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PubMed1997

An intestinal mucin is the target substrate for a baculovirus enhancin.

An invertebrate intestinal mucin (IIM) was identified from a lepidopterous insect, Trichoplusia ni. The IIM is a major protein constituent of the peritrophic membrane that facilitates the digestive process, as well as protecting invertebrate digestive tracts from microbial infections. The IIM demonstrated biochemical characteristics similar to vertebrate mucins, but exhibited strong association with the chitin-containing peritrophic membrane matrix. We have demonstrated that a baculovirus enhancin, which is encoded and carried by specific baculoviruses, has mucin-degrading activity both in vitro and in vivo. The in vivo degradation of IIM by enhancin was correlated with the enhancement of baculovirus infections in insects. These findings have shown that viruses have evolved a novel strategy to overcome intestinal mucinous barriers against microorganisms by utilizing a mucin-degrading enzyme.

Animals↗

PubMed2001

Beneficial effects of growth hormone on bacterial translocation during the course of acute necrotizing pancreatitis in rats.

Because bacterial translocation from the gut is one of the important sources of bacterial infection in acute necrotizing pancreatitis (ANP) and growth hormone (GH) has the ability to promote the intestinal epithelial proliferation, we investigated the effects of GH on bacterial translocation in a rat ANP model. ANP was induced in rats by injection of 5% sodium taurocholate into the biliopancreatic duct. The rats with ANP were treated with either human recombinant GH or placebo. Laparotomized animals without induction of ANP (sham operation [SO]) served as controls. At 24 hours after operation, blood was drawn for bacterial culture and determination of amylase, lipase, and endotoxin. Peritoneal fluid and specimens of mesenteric lymph nodes (MLN), liver, pancreas, and spleen were taken for bacterial culture by standard techniques. Intestinal mucosal permeability was assessed by measuring the movement of 125I-labeled albumin from blood to intestinal lumen. Insulin-like growth factor-1 (IGF-1) mRNA was detected in the liver and ileum by reverse transcriptase-polymerase chain reaction (RT-PCR). Morphologic changes of pancreas and ileum were also analyzed. Administration of GH significantly decreased the serum amylase, lipase activities, plasma endotoxin level, and incidence of bacterial translocation. Moreover, the survival rate of ANP rats was improved. The severity of inflammation in pancreas and ileum was alleviated by GH treatment. Ileal mucosal thickness, villus height, and crypt depth in GH treatment rats were obviously increased compared with those of ANP rats. The intestinal permeability was markedly improved in the GH group versus the ANP group. GH treatment resulted in up-regulation of IGF-1 mRNA expression in ileum, but not in liver. These results suggested that exogenous GH had beneficial effects in maintaining the integrity of intestinal mucosal barrier and reducing the incidence of bacterial translocation in rats with ANP. One of the mechanisms might be the up-regulation of IGF-1 mRNA in intestine by GH treatment.

Amylases↗

PubMedDate not supplied

Cell culture techniques for the study of drug transport.

The growth of differentiated cell monolayers on microporous filters is providing powerful new techniques for investigating the transport of drug and delivery systems across defined cellular barriers, and for discriminating between different routes and mechanisms. The growth, characterization and potential use of these systems is illustrated by studies on the human Caco-2 cell system which provides an in vitro model of the intestinal epithelial barrier. This system, still in the early stages of characterization and development, displays a number of carrier-mediated and vesicular transport systems found in the intestine in vivo, and is thus providing a useful system for studying the intestinal transport of drugs including peptides and proteins.

Biological Transport↗

PubMed2006

Inflammatory bowel disease and the apical junctional complex.

A critical function of the intestinal mucosa is to form a barrier that separates luminal contents from the underlying interstitium. This intestinal barrier is primarily regulated by the apical junctional complex (AJC) consisting of tight junctions (TJs) and adherens junctions (AJs) and is compromised in a number of intestinal diseases, including inflammatory bowel disease (IBD). In vitro studies have demonstrated that proinflammatory cytokines, such as interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha), that are increased in the intestinal mucosa of patients with IBD can induce a leaky mucosal barrier. There is a growing evidence that the increased permeability and altered AJC structure observed in IBD are mediated by internalization of junctional proteins. This review summarizes barrier defects observed in IBD and addresses mechanisms by which proinflammatory cytokines, such as IFN-gamma and TNF-alpha, modulate AJC structure and epithelial barrier function.

