinal microbiota and functional nutrients such as Vitamin A and vegetal fibers. Mucoprotectants agents, such as gelatin tannate and xyloglucan, are in study to become part of the medical arsenal to treat Intestinal Hyperpermeability conditions.
... Intestinal flora displays important metabolic, immunologic, and gut protective functions modulated by the so-called "gut-brain axis" (Haak et al., 2018). Numerous models have shown that microbiota have the potentials to augment the proinflammatory effect of immune cells and even conduct the influx of immune effector cells into distant organs, probably mediated by microbe-associated molecular patterns including lipopolysaccharide (LPS), peptidoglycan, flagellin, and microbiota-derived metabolites (Magnotti et al., 1998;De-Souza and Greene, 2005). Moreover, the microbiota can induce the secretion of antibacterial factors from the gut-epithelial cells and, consequently, augment humoral responses against invading pathogens (Kim et al., 2017). ...
Sepsis susceptibility is significantly increased in patients with intracerebral hemorrhage (ICH), owing to immunosuppression and intestinal microbiota dysbiosis. To date, ICH with sepsis occurrence is still difficult for clinicians to deal with, and the mortality, as well as long-term cognitive disability, is still increasing. Actually, intracerebral hemorrhage and sepsis are mutually exacerbated via similar pathophysiological mechanisms, mainly consisting of systemic inflammation and circulatory dysfunction. The main consequence of these two processes is neural dysfunction and multiple organ damages, notably, via oxidative stress and neurotoxic mediation under the mediation of central nervous system activation and blood-brain barrier disruption. Besides, the comorbidity-induced multiple organ damages will produce numerous damage-associated molecular patterns and consequently exacerbate the severity of the disease. At present, the prospective views are about operating artificial restriction for the peripheral immune system and achieving cross-tolerance among organs via altering immune cell composition to reduce inflammatory damage.
... Бактериальная транслокация из просвета кишки в системную циркуляцию является ответственной за развитие бактериемии и сепсиса у больных с критическими состояниями [54]. Методами молекулярно-генетической диагностики доказано повышение кишечной проницаемости и бактериальная транслокация в кровоток при терминальной стадии почечной недостаточности, что способствует развитию воспалительной реакции [55]. ...
Overactive bladder (OAB) is a very common condition. OAB undoubtedly requires correction since it significantly affects the patient’s quality of life. Literature review showed that pharmacokinetic and metabolic characteristics of trospium chloride make it a drug of choice in elderly and comorbid patients. There is a clear correlation between intestine and bladder dysfunction. The effects of rebamipide discovered by experiments, such as restoration of the damaged urothelium structure and function, as well as suppression of the overactive bladder, require further in-depth study and introduction of the drug to clinical practice for treatment of patients with chronic cystitis and OAB.
... Currently, the diagnosis of AGI is poorly understood. Border et al [6] first reported an association between bacterial translocation and gutorigin sepsis in 1987. Since then, the gut has been shown to have a major role in the progression of systemic inflammatory response syndrome, sepsis, and multiple organ dysfunction syndrome (MODS). ...
Background:
Sepsis is a major medical challenge. Magnolol is an active constituent of Houpu that improves tissue function and exerts strong anti-endotoxin and anti-inflammatory effects, but the mechanism by which it reduces intestinal inflammation in sepsis is yet unclear.
Aim:
To assess the protective effect of magnolol on intestinal mucosal epithelial cells in sepsis and elucidate the underlying mechanisms.
Methods:
Enzyme-linked immunosorbent assay was used to measure tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, and regulated on activation, normal T-cell expressed and secreted (RANTES) levels in serum and ileal tissue in animal studies. The histopathological changes of the ileal mucosa in different groups were observed under a microscope. Cell Counting Kit-8 and cell permeability assays were used to determine the concentration of drug-containing serum that did not affect the activity of Caco2 cells but inhibited lipopolysaccharide (LPS)-induced decrease in permeability. Immunofluorescence and Western blot assays were used to detect the levels of RANTES, inhibitor of nuclear factor kappa-B kinase β (IKKβ), phosphorylated IKKβ (p-IKKβ), inhibitor of nuclear factor kappa-B kinase α (IκBα), p65, and p-p65 proteins in different groups in vitro.
Results:
In rats treated with LPS by intravenous tail injection in the presence or absence of magnolol, magnolol inhibited the expression of proinflammatory cytokines, IL-1β, IL-6, and TNF-α in a dose-dependent manner. In addition, magnolol suppressed the production of RANTES in LPS-stimulated sepsis rats. Moreover, in vitro studies suggested that magnolol inhibited the increase of p65 nucleation, thereby markedly downregulating the production of the phosphorylated form of IKKβ in LPS-treated Caco2 cells. Specifically, magnolol inhibited the translocation of the transcription factor nuclear factor-kappa B (NF-κB) from the cytosol into the nucleus and down-regulated the expression level of the chemokine RANTES in LPS-stimulated Caco2 cells.
Conclusion:
Magnolol down-regulates RANTES levels by inhibiting the LPS/NF-κB signaling pathways, thereby suppressing IL-1β, IL-6, and TNF-α expression to alleviate the mucosal barrier dysfunction in sepsis.
... W 2005 roku D.A. De-Souza i wsp. opublikowali metaanalizę, z której wywnioskowano, że podaż glutaminy daje lepsze rokowanie oraz powoduje mniejszą częstość infekcji u pacjentów w stanie krytycznym, co prawdopodobnie wiąże się z utrzymaniem funkcji bariery jelitowej [35]. Metaanalizy przeprowadzone w kolejnych latach również pokazały istotne zmniejszenie częstości infekcji, a także skrócenie czasu pobytu w szpitalu oraz zmniejszenie śmiertelności pacjentów w stanie krytycznym w efekcie suplementacji glutaminy [36,37]. ...
Introduction and objective
Intestinal barrier dysfunction may promote increased migration of antigens, bacteria and toxins from the intestinal lumen into the bloodstream. This condition is observed in the course of various diseases, both acute and chronic. Modifying the intestinal barrier function could potentially affect the course of these diseases and patient prognosis. The aim of this article was to assess the role of selected nutritional components and lifestyle on human intestinal barrier function.
Review methods
A literature review was conducted using information from the PubMed/MEDLINE and ScienceDirect databases published before January 2021.
Brief description of the state of knowledge
Diet and lifestyle are basic environmental factors that affect the intestinal barrier function. Adequate intake of dietary fibre and zinc is necessary to maintain proper barrier function. Glutamine is a particularly important amino acid in the maintenance of the epithelial barrier of the gastrointestinal tract, and the demand for it significantly increases in the course of various clinical conditions. A high-fat diet and alcohol can disrupt the structure of the intestinal barrier, which can have negative health effects. Gluten has a specific effect on the intestinal barrier permeability through the ability to release zonulin; however, under physiological conditions this process is strictly controlled and probably not clinically significant in healthy people. Lifestyle factors, such as mental stress and intense exercise, may disrupt the intestinal barrier function, contributing to an increase in intestinal permeability.
Summary
The available literature undoubtedly suggests a significant influence of many nutrients and lifestyle on the intestinal barrier function.
... ± 13.2, p > 0.05). In this case, the benefits of supplementation may have been due to the decrease in intestinal permeability [40,44,46], resulting thus, in the reduction of the incidence of infectious complications (39 vs. 64%, p < 0.02). The decrease of the infectious complications (4 vs. 12 cases, p < 0.005) could be possibly influenced by the increase of the nitrogen balance (12 ± 2 vs. 5 ± 1 g N, p < 0.05), as well as the levels of IgA (335.7 ± 31.44 vs. 357.81 ...
Under stress conditions, the metabolic demand for nutrients increases, which, if not met, may slow down or indeed stop the wound from healing, thus, becoming chronic wounds. This study aims to perform a systematic review and meta-analysis of the effect of arginine and glutamine supplementation on wound healing. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed for the systematic review and ten electronic databases were used. Five and 39 human studies met the inclusion criteria for arginine and glutamine, respectively. The overall meta-analysis demonstrated a significant effect of arginine supplementation on hydroxyproline content (MD: 4.49, 95% CI: 3.54, 4.45, p < 0.00001). Regarding glutamine supplementation, there was significant effect on nitrogen balance levels (MD: 0.39, 95% CI: 0.21, 0.58, p < 0.0001), IL-6 levels (MD: −5.78, 95% CI: −8.71, −2.86, p = 0.0001), TNFα levels (MD: −8.15, 95% CI: −9.34, −6.96, p < 0.00001), lactulose/mannitol (L/M) ratio (MD: −0.01, 95% CI: −0.02, −0.01, p < 0.00001), patient mortality (OR: 0.48, 95% CI: 0.32, 0.72, p = 0.0004), C-reactive protein (CRP) levels (MD: −1.10, 95% CI: −1.26, −0.93, p < 0.00001) and length of hospital stay (LOS) (MD: −2.65, 95% CI: −3.10, −2.21, p < 0.00001). Regarding T-cell lymphocytes, a slight decrease was observed, although it failed to reach significance (MD: −0.16, 95% CI: −0.33, 0.01, p = 0.07). Conclusion: The wound healing might be enhanced in one or at various stages by nutritional supplementation in the right dose.
... Glutamine has also been proven to decrease intestinal permeability and bacterial translocation in mice and in critical cryptosporidiosis patients [92][93][94]. In line with our present results, indicating a pivotal role of glutamine for C. parvum replication, treatments with compound 968, which blocks glutamine degradation by inhibiting mitochondrial glutaminase, led to a highly significant reduction of C. parvum development. ...
Simple Summary
Cryptosporidium parvum is one of the causal agents of cryptosporidiosis. This water-borne disease is responsible for around one million human deaths every year and the only approved anti-cryptosporidial drug for humans, i.e., nitazoxanide, lacks efficacy in immunocompromised patients. We here present, to the best of our knowledge, the first analyses of C. parvum impact on the metabolism of its host-cells under physiological oxygen conditions. Moreover, based on the here presented metabolic evidence, we blocked specific metabolic pathways in order to find new anti-cryptosporidial targets. Our findings besides confirming glycolysis as anti-cryptosporidial target prove glutaminolysis and lactate release as necessary for parasite replication.
Abstract
Cryptosporidium parvum is an apicomplexan zoonotic parasite recognized as the second leading-cause of diarrhoea-induced mortality in children. In contrast to other apicomplexans, C. parvum has minimalistic metabolic capacities which are almost exclusively based on glycolysis. Consequently, C. parvum is highly dependent on its host cell metabolism. In vivo (within the intestine) infected epithelial host cells are typically exposed to low oxygen pressure (1–11% O2, termed physioxia). Here, we comparatively analyzed the metabolic signatures of C. parvum-infected HCT-8 cells cultured under both, hyperoxia (21% O2), representing the standard oxygen condition used in most experimental settings, and physioxia (5% O2), to be closer to the in vivo situation. The most pronounced effect of C. parvum infection on host cell metabolism was, on one side, an increase in glucose and glutamine uptake, and on the other side, an increase in lactate release. When cultured in a glutamine-deficient medium, C. parvum infection led to a massive increase in glucose consumption and lactate production. Together, these results point to the important role of both glycolysis and glutaminolysis during C. parvum intracellular replication. Referring to obtained metabolic signatures, we targeted glycolysis as well as glutaminolysis in C. parvum-infected host cells by using the inhibitors lonidamine [inhibitor of hexokinase, mitochondrial carrier protein (MCP) and monocarboxylate transporters (MCT) 1, 2, 4], galloflavin (lactate dehydrogenase inhibitor), syrosingopine (MCT1- and MCT4 inhibitor) and compound 968 (glutaminase inhibitor) under hyperoxic and physioxic conditions. In line with metabolic signatures, all inhibitors significantly reduced parasite replication under both oxygen conditions, thereby proving both energy-related metabolic pathways, glycolysis and glutaminolysis, but also lactate export mechanisms via MCTs as pivotal for C. parvum under in vivo physioxic conditions of mammals.