Adherens Junctions↗

PubMed2005

Lipopolysaccharide-induced changes in mesenteric afferent sensitivity of rat jejunum in vitro: role of prostaglandins.

Bacterial translocation across the intestinal mucosal barrier leads to a macrophage-mediated inflammatory response, visceral hyperalgesia, and ileus. Our aim was to examine how mediators released into mesenteric lymph following LPS treatment influence intestinal afferent sensitivity and the role played by prostanoids in any sensitization. Intestinal lymph was collected from awake rats following treatment with either saline or LPS (5 mg/kg ip). Extracellular multiunit afferent recordings were made from paravascular mesenteric nerve bundles supplying the rat jejunum in vitro following arterial administration of control lymph, LPS lymph, and LPS. Mesenteric afferent discharge increased significantly after LPS lymph compared with control lymph. Peak discharge occurred within 2 min and remained elevated for 5 to 8 min. This response was attenuated by pretreatment with naproxen (10 microM), and restored upon addition of prostaglandin E(2) (5 microM) in the presence of naproxen, but AH6809 (5 microM), an EP(1)/EP(2) receptor(s) antagonist, failed to decrease the magnitude of LPS lymph-induced response. LPS itself also stimulated mesenteric afferent discharge but was unaffected by naproxen. TNF-alpha was significantly increased in LPS lymph compared with control lymph (1,583 +/- 197 vs. 169 +/- 38 pg/ml, P < 0.01) but exogenous TNF-alpha failed to evoke any afferent nerve discharge. We concluded that inflammatory mediators released from the gut into mesenteric lymph during endotoxemia have a profound effect on afferent discharge. These mediators influence afferent firing via the release of local prostaglandins.

Animals↗

PubMed2002

Interferon-gamma expression by intraepithelial lymphocytes results in a loss of epithelial barrier function in a mouse model of total parenteral nutrition.

OBJECTIVE: To determine the etiology of the loss of epithelial barrier function observed with the administration of total parenteral nutrition (TPN) in a mouse model. SUMMARY BACKGROUND DATA: Removal of enteral nutrition with the administration of TPN is associated with a loss of intestinal epithelial barrier function. The etiology of this barrier loss is not clear. Because intraepithelial lymphocytes (IELs) produce a number of cytokines that may alter epithelial permeability, the authors investigated IEL cytokine expression in a mouse model of TPN. METHODS: Adult C57BL/6 mice received TPN or enteral diet for 7 days. IELs were subsequently harvested and the mRNA expression of cytokines was measured. Epithelial barrier function was assessed in vitro with 51Cr-EDTA in Ussing chambers and was expressed as the permeability coefficient (Papp). RESULTS: IEL mRNA expression of interferon-gamma (IFN-gamma) rose from 0.14 +/- 0.07 in the control (enterally fed) group to 0.44 +/- 0.11 attomoles/microL in the TPN group (P <.05). Transforming growth factor-beta1 declined slightly but not significantly, from 0.75 +/- 0.35 to 0.55 +/- 0.18 attomoles/microL in the control and TPN groups, respectively. Epithelial barrier function declined significantly with TPN compared to controls. To assess the relevance of IFN-gamma changes, permeability in IFN-gamma knockout mice was studied. Barrier function was significantly higher in IFN-gamma knockout mice on TPN compared to C57BL/6 mice that received TPN. CONCLUSIONS: IEL cytokine expression changes significantly with TPN administration. The partial correction with IFN-gamma knockout mice suggests that an upregulation of IFN-gamma expression is one mechanism responsible for the loss of the epithelial barrier associated with TPN.

Animals↗

PubMed1990

Gut barrier function and the surgeon.