... Sepsis often leads to intestinal epithelial cell apoptosis (34) and tight junction protein destruction (20,35), resulting in increased permeability (36,37). Damage to the intestinal mucosal barrier leads to bacterial and endotoxin translocation into circulation, which exacerbates sepsis (38), and may even cause multiple organ failure (39,40). Therefore, the intestinal mucosal barrier, intestinal permeability and endotoxin levels are important indicators reflecting the severity of sepsis. ...
Atezolizumab can reduce immunosuppression caused by T lymphocyte apoptosis in various cancer types. The current study aimed to investigate whether this drug can also alleviate immunosuppression during sepsis. For that purpose, a C57BL/6 mouse sepsis model was generated. Mice were randomly assigned to three groups: Sham, cecal ligation and puncture (CLP) and atezolizumab groups. Atezolizumab was administered in vivo by intraperitoneal injection. The expression of programmed death ligand‑1 (PD‑L1) on neutrophils and programmed death‑1 (PD‑1) on T lymphocytes was evaluated, and endotoxin concentration, intestinal permeability, ileum histopathological score and tight junction protein expression were assessed to determine the extent of disease in each group. The rate of T lymphocyte apoptosis was determined to assess the effects of atezolizumab on T lymphocyte apoptosis in vivo and in vitro . Survival times were also recorded to compare mouse prognosis during sepsis. In the CLP group, the proportion of PD‑L1+ neutrophils was significantly higher at 48, 72 and 96 h in blood, and at 24, 48, 72 and 96 h in bone marrow, compared with those of the sham group (P<0.05). The proportion of PD‑1+ T lymphocytes was also upregulated at 72 h in blood. In the atezolizumab group, endotoxin concentration, intestinal permeability and ileum histopathological score were lower compared with those in the CLP group (P<0.05), whereas the expression of claudin‑1 and occludin proteins on ileum was higher compared with that in the CLP group (P<0.05). Both in vivo and in vitro experiments indicated that the rate of T lymphocyte apoptosis following atezolizumab treatment was lower compared with that in the CLP group (P<0.05). Survival analysis demonstrated that mice in the atezolizumab group survived longer compared with those in the CLP group (P<0.05). The current study demonstrated that treatment with atezolizumab may be an effective method for treating immunosuppression induced by sepsis.
... As mentioned previously, burn-induced gut barrier damage is associated with increased bacterial translocation to MLNs and systemic inflammation, which may lead to MOF and death (23,24). Accordingly, we confirmed our previous finding (11), that burn site infection with P. aeruginosa lead to a dramatic increase in the bacterial load in both MLNs and systemic blood and also showed that mice supplemented with IAP exhibited a significantly reduced bacterial load in both MLNs and systemic circulation ( Figure 3, A and B). ...
Severe burn injury induces gut barrier dysfunction and subsequently a profound systemic inflammatory response. In the present study, we examined the role of the small intestinal brush border enzyme, intestinal alkaline phosphatase (IAP), in preserving gut barrier function and preventing systemic inflammation after burn wound infection in mice. Mice were subjected to a 30% total body surface area dorsal burn with or without intradermal injection of Pseudomonas aeruginosa. Mice were gavaged with 2000 units of IAP or vehicle at 3 and 12 hours after the insult. We found that both endogenously produced and exogenously supplemented IAP significantly reduced gut barrier damage, decreased bacterial translocation to the systemic organs, attenuated systemic inflammation, and improved survival in this burn wound infection model. IAP attenuated liver inflammation and reduced the proinflammatory characteristics of portal serum. Furthermore, we found that intestinal luminal contents of burn wound–infected mice negatively impacted the intestinal epithelial integrity compared with luminal contents of control mice and that IAP supplementation preserved monolayer integrity. These results indicate that oral IAP therapy may represent an approach to preserving gut barrier function, blocking proinflammatory triggers from entering the portal system, preventing gut-induced systemic inflammation, and improving survival after severe burn injuries.
... As mentioned previously, burn-induced gut barrier damage is associated with increased bacterial translocation to MLNs and systemic inflammation, which may lead to MOF and death (23,24). Accordingly, we confirmed our previous finding (11), that burn site infection with P. aeruginosa lead to a dramatic increase in the bacterial load in both MLNs and systemic blood and also showed that mice supplemented with IAP exhibited a significantly reduced bacterial load in both MLNs and systemic circulation ( Figure 3, A and B). ...
... The loss of the structural integrity in the intestinal epithelial barrier may cause sepsis and subsequent multiple organ dysfunction syndromes, leading to a higher risk of mortality in burn victims [24][25][26]. Nonetheless, most of the supposed underlying mechanisms behind gut disruption were derived from other better investigated, critically ill populations [27,28]. Recently, as assumed by Wheatley et al. in a mouse model, among predisposing factors advanced age elicits a more severe degree of gut microbial dysbiosis following cutaneous burn injury than is manifest in younger mice [23]. ...
Burn damage can lead to a state of immune dysregulation that facilitates the development of infections in patients. The most deleterious impact of this dysfunction is the loss of the skin's natural protective barrier. Furthermore, the risk of infection is exacerbated by protracted hospitalization , urinary catheters, endotracheal intubation, inhalation injury, arterial lines and central venous access, among other mainstays of burn care. Currently, infections comprise the leading cause of mortality after major burn injuries, which highlights the improvements observed over the last 50 years in the care provided to burn victims. The need to implement the empirical selection of antibiotic therapy to treat multidrug-resistant bacteria may concomitantly lead to an overall pervasiveness of difficult-to-treat pathogens in burn centres, as well as the propagation of antimicrobial resistance and the ultimate dysregulation of a healthy microbiome. While preliminary studies are examining the variability and evolution of human and mice microbiota, both during the early and late phase burn injury, one must consider that abnormal microbiome conditions could influence the systemic inflammatory response. A better understanding of the changes in the post-burn microbiome might be useful to interpret the provenance and subsequent development of infections, as well as to come up with inferences on the prognosis of burn patients. This review aims to summarise the current findings describing the microbiological changes in different organs and systems of burn patients and how these alterations affect the risks of infections, complications, and, ultimately, healing.
Acute kidney injury (AKI) persists as one of the most common complications after cardiac surgery. Beyond being burdened by high morbidity and mortality rates, effective therapeutic options are still lacking. To date, the management of cardiac surgery-associated AKI (CSA-AKI) mainly focuses on preventive strategies, e.g. the implementation of standardized care bundles. Interestingly, recent experimental studies have suggested a potential nephroprotective role for both amino acids (AA) and proteins. As such, these compounds show multiple beneficial renal effects, spanning enhancement of renal blood flow, improved oxygenation, and recruitment of renal functional reserve. Moreover, clinical studies have investigated the therapeutic potential of single AA, AA combinations, and proteins. A recent large multicenter randomized controlled trial showed reduced AKI incidence in cardiac surgery patients receiving intravenous AA supplementation. However, these interventions have not yet demonstrated beneficial effects on major clinical outcomes, such as survival. Given the well-established AA safety profile and the underlying biological rationale supporting their use, this review summarizes the existing literature on the effects of various formulations and combinations of perioperative AA and protein on renal outcomes when administered in cardiac surgery patients.
Aneurysmal subarachnoid hemorrhage (aSAH) is a serious condition complicated by delayed cerebral ischemia (DCI), where inflammation plays a key role. Although altered gut permeability is noted in other conditions, its significance in aSAH remains unclear. Fatty acid-binding protein (FABP-I), lipopolysaccharide-binding protein (LBP), and soluble CD-14 (sCD-14) are established markers of barrier dysfunction. This study investigates gut permeability marker changes in early and late aSAH phases. The study included 177 aSAH patients and 100 controls. Serum samples were collected on days 1 (D1) and 9 (D9) after ictus. FABP-I, LBP, and sCD-14 levels were measured via ELISA, and clinical data were recorded. Outcomes were assessed using the 90-day modified Rankin scale (mRS 0–3 = favorable outcome). Serum FABP-I was significantly lower in aSAH patients (p < 0.05), while LBP and sCD-14 were higher (p < 0.001) compared to controls. FABP-I did not differ between outcome groups, but LBP and sCD-14 were significantly elevated in unfavorable outcomes (p < 0.001). These markers differed in patients without in-hospital infection, with higher levels noted in DCI patients during the later phase (p < 0.05). In aSAH patients without infection, differences in LBP and sCD-14 levels between outcome groups suggest potential endotoxin release from microbial systems, contributing to neuroinflammation and influencing outcomes.
Accumulating evidence suggest that ghrelin plays a role as an antiseptic peptide. The present study aimed to clarify whether the brain may be implicated ghrelin's antiseptic action. We examined the effect of brain ghrelin on survival in a novel endotoxemic model achieved by treating rats with lipopolysaccharide (LPS) and colchicine. The observation of survival stopped three days after chemicals' injection or at death. Intracisternal ghrelin dose-dependently reduced lethality in the endotoxemic model; meanwhile, neither intraperitoneal injection of ghrelin nor intracisternal des-acyl-ghrelin injection affected the mortality rate. The brain ghrelin-induced lethality reduction was significantly blocked by surgical vagotomy. Moreover, intracisternal injection of a ghrelin receptor antagonist blocked the improved survival achieved by intracisternal ghrelin injection or intravenous 2-deoxy-d-glucose administration. Intracisternal injection of an adenosine A2B receptor agonist reduced the lethality and the ghrelin-induced improvement of survival was blocked by adenosine A2B receptor antagonist. I addition, intracisternal ghrelin significantly blocked the colonic hyperpermeability produced by LPS and colchicine. These results suggest that ghrelin acts centrally to reduce endotoxemic lethality. Accordingly, activation of the vagal pathway and adenosine A2B receptors in the brain may be implicated in the ghrelin-induced increased survival. Since the efferent vagus nerve mediates anti-inflammatory mechanisms, we speculate that the vagal cholinergic anti-inflammatory pathway is implicated in the decreased septic lethality caused by brain ghrelin.
The relevance of studying the measures to prevent the development of endotoxemia in acute intestinal obstruction is stipulated with an increasing incidence of multiple organ failure in debilitated patients and infectious−toxic shock. The development of endotoxemia is often accompanied with a secondary infection. Toxic effects of bacteria in small intestine, the trigger of which is their translocation and transformation of the small intestine into a focus of microbial invasion, prolongs the postoperative period, which increases the length of stay in the surgical hospital. Much attention is paid to the pathogenesis of the development of small bowel contamination syndrome, which results in changes in intestinal biocenosis and increased intoxication of the body, which worsens the patient general condition. To examine the results of entersorption as a method of detoxification and control of infectious and toxic complications in the patients with an acute intestinal obstruction before surgery to optimize surgical tactics and prevent post−surgery complications, a study was conducted in 36 patients with different stages of the disease. The effectiveness of detoxification in the combined treatment of an acute intestinal obstruction has been confirmed, which is indicated by the reduced pain, regression of radiological signs of obstruction in the patients and early normalization of their main clinical, laboratory and instrumental parameters. The use of the method of enterosorption as part of a comprehensive approach in the period after surgery contributed to the early restoration of intestinal motility, reducing the number of complications, improving the general condition of patients. Thus, the method of enterosorption is one of the most effective of modern detoxification methods, which determines its relevance and further prospects to study this problem. Key words: acute intestinal obstruction, endotoxemia, enterosorption.
Background: Burn patients are characterized by alterations within the immune system, increased exposure to infectious complications, sepsis, and potentially organ failure and death. Glutamine supplementation to parenteral nutrition has been proven to be related to improved clinical outcomes in trauma patients. We studied the effect of glutamine supplementation on infection and clinical outcomes among burn patients. Methodology: Sixty burn patients were randomly divided into two equal groups. Group I received 0.5 gm/kg/day glutamine infusion as a part of parenteral nutrition for seven days after ICU admission. Group II received an intravenous placebo by continuous infusion (24 h/day). The primary outcome was the presence of infection assessed by the wound culture over a 15-days period. The secondary outcomes were: blood culture, WBCs count, serum C-reactive protein (CRP) and procalcitonin, sequential organ failure assessment (SOFA) score, and length of stay within the intensive care unit. Results: The results showed that the incidence of positive wound culture was considerably reduced within the glutamine group, e.g., 6 (10%) patients) vs. control 19 (33%) patients; P < 0.001). The incidence of positive blood culture was significantly reduced within the study group (1 case) vs. control (9 cases; P = 0.006). In addition, the WBC, serum CRP and procalcitonin were better; and the SOFA score and the ICU-stay were reduced within the glutamine group vs. the control group. Conclusion: The present results prove that IV glutamine supplementation in adult burn patients can reduce the impact of infectious morbidity and improve the clinical outcome. Ethical committee approval: 19/5/2019 ANETS 4 Trial registration: www.clinicaltrials.gov No. NCT05140772 Abbreviations: ICU - intensive care unit; SOFA - Sequential Organ Failure Assessment; CRP - C-reactive protein; GFR- glomerular filtration rate; TBSA - total body surface area; BMI – Body mass index Key words: Glutamine; Infection; Burn; ICU; Mortality Citation: Eskandr AM, Attalla HA, Massoud ME, Alaa-Eldin A. Aiad AEA. A randomized, controlled study to evaluate the effect of parenteral glutamine on the reduction of infection related morbidity in burn patients in ICU. Anaesth. pain intensive care 2022;26(2):318-325; DOI: 10.35975/apic.v26i3.1898 Received: December 24. 2021, Reviewed: January 18, 2022, Accepted: January 29, 2022
Background: In the past decades, the prevalence of metabolic diseases, particularly diabetes, hyperlipidemia, obesity, non-alcoholic fatty liver disease (NAFLD), has increased dramatically, thereby causing great public health and economic burden worldwide. Traditional Chinese Medicine (TCM) served as an effective therapeutic choice. Xiao-Ke-Yin (XKY) is a medicine and food homology TCM formula consisted of nine “medicine and food homology” herbs, which was used to ameliorate metabolic diseases, such as insulin resistance, diabetes, hyperlipidemia and non-alcoholic fatty liver disease. However, despite its therapeutic potential on metabolic disorders, the underlying mechanisms remain unclear. This study aimsto evaluate the therapeuticeffectiveness of XKY on glucolipid metabolism dysfunction, and explored the potential mechanisms in db/db mice.
Methods: To verify the effects of XKY, db/db mice were treated with different concentrations of XKY (5.2, 2.6 and 1.3 g/kg/d) and Metformin (0.2 g/kg/d, a hypoglycemic positive control) for 6 weeks, respectively. During this study, we detected the body weight (BW) and fasting blood glucose (FBG), oral glucose tolerance test (OGTT), insulin tolerance test (ITT), daily food intake and water intake. At the end of the animal experiment, blood samples, feces, livers and intestine tissues of mice in all groups were collected. The potential mechanisms were investigated by using hepatic RNA sequencing, 16S rRNA sequencing of gut microbiota and metabolomics analysis.
Results: XKY efficiently mitigated hyperglycemia, IR, hyperlipidemia, inflammation and hepatic pathological injury in a dose dependent manner. Mechanistically, hepatic transcriptomic analysis showed that XKY treatment significantly reversed the upregulated cholesterol biosynthesis which was further confirmed by RT-qPCR. Additionally, XKY administration maintained intestinal epithelial homeostasis, modulated gut microbiota dysbiosis, and regulated its metabolites. In particular, XKY decreased secondary bile acid producing bacteria (Clostridiaand Lachnospircaeae) and lowered fecal secondary bile acid (lithocholic acid (LCA) and deoxycholic acid (DCA)) levels to promote hepatic bile acid sythesis via inhibiting LCA/DCA-FXR-FGF15 signalling pathway. Furthermore, XKY regulated amino acid metabolism including arginine biosynthesis, alanine, aspartate and glutamate metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, and tryptophan metabolism likely through increasing Bacilli, Lactobacillaceae and Lactobacillus, and decreasing Clostridia, Lachnospircaeae, Tannerellaceaeand Parabacteroides.
Conclusion: Taking together, our findings demonstrate that XKY is a promising “medicine food homology” formula for ameliorating glucolipid metabolism and reveal that the therapeutic effects of XKY may due to its downregulation on hepatic cholesterol biosynthesis, modulation the dysbiosis of gut microbiota and metabolites.
Surgical science has driven innovation and inquiry across adult and pediatric disciplines that provide critical care regardless of location. Surgically originated but broadly applicable knowledge has been globally shared within the pages Critical Care Medicine over the last 50 years.
BACKGROUND: Cholestasis caused by obstruction of the common bile duct and may developed gut-derived sepsis due to reactive oxygen species (ROS) accumulation. Ursodeoxycholic acid (UDCA) and glutathione are widely known for their antioxidant properties, that might be beneficial against ROS. However, the effects of UDCA-glutathione combination against ROS have not been well elucidated in previous studies. Thus, this study was conducted to evaluate tumor necrosis factor (TNF)-α level and height of terminal ileal mucosal villus after UDCA-glutathione administration in cholestasis rat model.
METHODS: Twenty-eight male Sprague Dawley rats were randomly grouped into four treatment groups, each group consisted of seven rats that had previously undergone bile duct ligation. Three groups received treatment of UDCA-glutathione combination on stratified dose, while the other one only received UDCA. Each treatment was given for 21 days. Ileal samples were collected from the rats and stained with mouse anti TNF-a antibody and hematoxylin-eosin (HE). Immunohistochemistry and histopathological examination were done using microscope and then calculated with ImageJ.
RESULTS: The combination of UDCA and glutathione treatment decreased the TNF-α expression (p
Background & Aims
The gut microbiome has been suggested to play a role in gut barrier hemostasis, but data are scarce and limited to animal studies. Therefore, we aimed to assess if alterations in gut microbial composition and functional pathways are associated with gut barrier function in a cohort of healthy first-degree relatives of patients with Crohn’s disease.
Methods
We utilized the Genetic Environmental Microbial (CCC-GEM) cohort of healthy first-degree relatives of patients with Crohn’s disease. Gut barrier function was assessed using urinary fractional excretion ratio of lactulose to mannitol (LMR). Microbiome composition was assessed by sequencing fecal 16S rRNA. The cohort was divided into a discovery cohort (n=2,472) and a validation cohort (n=655). A regression model was used to assess microbial associations with LMR. A Random Forest classifier algorithm was performed to assess microbial community contribution to barrier function.
Results
Subjects with impaired barrier function (LMR>0.025) had reduced alpha-diversity (Chao1 index, p=4.0e-4) and altered beta-diversity (Bray-Curtis dissimilarity index, R²=0.001, p=1.0e-3) compared to subjects with LMR≤0.025. When taxa were assessed individually, we identified eight genera and 52 microbial pathways associated with LMR>0.025 (q<0.05). Four genera (decreased prevalence of Adlercreutzia, Clostridia UCG 014, and Clostridium sensu stricto 1 and increased abundance of Colidextribacter) and eight pathways (including decreased biosynthesis of glutamate, tryptophan and threonine) were replicated in the validation cohort. Random forest approach revealed that bacterial community is associated with gut barrier function (p= 1.4e-6, area under the curve 0.63).
Conclusions
Gut microbiome community and pathways are associated with changes in gut barrier function. These findings may identify potential microbial targets to modulate gut barrier.
Patients suffering from severe multiple trauma injuries may develop multiple organ failure and polycompartment syndrome as early or mid-term complications. Excessive inflammatory response as a consequence of a high energy injury along with side effects of resuscitative treatments are the pathophysiological pathways to these clinical conditions, leading to increased systemic permeability. Patients undergoing multiple organ failure usually need sedation and mechanical ventilation for coexistent respiratory failure, fluid and vasoactive drugs as first-line treatment for circulatory collapse, artificial nutrition and often extracorporeal multiorgan supports to gain time avoiding death for treatment failure. All these treatments must be titrated to judicious targets, usually accepting compromises between the optimal target for a single organ failure, and the detrimental effect on multiple organ failure. Authors try to explain the principles of this therapeutic approach aimed at being an ally of the patient’s physiological response to the injury, and not a second injury itself.
Glutamine is the most abundant amino acid in the human body that is involved in various metabolic processes. The development of hypermetabolic and hypercatabolic syndrome that accompanies critical conditions of ICU patients is associated with a decrease in the concentration of glutamine, especially in the blood plasma and muscles. This process may last for quite a long time and lead to a number of complications up to a fatal outcome. This review was aimed to analyze clinical studies conducted over the past 20 years that demonstrate the effect of intravenous infusion of glutamine dipeptide as part of balanced parenteral nutrition on the perioperative period: the severity of inflammatory response; the state of the intestinal mucosa; the incidence and severity of complications; mortality; the duration of stay in the ICU and hospital in general, etc. The analysis was performed using systematic reviews and meta-analyses based on randomized double-blind, placebo-controlled trials in different countries selected in the main databases (PubMed, EMBASE, Web of Science, The Cochrane Library, etc.). Most of the reports state that the inclusion of glutamine dipeptide in nutritional and metabolic therapy (NMT) in surgical patients reduces the frequency and severity of infectious complications and mortality, reduces the length of stay in ICU and in hospital in general, improves the biochemical parameters that reflect the condition of patients, and reduces the treatment costs. Thus, the conducted systematic reviews and meta-analyses confirm that the use of the parenteral form of glutamine dipeptide (Dipeptiven 20%) as part of balanced standard parenteral nutrition (PN) is a clinically and pharmacoeconomically justified strategy of NMT in surgical ICU patients.
Diarrhea-predominant irritable bowel syndrome is a common functional gastrointestinal disorder that manifests with abdominal pain and diarrheal bowel patterns, without structural explanation. Diarrhea-predominant irritable bowel syndrome is a heterogeneous condition resulting from diverse pathophysiologic processes. Treatment strategies with varied mechanisms of action are beneficial in its management. The clinician must become familiar with a multi-dimensional approach to irritable bowel syndrome. The 3 approved medications are central to disease management. Effective treatment uses off-label medications and emerging therapies and a growing number of over-the-counter and supplemental agents to optimize symptom improvement for the patient with diarrhea-predominant irritable bowel syndrome.
Short chain fatty acids readily crosses the gut-blood and blood-brain barrier and acts centrally to influence neuronal signaling. We hypothesized that butyrate, a short-chain fatty acid produced by bacterial fermentation, in the central nervous system may play a role in the regulation of intestinal functions. Colonic permeability and visceral sensation was evaluated in rats. Septic lethality was evaluated in a sepsis model induced by subcutaneous administration of both lipopolysaccharide and colchicine. Intracisternal butyrate dose-dependently improved colonic hyperpermeability and visceral nociception. In contrast, subcutaneous injection of butyrate failed to change it. Intracisternal orexin 1 receptor antagonist or surgical vagotomy blocked the central butyrate-induced improvement of colonic hyperpermeability. The improvement of intestinal hyperpermeability by central butyrate or intracisternal orexin-A was blocked by cannabinoid 1 or 2 receptor antagonist. Intracisternal butyrate significantly improved survival period in septic rats. These results suggest that butyrate acts in the central nervous system to improve gut permeability and visceral nociception through cannabinoid signaling. Endogenous orexin in the brain may mediate the reduction of intestinal hyperpermeability by central butyrate through the vagus nerve. We would suggest that improvement of leaky gut by central butyrate may induce visceral antinociception and protection from septic lethality.
Background:
Increased intestinal permeability (IP) is associated with sepsis in the Intensive Care Unit (ICU). This study aimed to pilot a sensitive multi-sugar test to measure IP in critically ill patients in the non-fasted state.
Methods:
Critically ill mechanically ventilated adults were recruited from two ICUs in Australia. Measurements were completed within three days of admission using a multi-sugar test measuring gastroduodenal (sucrose recovery), small bowel (lactulose-rhamnose [L-R] and lactulose-mannitol [L-M] ratios) and whole gut permeability (sucralose-erythritol [S-E] ratio) in 24-hour urine samples. Urinary sugar concentrations were compared at baseline and post-sugar ingestion, and IP sugar recoveries and ratios were explored in relation to known confounders including renal function.
Results:
Twenty-one critically ill patients (12 males, median 57 years) participated. Group median concentrations of all sugars were higher following sugar administration; however, sucrose and mannitol increases were not statistically significant. Within individual patients, sucrose and mannitol concentrations were higher in baseline than post-sugar ingestion in nine (43%) and four (19%) patients, respectively. Patients with impaired (n = 9) versus normal (n = 12) renal function had a higher L-R ratio (median 0.130 versus 0.047,p = 0.003), a lower rhamnose recovery (median 15 versus 24%,p = 0.007) and no difference in lactulose recovery (median 2.5 versus 2.4%,p = 0.508).
Conclusion:
Small bowel and whole gut permeability measurements are possible to complete in the non-fasted state, while gastroduodenal permeability could not be measured reliably. For small bowel IP measurements, the L-R ratio is preferred over the L-M ratio. Alterations in renal function may reduce the reliability of the multi-sugar IP test, warranting further exploration. This article is protected by copyright. All rights reserved.
The purpose of the first multidisciplinary Consensus: to comprehensively analyze the pathophysiological, clinical, and pharmacotherapeutic aspects of the syndrome of increased epithelial permeability (SPEP) as one of the basic mechanisms of the development of human pathology. The Consensus presents the structure of the three main levels of cytoprotection: preepithelial, epithelial and subepithelial, and the structure of intercellular tight contacts in epithelial tissues and endothelium is considered in detail. The clinical sections of the Consensus are devoted to the role of SPEP in diseases of the digestive system, cardio-cardiovascular and other visceral systems. A separate section summarizes the materials illustrating the significant role of SPEP in mental disorders and diseases of the nervous system. A separate chapter of the Consensus is devoted to cytoprotective therapy in SPEP. Cytoprotective effects of such proton pump inhibitor as rabeprazole, bismuth preparations and probiotics have been shown. Special attention is paid to the clinical and pharmacological specialties of the cytoprotector of rebamipide. Clinical the effectiveness of rebamipide shown as in functional, so in organic lesions of the digestive system. Its anti-cancer preventive effects are of practical importance. © 2021 Vserossiiskoe Obshchestvo Kardiologov. All rights reserved.
In recent years, the effect of critical conditions on intestine and the role of such changes in maintenance and progression of systemic disorders are of particular attention. This issue is relevant in critically ill neurosurgical patients too. Intestine morphology and microbiome changes in these patients represent a wide field for researches in intensive care and prevention of secondary damage to other organs and systems. This review ensures a current approach to the problem of intestine morphology and microbiome changes in critically ill neurosurgical patients. We reviewed the data from clinical studies and experiments reproducing a critical condition in animals. Most publications are indexed in the PubMed, e-library, Google Scholar databases. We also analyzed the data from NEJM, JAMA, Lancet, Critical Care and other issues. The manuscript contains an overview of 44 foreign and 13 domestic references; over 50% of researches were published within the past 5 years. Searching depth was over 50 years.
Orexins are neuropeptides implicated in several physiological functions. Accumulating findings suggest a relationship between orexin and sepsis. A recent study demonstrated that orexin acts centrally to improve conditions in sepsis. The present study aims to clarify the precise mechanisms by which central orexin could induce a protective action against septic conditions. We established a new septic model by treating rats with lipopolysaccharide (LPS) and colchicine and used this to examine the effect of brain orexin on survival. Observation of survival was stopped three days after the chemicals injection or at death. We established a lethal model (rats died within 24 h) by injecting subcutaneously a combination of 1 mg/kg LPS and 1 mg/kg colchicine. A Toll-like receptor 4 (TLR4) inhibitor completely blocked lethality, suggesting a vital role of LPS-TLR4 signaling in the process. Intracisternal orexin-A dose-dependently reduced lethality in the sepsis model while neither intracisternal orexin-B nor intraperitoneal orexin-A changed the mortality rate. Vagal stimulation with carbachol or 2-deoxy-D-glucose improved survival and atropine potently blocked the protection by carbachol or 2-deoxy-D-glucose. The orexin-A-induced reduction of lethality was significantly blocked by atropine or surgical vagotomy. Intracisternal injection of an OX1 receptor antagonist blocked the improvement of survival by intracisternal injection of orexin-A, carbachol, or 2-deoxy-D-glucose. These results suggest that orexin acts centrally to reduce the lethality in our septic model treated (LPS and colchicine). Activation of the vagal cholinergic pathway may mediate the action of orexin, and the OX1 receptor in the brain might play a role in the process. Since the efferent vagus nerve mediates anti-inflammatory mechanisms, we speculate that the vagal cholinergic anti-inflammatory pathway is implicated in the mechanisms of septic lethality reduction by brain orexin.
Under normal conditions, the intestinal flora and the body are in dynamic equilibrium. When the barrier function of the intestinal tract is damaged due to various reasons, changes in the number and proportion of bacteria or spatial displacement result in bacterial translocation (BT), which ultimately leads to multiple organ dysfunction syndrome (MODS). Endogenous infections and endotoxemia caused by intestinal flora and endotoxin translocation are the origins of inflammatory responses, and the intestinal tract is the organ in which MODS both initiates and targets. Only by ensuring the integrity of the intestinal mucosal barrier can intestinal BT be effectively prevented. Elimination of the primary disease and maintaining blood and oxygen supply to the intestine is the most basic treatment. Early initiation of the intestinal tract, establishment of enteral nutrition, and selective digestive decontamination are also highly effective treatments. Early diagnosis, intervention, or prevention of BT may be a new avenue or important connection in the treatment of various diseases. The mechanism of BT, detection techniques, prevention and treatment, and its interaction with parenteral diseases were reviewed.
The integrity of the gastrointestinal mucosa is a key element in preventing systemic absorption of enteric toxins and bacteria. In the critically ill, breakdown of gut barrier function may fuel sepsis. Malnourished patients have an increased risk of postoperative sepsis; however, the effects of malnutrition on intestinal barrier function in man are unknown.
To quantify intestinal barrier function, endotoxin exposure, and the acute phase cytokine response in malnourished patients.
Malnourished and well nourished hospitalised patients.
Gastrointestinal permeability was measured in malnourished patients and well nourished controls using the lactulose:mannitol test. Endoscopic biopsy specimens were stained and morphological and immunohistochemical features graded. The polymerase chain reaction was used to determine mucosal cytokine expression. The immunoglobulin G antibody response to endotoxin and serum interleukin 6 were measured by enzyme linked immunosorbent assay.
There was a significant increase in intestinal permeability in the malnourished patients in association with phenotypic and molecular evidence of activation of lamina propria mononuclear cells and enterocytes, and a heightened acute phase response.
Intestinal barrier function is significantly compromised in malnourished patients, but the clinical significance is unclear.
Ratios of lactulose/mannitol excretion in urine have been used to assess the extent of intestinal permeability in various disease and trauma conditions. Reported studies have used this technique to correlate altered gastrointestinal mucosal permeability to translocation of bacteria and endotoxin, leading to occult sepsis in burn patients. Enzymatic methods of analysis for urine concentrations of mannitol and lactulose were used in these studies. We have found that urine from patients with severe burns frequently contains compounds that interfere with the enzymatic methods. We describe using gas-liquid chromatography to determine mannitol and lactulose simultaneously in the urine of burn patients. To avoid the multiple peaks for the anomeric forms of the reducing sugars during precolumn trimethylsilyl derivatization, we converted the sugars to oximes before the silylation step. The method gave good recoveries of mannitol and lactulose added to burn patients' urine samples. Unlike the enzymatic methods, gas-liquid chromatography eliminates the effect of interfering compounds and allows for the simultaneous determination of both sugars in urine samples.
Alterations in intestinal permeability have been postulated to occur after thermal injury. We evaluated the status of intestinal permeability during the first 2 postburn weeks in 15 subjects by measuring the differential excretion of enterally administered lactulose and mannitol. The mean age and burn size of the patients were 32.7 +/- 3.6 years and 53.3% +/- 5.1% of the total body surface area, respectively. Ten healthy volunteers were also studied. The lactulose-mannitol excretion ratio was 0.159 +/- 0.017 for the patients and 0.017 +/- 0.003 for controls. The increased ratio did not correlate with burn size or postburn day. Patients who developed significant clinical infections during their first 2 postburn weeks had lactulose-mannitol ratios on postburn day 2 that were significantly higher than those of controls and patients who did not develop infections. This suggests a relationship between susceptibility to infection and early alterations in intestinal permeability.
Animal studies implicate gut bacterial translocation via the portal vein as a major factor in the pathogenesis of postinjury multiple organ failure (MOF). We therefore inserted portal vein catheters for sequential blood sampling in the operating room, at 6, 12, 24, and 48 hours, and 5 days postoperatively in 20 injured patients (13 blunt, seven penetrating; mean age, 34 years) requiring emergent laparotomy and who were at known risk for MOF. The mean Revised Trauma Score was 6.4 +/- 0.4, and the Injury Severity Score, 29.3 +/- 2.3. Twelve (60%) patients arrived in shock (SBP less than 90 torr). Eight (2%) of 212 portal blood cultures were positive; seven were presumed contaminants. The only positive systemic culture (total, 212) was a Staphylococcus aureus on day 5 in a patient with a concurrent staphyloccal pneumonia. In the first 48 hours, we could not detect endotoxin in portal or systemic blood. Additionally, simultaneous portal and systemic blood levels of complement fragment C3a, tumor necrosis factor, and interleukin-6 were nearly identical and, specifically, were not different in those patients who developed MOF. In summary, this prospective clinical study has not confirmed portal or systemic bacteremia within the first 5 days postinjury, despite an eventual 30% incidence of MOF.
The noninvasive assessment of intestinal permeability in humans has a 20-year history. Because the tests are increasingly used in clinical practice and research and because there is much controversy, we reviewed the literature and outlined the potential and possible shortcomings of these procedures. Data was obtained from personal files and from a systemic search through MEDLINE and EMBASE. The principle of the differential urinary excretion of orally administered test markers is explained with reference to the desired physicochemical properties of the markers and how the principle can be exploited to allow assessment of various other gastrointestinal functions. The use of intestinal permeability tests for diagnostic screen for small bowel disease and assessment of responses to treatment, the pathogenesis of disease, normal intestinal physiology, and the effect of drugs and toxins on the intestine is described and reviewed. The controversy surrounding the anatomic location of the permeation pathways that the markers use is highlighted. Noninvasive tests of intestinal permeability have fulfilled early promises of usefulness in clinical practice and research. There is now a need for integrated research into the basic mechanisms of regulatory control of the intestinal barrier function.
Mitochondrial and cytosolic aconitases have been indicated as major targets of .NO- and O2-.-mediated toxicity in cells due to the oxidant-mediated disruption of the [4Fe-4S] prosthetic group. However, under circumstances in which both .NO and O2-. are generated, their almost diffusion-controlled combination reaction (k = 6.7 x 10(9) M-1 s-1), leading to the formation of peroxynitrite anion (ONOO-), can out-compete the direct reactions of .NO and O2-. with aconitase and even the enzymatic dismutation of O2-. by superoxide dismutase. In this work, we report that ONOO- reacts with isolated pig heart mitochondrial aconitase at 1.4 x 10(5) M-1 s-1, resulting in a significant loss of enzymatic activity. Aconitase activity was totally recovered after postincubation with thiols and ferrous iron, indicating that ONOO- reactions with the enzyme involve the perturbation of the labile Fe alpha to yield the inactive [3Fe-4S] cluster, which is also evident by spectral changes. On the other hand, anaerobic exposure of isolated aconitase to high concentrations of .NO (> 100 microM) led to a moderate inhibition of the enzyme, which could be fully overcome by .NO displacement under an argon-saturated atmosphere, in agreement with the formation of a reversible inhibitory complex between .NO and the active site of aconitase. Superoxide inactivated mitochondrial aconitase at (3.5 +/- 2) x 10(6) M-1 s-1, a reaction rate 3 orders of magnitude slower than its reaction rate with .NO. O2-. could represent the main mechanism of inactivation of the enzyme in systems in which it is formed without significant concomitant production of .NO. Our results imply that the mechanisms by which .NO and O2-. inactivate aconitase in cell systems may not be simple due to their direct reactions with the iron-sulfur cluster, but may rely on the formation of ONOO-.
OBJECTIVE--To determine the clinical benefits of selective decontamination of the digestive tract in patients treated in intensive care units. DESIGN--Meta-analysis of 22 randomised trials that compared different combinations of oral non-absorbable antibiotics, with or without a systemic component, with no treatment in controls. SUBJECTS--4142 patients seen in general and specialised intensive care units around the world. 2047 received some form of antibiotic treatment, the remainder no prophylaxis. DATA ANALYSIS--Each trial was reviewed through direct contact with study investigators. Data collected were: the randomisation procedure, number of patients, number excluded from the analysis, and numbers of respiratory tract infections and deaths. Data were combined according to an intention to treat analysis with the Mantel-Haenszel-Peto method. MAIN OUTCOME MEASURES--Respiratory tract infections and total mortality. RESULTS--Selective decontamination of the digestive tract significantly reduced respiratory tract infections (odds ratio 0.37; 95% confidence interval 0.31 to 0.43). The value of the common odds ratio for total mortality (0.90; 0.79 to 1.04) suggested at best a moderate treatment effect, reaching statistical significance only when the subgroup of trials of topical and systemic treatment combined was considered separately (odds ratio 0.80; 0.67 to 0.97). No firm conclusions could be drawn owing to large variations in patient mix and severity within and between trials. CONCLUSIONS--The findings strongly indicate that selective decontamination significantly reduces infection related morbidity in patients receiving intensive care. They also highlight why definite conclusions about the effect of prophylaxis on mortality cannot be drawn despite the large number of trials available. Based on the most favourable results obtained by pooling data from trials in which combined topical and systemic treatment was used it may be estimated that 6 (range 5-9) and 23 (13-139) patients would need to be treated to prevent one respiratory tract infection and one death respectively.
In its broadest terms, intestinal bacterial translocation can be defined as the passage of bacteria (both live and dead) and bacterial products (such as exotoxins, endotoxins, and cell wall fragments) from the intestinal lumen to otherwise sterile extraintestinal sites. Investigators studying immune mechanisms at mucosal surfaces have long recognized that epithelial uptake and processing of intestinal antigens is a complex process, needed not only to establish the immune status of the host, but to continually regulate the immune response (both inductive and suppressive) to intestinal antigens [1]. The transmigration of intestinal bacteria was initially viewed with skepticism by many physicians; however, in recent years, the existence of bacterial translocation (BT) has become generally accepted among clinicians, although the clinical significance of this process remains a subject of debate.
The gut serves not only as a physiologic portal for the entry of water and nutrients into the body, but also as a barrier limiting the systemic absorption of intraluminal microbes and/or microbial products. The intestinal epithelium per se represents a critical barrier against systemic absorption of intralumenal microbes and microbial products. The ability of the intestinal epithelium to selectively permit the absorption of nutrients, electrolytes, and water, but restrict the passage from the lumen of larger, potentially toxic hydrophilic compounds is thought to be mediated by the tight junctions (“zonula occludens”) surrounding each cell in the epithelial sheet [1]. Under normal circumstances, tight junctions exclude passive movement of hydrophilic noncharged compounds with a molecular radius > 11.5 Å [1]. Substances that are therefore prevented from paracellular transepithelial movement include the amphipathic compound, lipopolysaccharide (LPS) [2], as well as a variety of other bacteria-derived proinflammatory hydrophilic compounds, such as formyl-methionyl-leucyl-phenylalanine (FMLP)
Objective:
To examine the relationship between glutamine supplementation and hospital length of stay, complication rates, and mortality in patients undergoing surgery and experiencing critical illness.
Data sources:
Computerized search of electronic databases and search of personal files, abstract proceedings, relevant journals, and review of reference lists.
Study selection:
We reviewed 550 titles, abstracts, and articles. Primary studies were included if they were randomized trials of critically ill or surgical patients that evaluated the effect of glutamine vs. standard care on clinical outcomes. DATA EXTRACTION We abstracted relevant data on the methodology and outcomes of primary studies in duplicate, independently. DATA SYNTHESIS There were 14 randomized trials comparing the use of glutamine supplementation in surgical and critically ill patients. When the results of these trials were aggregated, with respect to mortality, glutamine supplementation was associated with a risk ratio (RR) of 0.78 (95% confidence interval [CI], 0.58-1.04). Glutamine supplementation was also associated with a lower rate of infectious complications (RR, 0.81; 95% CI, 0.64-1.00) and a shorter hospital stay (-2.6 days; 95% CI, -4.5 to -0.7). We examined several -specified subgroups. Although there were no statistically significant subgroup differences detected, there were some important trends. With respect to mortality, the treatment benefit was observed in studies of parenteral glutamine (RR, 0.71; 95% CI, 0.51-0.99) and high-dose glutamine (RR, 0.73; 95% CI, 0.53-1.00) compared with studies of enteral glutamine (RR, 1.08; 95% CI, 0.57-2.01) and low-dose glutamine (RR, 1.02; 95% CI, 0.52-2.00). With respect to hospital length of stay, all of the treatment benefit was observed in surgical patients (-3.5 days; 95% CI, -5.3 to -1.7) compared with critically ill patients (0.9 days; 95% CI, -4.9 to 6.8).
Conclusion:
In surgical patients, glutamine supplementation may be associated with a reduction in infectious complication rates and shorter hospital stay without any adverse effect on mortality. In critically ill patients, glutamine supplementation may be associated with a reduction in complication and mortality rates. The greatest benefit was observed in patients receiving high-dose, parenteral glutamine.
The incidence of multiple organ failure syndrome (MOFS) has increased dramatically in most intensive care units (ICU) in the United States and is now the leading cause of death after sepsis, trauma, and burns (1). Despite advances in resuscitation, availability of potent antibiotics, and modern techniques of organ support (2), the survival of critically ill patients with MOFS has not significantly improved since the syndrome was first described over 2 decades ago (3). In the ICU, the monitoring and management of critically ill patients with MOFS has relied, in large part, on readily available measurements of global hemodynamics and oxygen transport. Given the increased understanding of the special role of splanchnic hypoperfusion in the pathophysiology of sepsis and MOFS (4-5), investigators have focused more recently on regional blood flow and oxygen metabolism in these patients (6). In this article, we first present a clinical overview of sepsis and MOFS. Current concepts of the pathogenesis and pathophysiology of MOFS are discussed, with particular emphasis on the roles of splanchnic ischemia and gut barrier failure in the development of both sepsis and the maintenance of the systemic inflammatory response that leads to MOFS. Alterations in both global and regional oxygen transport in septic shock are described to emphasize the limitations of global monitoring in the assessment of splanchnic tissue oxygenation. The role of gastric tonometry in the monitoring of splanchnic oxygenation and its utility in critically ill patients is then analyzed. In addition, the effects and clinical implications of commonly used vasoactive agents on intestinal oxygenation are discussed. Finally, novel therapeutic strategies based on the 'gut-origin hypothesis' of MOFS are reviewed.
Background
Clostridium difficile can be recovered from many high-risk hospitalized patients receiving broad-spectrum antibiotic therapy. Clostridium difficile toxins A and B have been associated with increased intestinal permeability in vitro and there is growing evidence that increased intestinal permeability may be a common mechanism whereby enteric bacteria penetrate the intestinal epithelium.Hypothesis
Clostridium difficile–induced alterations in the intestinal barrier facilitate microbial penetration of the intestinal epithelium, which in turn facilitates the translocation of intestinal bacteria.Design
Mature Caco-2 enterocytes were pretreated with varying concentrations of toxin A or toxin B followed by 1 hour of incubation with pure cultures of either Salmonella typhimurium, Escherichia coli, or Proteus mirabilis. The effects of toxins A and B on enterocyte viability, cytoskeletal actin, and ultrastructural topography were assessed using vital dyes, fluorescein-labeled phalloidin, and scanning electron microscopy, respectively. The toxins' effects on bacterial adherence and bacterial internalization by cultured enterocytes were assessed using enzyme-linked immunosorbent assay and quantitative culture, respectively. Epithelial permeability was assessed by changes in transepithelial electrical resistance and by quantifying paracellular bacterial movement through Caco-2 enterocytes cultivated on permeable supports.Results
Neither toxin A nor toxin B had a measurable effect on the numbers of enteric bacteria internalized by Caco-2 enterocytes; however, both toxins were associated with alterations in enterocyte actin, decreased transepithelial electrical resistance, and increased bacterial adherence and paracellular transmigration.Conclusion
Clostridium difficile toxins A or B may facilitate bacterial adherence and penetration of the intestinal epithelial barrier.
• Alterations in intestinal permeability have been postulated to occur after thermal injury. We evaluated the status of intestinal permeability during the first 2 postburn weeks in 15 subjects by measuring the differential excretion of enterally administered lactulose and mannitol. The mean age and burn size of the patients were 32.7±3.6 years and 53.3%±5.1% of the total body surface area, respectively. Ten healthy volunteers were also studied. The lactulose-mannitol excretion ratio was 0.159±0.017 for the patients and 0.017±0.003 for controls. The increased ratio did not correlate with burn size or postburn day. Patients who developed significant clinical infections during their first 2 postburn weeks had lactulose-mannitol ratios on postburn day 2 that were significantly higher than those of controls and patients who did not develop infections. This suggests a relationship between susceptibility to infection and early alterations in intestinal permeability.
(Arch Surg. 1992;127:26-30)
Bacterial translocation is a phenomenon in which live bacteria cross the intestinal barrier. The definition may be broadened to include transmural passage of bacterial cell wall components such as lipopolysaccharide and peptidoglycan polysaccharide. After translocation, bacteria or their products reach the mesenteric lymph nodes. From there, it is possible that enteric bacteria, their cell wall components, or both may disseminate throughout the body, causing sepsis, shock, multisystem organ dysfunction, or death of the host. Bacterial translocation and its complications have been shown clearly to occur in animal models, but its existence and importance in humans has been difficult to ascertain. The purpose of this review is to evaluate the data from studies in humans on the occurrence of bacterial translocation and, more importantly, to evaluate its role as a cause of death in humans. Studies from trauma and intensive care centers often imply that bacterial translocation is a major contributor to sepsis, shock, and multisystem organ failure in humans. However, the data reviewed herein do not support that view clearly. Carefully designed studies are needed to determine the relevance of bacterial translocation in human disease.
Animal studies implicate gut bacterial translocation via the portal vein as a major factor in the pathogenesis of postinjury multiple organ failure (MOF). We therefore inserted portal vein catheters for sequential blood sampling in the operating room, at 6, 12, 24, and 48 hours, and 5 days postoperatively in 20 injured patients (13 blunt, seven penetrating; mean age, 34 years) requiring emergent laparotomy and who were at known risk for MOF. The mean Revised Trauma Score was 6.4 +/- 0.4, and the Injury Severity Score, 29.3 +/- 2.3. Twelve (60%) patients arrived in shock (SBP < 90 torr). Eight (2%) of 212 portal blood cultures were positive; seven were presumed contaminants. The only positive systemic culture (total, 212) was a Staphylococcus aureus on day 5 in a patient with a concurrent staphyloccal pneumonia. In the first 48 hours, we could not detect endotoxin in portal or systemic blood. Additionally, simultaneous portal and systemic blood levels of complement fragment C3a, tumor necrosis factor, and interleukin-6 were nearly identical and, specifically, were not different in those patients who developed MOF. In summary, this prospective clinical study has not confirmed portal or systemic bacteremia within the first 5 days postinjury, despite an eventual 30% incidence of MOF.
• Thermal injury may be associated with disruption of normal gut barrier integrity. To test this hypothesis, we assessed intestinal permeability with the nonmetabolizable, poorly absorbed disaccharide lactulose, which is efficiently excluded by the normal intestinal mucosa. Permeability studies were performed in 15 burned patients (aged 18 to 67 years; mean burn size, 40%) and 11 healthy controls. Lactulose, 10 g, was administered enterally, together with 5 g of mannitol as a control, and urinary excretion rates were determined. Lactulose excretion and the lactulose/mannitol excretion ratio increased threefold (160±30 vs 57±7 μmol and 0.113±0.033 vs 0.035±0.005) in the infected patients (sepsis score, 10±2; burn size, 38%±6%). In contrast, noninfected burn patients (sepsis score, 0) had permeability values similar to those of controls (66±10 μmol and 0.036±0.007). Permeability increased as the severity of infection increased. Infection in burn patients is associated with increased bowel permeability. The intestine may be a primary source of sepsis. Alternatively, the systemic response to infection may alter gut barrier function, which could facilitate translocation of bacteria and absorption of endotoxin.
(Arch Surg 1988;123:1313-1319)
The human gastrointestinal tract is colonized by a dense population of microorganisms, referred to as the bacterial flora. Although the gut provides a functional barrier between these organisms and the host, bacterial translocation is a common event in the healthy person. However, in critically ill patients, with various underlying diseases, this bacterial translocation may lead to infections and consequently to a further reduction in general health status. The mechanism of bacterial translocation is widely, and somehow controversially investigated in vitro and in animal models. In human studies, several diseases have been associated with bacterial translocation. However, methodological shortcomings, insufficient populations and conflicting results leave many open questions. This is also reflected in the various published therapeutic strategies. To overcome this problem more investigations in humans are needed, especially in techniques for detecting bacterial translocation.
Background:
We have shown that the combination of surgical stress and starvation in mice is associated with a defect in epithelial permeability and increased numbers of mucosa-associated Escherichia coli in the cecum. The aim of this study was to determine the specific role of mucosa-associated E coli on epithelial barrier dysfunction in this model.
Methods:
Cecal E coli were harvested from mice 48 hours after a sham operation (control mice) or after a 30% surgical hepatectomy with only water provided ad libitum (short-term starvation) after the surgical procedure. Strains were tested for their ability to adhere to and alter the transepithelial electrical resistance (TEER) of cultured young adult mouse colon epithelial cells. TEER changes were further characterized by mannitol fluxes to confirm a defect in paracellular permeability.
Results:
Strains of cecal E coli harvested from hepatectomy-starved mice adhered to and altered the permeability of young adult mouse colon cells, whereas E coli from the cecum of control mice were less adherent and had no effect on epithelial permeability. The effect of the strains harvested from mice after hepatectomy on the TEER of young adult mouse colon cells was inhibited by mannose and reversed by ciprofloxacin.
Conclusion:
The combination of surgical stress and short-term starvation is associated with a greater abundance of adherent and barrier-altering strains of E coli in the mouse cecum.
Objective.
—To determine the prevalence of intensive care unit (ICU)—acquired infections and the risk factors for these infections, identify the predominant infecting organisms, and evaluate the relationship between ICU-acquired infection and mortality.
Ischaemia-reperfusion injury (IRI) is of obvious relevance in situations where there is an interruption of blood supply to the gut, as in vascular surgery, or in the construction of free intestinal grafts. It is now appreciated that IRI also underlies the gut dysfunction that occurs in early shock, sepsis, and trauma. The events that occur during IRI are complex. However, recent advances in cellular biology have started to unravel these underlying processes. The aim of this review is to provide an outline of current knowledge on the mechanisms and consequences of IRI.
Initially, IRI appears to be mediated by reactive oxygen metabolites and, at a later stage, by the priming and activation of polymorphonuclear neutrophils (PMN). Ischaemia-reperfusion injury can diminish the barrier function of the gut, and can promote an increase in the leakage of molecules (intestinal permeability) or the passage of microbes across the wall of the bowel (bacterial trans-location). Ischaemia-reperfusion injury to the gut can result in the generation of molecules that may also harm distant tissues.
The TJ is a highly dynamic rate-limiting barrier for passive transepithelial solute flow. It is not only physiologically regulated but is modulated in various disease states as well. Such modulations occur as a result of epithelial cell interactions with immune cells or immune cell products and thus epithelial barrier function appears to be regulated in disease states.
Alterations in intestinal permeability reflect one component of intestinal epithelial barrier function. The objective of this study was to assess the degree of derangement of intestinal permeability in critically ill patients and to investigate the relationship of this to markers of disease severity and sepsis. Sixteen patients admitted to the intensive care unit for a variety of problems were studied with the severity of illness and degree of sepsis recorded daily. A differential sugar absorption test, using lactulose and mannitol as markers, was performed, and in 10 patients this was repeated after an interval of between 4-11 days. The use of the lactulose/mannitol (L/M) ratio corrects for variables unrelated to permeability such as gastric emptying. The L/M ratio was significantly higher in patients (median 0.98) compared to normal controls (median 0.008). The ratios showed no relation to disease severity or sepsis. These results establish that increased intestinal permeability occurs in the general ICU patient but that it is not uniquely related to sepsis. The extent of this abnormality suggests that further study is required to show the various influences on this process.
Bacterial translocation (BT) occurs after thermal injury in rodents in association with intestinal barrier loss. Infection complicating thermal injury may also affect the intestine producing bowel atrophy. To study these relationships, Wistar rats received either 30% scald followed by wound inoculation with Pseudomonas; 30% scald with pair feeding to infected animals; or sham injury as controls. On days 1, 4, and 7 after injury animals were killed with examination of the bowel and culture of the mesenteric lymph nodes (MLN), livers, spleens, and blood. All burned animals demonstrated BT to the MLN on day 1 after injury, but only burn-infected animals had continued BT on days 4 and 7, with progression of BT to the abdominal organs and blood. Burn injury and infection also resulted in significant atrophy of small bowel mucosa temporally associated with continued BT. Thus injury complicated by infection results in prolonged and enhanced bacterial translocation, perhaps due to failure to maintain the mucosal barrier.
There is increasing direct experimental and indirect clinical evidence to indicate that under certain conditions intestinal barrier function may be lost in trauma victims. No direct measurements, however, have been performed in patients to determine whether intestinal permeability is increased shortly after a major thermal injury in the absence of infection. Fifteen hemodynamically stable burn patients with burns on more than 20% of their body surface (39% +/- 12%) had their intestinal permeability measured within 24 hours of injury with use of the two nonmetabolizable sugars lactulose and mannitol as permeability markers. Lactulose absorption was fourfold higher in the patients (223 +/- 54 mumol) than in the controls (58 +/- 11 mumole; p less than 0.02), whereas the lactulose/mannitol ratio was threefold higher (5.2 vs 1.7; p less than 0.05). Thus intestinal permeability was increased in patients with moderate to major burn injuries shortly after injury.
Bacterial translocation and ileal and cecal injury have been shown to occur 24 h after limited periods of hemorrhagic shock. The present studies were performed to determine the temporal sequence of mucosal injury, permeability, and bacterial translocation after hemorrhagic shock. The results indicated that bacterial translocation and mucosal injury have occurred by 2 h after a 30-min episode of shock (mean arterial pressure 30 mm Hg). Although the histologic extent of the intestinal mucosal injury was less at 2 h postshock than at 24 h postshock, at both times intestinal barrier function was lost as measured by permeability to horseradish peroxidase. Since the role of translocating bacteria in potentiating the loss of intestinal barrier function after shock is unclear, the second goal was to determine whether the extent of shock-induced mucosal injury and permeability could be reduced or abrogated by antibiotic decontamination of the gut. The extent of shock-induced mucosal injury and intestinal permeability was similar between rats with a normal gut flora (greater than 10(6) bacteria/g cecum) and antibiotic-decontaminated rats (less than 10(3) bacteria/g cecum) 2 h postshock, although the incidences of bacterial translocation were 67% and 0, respectively. Thus, shock-induced mucosal permeability and injury appear not to be directly related to the presence of translocating bacteria.
• Indirect clinical evidence has accumulated indicating that the gut may be a reservoir for microorganisms causing systemic infection in man. Our experimental results, in a variety of animal models, demonstrate that bacteria can translocate across the mucosal barrier and cause systemic infections. To determine directly whether bacterial translocation occurs in man, we cultured mesenteric lymph nodes (MLNs) obtained at laparotomy from 42 patients, none of whom were clinically infected. Ten (59%) of 17 patients with intestinal obstruction (none of whom had necrotic bowel) had bacteria in their MLNs, in contrast to one (4%) of 25 patients operated on for other reasons. The most common bacteria cultured from the MLNs was Escherichia coli. Thus, it appeared that simple intestinal obstruction of the colon or small bowel in the absence of necrotic bowel was associated with bacterial translocation.
(Arch Surg 1989;124:699-701)
• Indirect clinical evidence has accumulated indicating that the gut may be a reservoir for microorganisms causing systemic infection in man. Our experimental results, in a variety of animal models, demonstrate that bacteria can translocate across the mucosal barrier and cause systemic infections. To determine directly whether bacterial translocation occurs in man, we cultured mesenteric lymph nodes (MLNs) obtained at laparotomy from 42 patients, none of whom were clinically infected. Ten (59%) of 17 patients with intestinal obstruction (none of whom had necrotic bowel) had bacteria in their MLNs, in contrast to one (4%) of 25 patients operated on for other reasons. The most common bacteria cultured from the MLNs was Escherichia coli. Thus, it appeared that simple intestinal obstruction of the colon or small bowel in the absence of necrotic bowel was associated with bacterial translocation.
(Arch Surg 1989;124:699-701)
1. Factors affecting the intestinal uptake and urinary excretion of mannitol, lactulose and 51Cr-labelled ethylenediaminetetra-acetate (51Cr-EDTA), have been investigated in normal subjects and three patients with ileostomy.
2. The distribution volume of markers within the body, the rate of disappearance from plasma and renal clearance were assessed after an intravenous injection of a mixture of mannitol (2 g), [14C]mannitol (10 μCi), lactulose (0.1 g) and 51Cr-EDTA (5 μCi).
3. The urinary recovery of all the intravenously administered markers was close to 100%. Distribution volumes and patterns of excretion were virtually identical. Oxidation of intravenously administered mannitol accounted for only about 1% of the dose.
4. The passage of an orally administered mixture of markers was traced through the intestine and into urine. Transit time through the gastrointestinal tract was measured by the breath hydrogen method and by radionuclide scanning.
5. The passage of markers from mouth to the large bowel was essentially complete by 3.5 h. In some subjects the marker appeared in the large bowel as early as 30–40 min but in others it took three times as long.
6. After an oral dose the urinary excretion of mannitol fell progressively from 2 to 6 h, whereas the excretion of lactulose and 51Cr-EDTA increased slightly. As a consequence the lactulose/mannitol and 51Cr-EDTA/mannitol ratios in urine collected between 0 and 2 h were more than twofold higher than in urine collected between 4 and 6 h (P < 0.001). After 6 h, the urinary excretion of mannitol and lactulose declined rapidly in all subjects, and was similar to the pattern of excretion of 51Cr-EDTA in subjects with an ileostomy. In contrast, in normal subjects, the excretion of 51Cr-EDTA did not decline rapidly but continued for 24–48 h.
7. Differences in the excretion of mannitol, lactulose and 51Cr-EDTA after oral dosing is due to differences in the temporal pattern of absorption of these markers and not to differences in their distribution volume, oxidation or their clearance by the kidney.
8. The data suggest that the uptake of lactulose by the small intestine persists for longer than the uptake of mannitol, and show that 51Cr-EDTA is readily absorbed in the colon. This study indicates factors which must be considered in the design and interpretation of tests of small intestinal permeability.
Administration of an elemental diet to rats given methotrexate (MTX), 20 mg/kg intraperitoneally (ip), results in 100% mortality from severe enterocolitis. Previous studies indicate that glutamine (GLN), which is not present in elemental diets, is the preferred oxidative substrate for the gut' and may facilitate intestinal recovery after injury. ² This study investigated the effects of a glutamine‐supplemented elemental diet (GLN‐ED) on nutritional status, intestinal morphometry, bacterial translocation and survival in this lethal model of intestinal injury. Three experiments were performed. In the first experiment, rats received an intragastric elemental diet supplemented with either 2% GLN or an equivalent amount of glycine (Control). After 4 days animals received either MTX, 20 mg/kg ip, or saline ip and were killed 3 days later. The GLN‐ED resulted in significantly decreased weight loss, improved nitrogen retention, and increased mucosal weight, protein, and DNA content of the jejunum and colon.
In the second experiment rats were assigned to diet as in the first experiment, but all animals received MTX. Control diet animals died within 120 hrs of MTX administration. The GLN‐ED group had significantly longer survival time and decreased mortality.
In the third experiment animals were assigned to diet and MTX as in the first experiment. Ninety‐six hrs later aortic blood cultures revealed enteric bacteremia in animals administered MTX. GLN‐ED resulted in a significant reduction in the incidence of bacteremia.
These experiments showed that a GLN‐ED significantly improved nutritional status, decreased intestinal injury, decreased bacterial translocation, and resulted in improved survival in a lethal model of enterocolitis. (Journal of Parenteral and Enteral Nutrition 12 :325–331, 1988)
Thermal injury may be associated with disruption of normal gut barrier integrity. To test this hypothesis, we assessed intestinal permeability with the nonmetabolizable, poorly absorbed disaccharide lactulose, which is efficiently excluded by the normal intestinal mucosa. Permeability studies were performed in 15 burned patients (aged 18 to 67 years; mean burn size, 40%) and 11 healthy controls. Lactulose, 10 g, was administered enterally, together with 5 g of mannitol as a control, and urinary excretion rates were determined. Lactulose excretion and the lactulose/mannitol excretion ratio increased threefold (160 +/- 30 vs 57 +/- 7 mumol and 0.113 +/- 0.033 vs 0.035 +/- 0.005) in the infected patients (sepsis score, 10 +/- 2; burn size, 38% +/- 6%). In contrast, noninfected burn patients (sepsis score, 0) had permeability values similar to those of controls (66 +/- 10 mumol and 0.036 +/- 0.007). Permeability increased as the severity of infection increased. Infection in burn patients is associated with increased bowel permeability. The intestine may be a primary source of sepsis. Alternatively, the systemic response to infection may alter gut barrier function, which could facilitate translocation of bacteria and absorption of endotoxin.
Previous investigations of a treated model of hemorrhagic shock in the rat indicated the frequent occurrence of bacteremia that appeared to derive from the gut. This paper determines the incidence of bacteremia and endotoxemia during the acute shock period and compares this with similar observations in humans in varying degrees of shock. Studies in 26 rats indicated that bacteremia and endotoxemia was present in 50% and 87%, respectively, by the end of 2 hours at a mean arterial pressure of 30 mmHg. Observations in 50 patients admitted to the trauma unit showed that positive bacterial blood cultures were present in 56% when the admission systolic blood pressure was 80 mmHg or less (p less than 0.01 compared with either of the other groups). Endotoxemia was noticed in two such patients. Direct access of bacteria and endotoxin to the blood stream may occur during hemorrhagic or traumatic shock and is the probable cause of subsequent sepsis in traumatized patients when no other source is apparent.
A quantitative endotoxin assay was applied in this study of endotoxin transport from the infected abdomen. In rats with fecal peritonitis, extremely high concentrations were found in thoracic duct lymph (approximately 400 times higher than those found in arterial and portal vein plasma). Taking flow rates into account, the thoracic duct carries 34 ng/hour and the protal vein 49 ng/hour after 2 hours of peritonitis. Endotoxin quantities transported by the portal vein never exceed the proposed endotoxin filtrating capacity of the liver. Furthermore, the onset of systemic endotoxemia parallels the appearance of endotoxin in the thoracic duct. The hypothesis put forward is that the development of systemic endotoxemia is mainly mediated by lymphatic transport. The results also indicate that endotoxin is normally absorbed from the intestine and transported by portal blood.
As multiple-organ failure (MOF) has been generally associated with sepsis, the importance of bacterial sepsis was evaluated retrospectively in 55 trauma and 37 intra-abdominal-sepsis patients with MOF. The severity of MOF was graded, and an analysis was made of day of onset, incidence, severity, sequence, and mortality of organ failures. No difference was found between groups in sequence, severity, or mortality of organ failures. In contrast, bacterial sepsis was found in 65% of intra-abdominal-sepsis patients but only in 33% of trauma patients. It is concluded that sepsis is probably not the essential cause of MOF. Instead, an alternative hypothesis is presented involving massive activation of inflammatory mediators by severe tissue trauma or intra-abdominal sepsis, resulting in systemic damage to vascular endothelia, permeability edema, and impaired oxygen availability to the mitochondria despite adequate arterial oxygen transport.
The results of previous studies indicate that oxygen-derived free radicals are responsible for the increased vascular permeability produced by 1 h of intestinal ischemia. The aims of this study were 1) to test the hypothesis that the enzyme xanthine oxidase is the source of oxygen radicals in the ischemic bowel and 2) to assess the role of the hydroxyl radical in the ischemia-induced vascular injury. The capillary osmotic reflection coefficient was estimated from lymphatic protein flux data in the cat ileum for the following conditions: ischemia, ischemia plus pretreatment with allopurinol (a xanthine oxidase inhibitor), and ischemia plus pretreatment with dimethyl sulfoxide (a hydroxyl radical scavenger). The increased vascular permeability produced by ischemia was largely prevented by pretreatment with either allopurinol or dimethyl sulfoxide. These findings support the hypothesis that xanthine oxidase is the source of oxygen radicals produced during ischemia. The results also indicate that hydroxyl radicals, derived from the superoxide anion, are primarily responsible for the vascular injury associated with intestinal ischemia.
TNF-alpha is a widely distributed proinflammatory cytokine, involved in many disease states. Although it has widely distributed effects, a precise mechanism of action has never been described, in particular at the epithelial level. Morpho-functional changes of the intestinal epithelial monolayer HT29 cl.19A exposed to TNF-alpha were therefore assessed, using electron microscopy (including freeze-fracture replica analysis), as well as measurement of mannitol, Na+ and horseradish peroxidase fluxes across intestinal HT29 cl.19A cell monolayers using Ussing chambers. TNF-alpha receptors were induced on HT29 cl.19A cells by a small non-toxic dose of IFN-gamma (5 U/ml). After 4 h of the combined presence of TNF-alpha (10 ng/ml) and IFN-gamma (5 U/ml), the tight junction structure was altered as shown by a significant decrease in the average strand number measured in the apico-basal direction (5.50 +/- 2.70 vs 3.73 +/- 1.39 in control and treated cells respectively, P < 0.0001) and by a significant decrease in junctional depth (0.27 +/- 0.14 and 0.17 +/- 0.10 microns in control and treated cells respectively, P < 0.0001). These results are in agreement with a decrease in number of 'kiss' sites between contiguous membranes of TNF-alpha treated cells observed in ultrathin sections.(ABSTRACT TRUNCATED AT 250 WORDS)
During a nosocomial outbreak of infection due to vancomycin-resistant enterococci (VRE), rectal swabs that were collected
weekly were used to identify and isolate VRE carriers. Over 6 months, 1,458 stool specimens from 724 high-risk patients were
cultured, and 187 VRE isolates were recovered from 61 patients; 96% of the isolates were Enterococcus faecium. VRE tended to be isolated from clinical specimens from patients identified as VRE carriers by stool surveillance (P < .01). However, isolation of VRE from surveillance cultures preceded clinical isolation for only ∼50% of the patients from
whom a clinical VRE isolate was recovered. Mortality was greater (P < .05) among patients from whom a clinical VRE isolate was recovered than among patients from whom VRE was isolated only
by stool surveillance. The mortality (1 [17%] of 6) among patients for whom VRE was isolated from blood was similar to that
(10 [27%] of 37) among patients for whom vancomycin-susceptible enterococcus was isolated from blood (P = .97). Despite prompt initiation of contact precautions for VRE carriers, the incidence of fecal carriage of VRE remained
∼8% among this patient population for the 6-month period of the study.
To develop an objective scale to measure the severity of the multiple organ dysfunction syndrome as an outcome in critical illness.
Systematic literature review; prospective cohort study.
Surgical intensive care unit (ICU) of a tertiary-level teaching hospital.
All patients (n = 692) admitted for > 24 hrs between May 1988 and March 1990.
None.
Computerized database review of MEDLINE identified clinical studies of multiple organ failure that were published between 1969 and 1993. Variables from these studies were evaluated for construct and content validity to identify optimal descriptors of organ dysfunction. Clinical and laboratory data were collected daily to evaluate the performance of these variables individually and in aggregate as an organ dysfunction score. Seven systems defined the multiple organ dysfunction syndrome in more than half of the 30 published reports reviewed. Descriptors meeting criteria for construct and content validity could be identified for five of these seven systems: a) the respiratory system (Po2/FIO2 ratio); b) the renal system (serum creatinine concentration); c) the hepatic system (serum bilirubin concentration); d) the hematologic system (platelet count); and e) the central nervous system (Glasgow Coma Scale). In the absence of an adequate descriptor of cardiovascular dysfunction, we developed a new variable, the pressure-adjusted heart rate, which is calculated as the product of the heart rate and the ratio of central venous pressure to mean arterial pressure. These candidate descriptors of organ dysfunction were then evaluated for criterion validity (ICU mortality rate) using the clinical database. From the first half of the database (the development set), intervals for the most abnormal value of each variable were constructed on a scale from 0 to 4 so that a value of 0 represented essentially normal function and was associated with an ICU mortality rate of < 5%, whereas a value of 4 represented marked functional derangement and an ICU mortality rate of > or = 50%. These intervals were then tested on the second half of the data set (the validation set). Maximal scores for each variable were summed to yield a Multiple Organ Dysfunction Score (maximum of 24). This score correlated in a graded fashion with the ICU mortality rate, both when applied on the first day of ICU admission as a prognostic indicator and when calculated over the ICU stay as an outcome measure. For the latter, ICU mortality was approximately 25% at 9 to 12 points, 50% at 13 to 16 points, 75% at 17 to 20 points, and 100% at levels of > 20 points. The score showed excellent discrimination, as reflected in areas under the receiver operating characteristic curve of 0.936 in the development set and 0.928 in the validation set. The incremental increase in scores over the course of the ICU stay (calculated as the difference between maximal scores and those scores obtained on the first day [i.e., the delta Multiple Organ Dysfunction Score]) also demonstrated a strong correlation with the ICU mortality rate. In a logistic regression model, this incremental increase in scores accounted for more of the explanatory power than admission severity indices.
This multiple organ dysfunction score, constructed using simple physiologic measures of dysfunction in six organ systems, mirrors organ dysfunction as the intensivist sees it and correlates strongly with the ultimate risk of ICU mortality and hospital mortality. The variable, delta Multiple Organ Dysfunction Score, reflects organ dysfunction developing during the ICU stay, which therefore is potentially amenable to therapeutic manipulation. (ABSTRACT TRUNCATED)
To assess the literature documenting the existence of bacterial translocation in humans, the effects of enteral nutrition on bacterial translocation in humans, and the hypothesis that enteral nutrition prevents bacterial translocation in humans.
Sources included Medline search, references from review articles, and references from animal and human studies.
The goal was to include all animal and human studies directly addressing questions of bacterial translocation and nutritional status or nutritional support.
An attempt was made to briefly summarize methodology and findings of relevent studies. No general attempt was made to assess quality of individual studies.
Bacterial translocation is a well documented phenomenon in animal models. Starvation and malnutrition of themselves do not induce bacterial translocation, but may facilitate translocation in the presence of other systemic insults. Parenteral nutrition and many forms of enteral nutrition may induce and/or facilitate bacterial translocation. Chow and certain fiber sources seem protective. Moderate direct and several lines of indirect evidence support the existence of bacterial translocation in humans. There is no direct evidence and questionable indirect evidence suggesting that enteral nutrition prevents or modifies bacterial translocation in humans.
The hypothesis relating enteral nutrition and bacterial translocation in critically ill patients remains attractive, but unproven.
To determine the prevalence of intensive care unit (ICU)-acquired infections and the risk factors for these infections, identify the predominant infecting organisms, and evaluate the relationship between ICU-acquired infection and mortality.
A 1-day point-prevalence study.
Intensive care units in 17 countries in Western Europe, excluding coronary care units and pediatric and special care infant units.
All patients (> 10 years of age) occupying an ICU bed over a 24-hour period. A total of 1417 ICUs provided 10 038 patient case reports.
Rates of ICU-acquired infection, prescription of antimicrobials, resistance patterns of microbiological isolates, and potential risk factors for ICU-acquired infection and death.
A total of 4501 patients (44.8%) were infected, and 2064 (20.6%) had ICU-acquired infection. Pneumonia (46.9%), lower respiratory tract infection (17.8%), urinary tract infection (17.6%), and bloodstream infection (12%) were the most frequent types of ICU infection reported. Most frequently reported micro-organisms were Enterobacteriaceae (34.4%), Staphylococcus aureus (30.1%;[60% resistant to methicillin], Pseudomonas aeruginosa (28.7%), coagulase-negative staphylococci (19.1%), and fungi (17.1%). Seven risk factors for ICU-acquired infection were identified: increasing length of ICU stay (> 48 hours), mechanical ventilation, diagnosis of trauma, central venous, pulmonary artery, and urinary catheterization, and stress ulcer prophylaxis. ICU-acquired pneumonia (odds ratio [OR], 1.91; 95% confidence interval[Cl], 1.6 to 2.29), clinical sepsis (OR, 3.50; 95% Cl, 1.71 to 7.18), and bloodstream infection (OR, 1.73; 95% Cl, 1.25 to 2.41) increased the risk of ICU death.
ICU-acquired infection is common and often associated with microbiological isolates of resistant organisms. The potential effects on outcome emphasize the importance of specific measures for infection control in critically ill patients.
Glutamine has been shown to be an important dietary component for the maintenance of gut metabolism. The purpose of this study was to assess the potential benefit of glutamine-enriched diets on experimental gut-derived sepsis.
BALB/c mice were fed either 2% glutamine-supplemented or 1% glycine-supplemented (near-isonitrogenous control) AIN-76A diets. Control mice received either nonsupplemented AIN-76A or regular Purina Rodent Laboratory Mouse Chow 5001 diets. After 10 days of feeding, the mice were transfused with allogeneic blood (from C3H/HeJ mice), and the feeding protocols were continued for an additional 5 days. The mice then underwent gavage with 10(10) Escherichia coli labeled with either indium-111 oxine or [14C]glucose followed immediately by a 20% burn injury. Some mice were observed 10 days postburn for survival rates. Others were killed 4 hours after burn, and the mesenteric lymph nodes, liver, and spleen were harvested to determine radionuclide and bacterial colony counts. The percentages of viable translocated E coli were also calculated.
Mice fed glutamine-enriched diets had a lower degree of translocation (as measured by both radionuclide and bacterial counts) to the tissues than did the other groups and had an improvement in the ability to kill translocated E coli (as measured by the percentage of viable bacteria). Survival was significantly higher in the group fed 2% glutamine (81%) compared with the groups fed 1% glycine (36%), AIN-76A (35%), and Purina Rodent Laboratory Mouse Chow 5001 (36%) diets (p < .004).
Glutamine-supplemented enteral diets may exert important benefits in preventing gut-origin sepsis after trauma.
Long-term total parenteral nutrition is accompanied with mucosal atrophy and subsequent malabsorption syndrome. Current information attests the important role of glutamine in maintaining intestinal structure and function. The aim of this study was to investigate the effect of glutamine dipeptide supplementation on small intestinal absorption capacity during critical illness.
Twelve intensive care unit patients were uniformly randomized to receive isonitrogenous (0.26 g nitrogen.kg-1.day-1) and isoenergetic (155 kJ.kg-1.day-1) parenteral nutrition over 9 days. The control group received a conventional amino acid solution (1.5 g amino acids.kg-1.day-1), and the test group received a complete amino acid solution containing the dipeptide L-alanyl-L-glutamine (20 g/L). On days 8 and 9, a modified D-xylose test was performed.
Excretion of D-xylose during the 5-hour test period was 7.4 +/- 1.1 g (test) vs. 3.8 +/- 0.9 g (control) (P < 0.05). The 2-hour serum D-xylose concentration was 38.7 +/- 3.0 (test) vs. 27.8 +/- 2.9 mg/100 mL (control) (P < 0.05). Kinetic evaluation showed higher maximum D-xylose blood concentration and higher values for the area under the curve with the peptide.
The results strongly suggest that glutamine dipeptide-containing total parenteral nutrition prevents intestinal atrophy and increased permeability associated with glutamine-free parenteral nutrition.
Gut permeability was studied in multiply injured patients with respect to the development of multiple organ failure (MOF). Two groups were defined according to MOF score (threshold 10 points) as to whether MOF developed (group 1; n = 11, four deaths) or did not (group 2; n = 21, no death). Gut permeability was determined from the ratio of urinary excretion of enterally administered lactulose and mannitol. Serum elastase concentrations were also determined. Mean(s.e.m.) gut permeability was abnormal during the entire study (day 1: group 1--5.1(2.1) versus group 2--10.6(4.1) (P not significant; P < 0.001 versus normal volunteers, 0.56(0.24)). An increase on days 3 and 5 correlated with serum elastase levels only in patients in group 1 (rs = 0.71, P < 0.01). Severe injury leads to increased intestinal permeability, which is related to a systemic inflammatory response.
Gut translocation of enteric organisms across the intact intestinal mucosa has been postulated as a potential source of sepsis in susceptible patients. However, little is known of its occurrence or significance in humans. The aim of this study was to determine the prevalence of gut translocation of bacteria in humans and attempt to identify any predisposing factors to its occurrence.
A consecutive series of 267 general surgical patients were examined for evidence of bacterial translocation by bacterial analysis of intestinal serosa and mesenteric lymph nodes taken at the time of surgery.
Translocation occurred in 10.3% of patients overall. Both aerobic and anaerobic bacteria translocated. Excluding patients with distal intestinal obstruction and those with inflammatory bowel disease in whom translocation was more common, the prevalence was 5%. Neither jaundice, nutritional status, nor total parenteral nutrition predisposed to translocation. Similarly, mucosal atrophy did not predispose to this phenomenon. The development of postoperative septic complications was twice as common in patients with translocation as in those without, but mortality was unaffected.
Translocation occurs as a spontaneous event in humans, but its clinical significance remains to be defined.