There is accumulating evidence that multiple organ failure is not always the result of an established septic focus. Increasing attention has centred on the gut as a reservoir of bacteria (and bacterial endotoxins) that can traverse the intestinal mucosal barrier (a process called 'bacterial translocation') and initiate the septic state. Although the link between haemorrhagic shock and sepsis was recognized decades ago, the full experimental demonstration of this phenomenon is more recent. It was shown to occur in three main settings: physical disruption of the gut mucosa, impaired defence mechanisms and altered gut microbial ecology. Conditions such as haemorrhagic shock, burns, protein malnutrition and sepsis are seen in the severely ill surgical patient or the multiply injured, and are known to cause various combinations of circumstances favourable to bacterial translocation and endotoxin absorption. These may play an important role in the mortality of the critically ill.

Animals↗

PubMed2003

Pseudomonas aeruginosa expresses a lethal virulence determinant, the PA-I lectin/adhesin, in the intestinal tract of a stressed host: the role of epithelia cell contact and molecules of the Quorum Sensing Signaling System.

OBJECTIVE: We have previously demonstrated that P. aeruginosa can have profound effects on the intestinal epithelial barrier via one of its virulence factors, the PA-I lectin/adhesin. The aims of the present study were to further characterize the interaction of P. aeruginosa and the intestinal epithelium using both in vitro and in vivo approaches. METHODS: In vitro assays examining the effect of bacterial growth phase, epithelial cell contact, and butanoyl homoserine lactone (C4-HSL), a quorum sensing signaling molecule know to affect various extracellular virulence factors in P. aeruginosa, on PA-I expression in P. aeruginosa were performed. In vivo studies were carried out by modeling catabolic stress in mice using a 30% surgical hepatectomy and direct introduction of P. aeruginosa and various virulence components into the cecum. The effect of this model on PA-I expression in P. aeruginosa was determined. RESULTS: Results demonstrated that PA-I expression in P. aeruginosa is affected by its phase of growth, its contact to the intestinal epithelium, and its exposure to the quorum sensing molecule, C4-HSL. Furthermore, data from the present study suggest that the PA-I lectin/adhesin of P. aeruginosa may be increased in vivo by local factors within the cecum of mice in response to surgical stress. CONCLUSIONS: These data indicate that multiple factors present in the intestinal microenvironment of a stressed host may induce certain opportunistic pathogens to express key virulence factors leading to a state of lethal gut-derived sepsis.

Adhesins, Bacterial↗

PubMed2003

Cytokine activation and intestinal mucosal and renal dysfunction are reduced in endovascular AAA repair compared to surgery.

PURPOSE: To compare endovascular (EVR) to open repair (OR) of abdominal aortic aneurysm (AAA) for cytokine activation, changes in the intestinal mucosal barrier, and renal dysfunction. METHODS: In a prospective nonrandomized study, 15 patients admitted to a university hospital for elective infrarenal AAA repair (8 OR and 7 EVR) were recruited. Intestinal permeability was assessed preoperatively (PO), at day 1 (D1), and at day 3 (D3) after surgery using the lactulose/mannitol differential excretion (LMR) test. Renal damage was assessed from measurements of the urinary albumin:creatinine ratio (ACR); cytokine activation was based on the urinary concentration of tumor necrosis factor receptor p55 (TNF-Rp55) at the same time points. Serum creatinine and urea concentrations were measured preoperatively and daily for 5 days postoperatively. RESULTS: A significant increase in LMR was found in the OR group at D1 and D3 compared to PO (p<0.05). The LMR increase at D3 was significantly greater in the OR group (p<0.01). A significant difference was observed in the percentage rise in ACR on D1 in the OR group compared to the EVR group (p<0.005). The urinary TNF-Rp55 concentration was significantly elevated in the OR group at D1 (p<0.05) and D3 (p<0.05) compared to baseline; in the EVR group, it was elevated at D1 (p<0.05) compared to PO. The difference was also significant for this marker between the 2 groups at D1 (p<0.01). No significant change was observed in the serum creatinine or urea concentrations in either group perioperatively. CONCLUSIONS: Endovascular AAA repair is associated with less cytokine production and less intestinal and renal dysfunction compared to the open approach.

Aged↗

PubMed2003

[An experimental study on the prevention and treatment of postburn intestinal injury and bacterial translocation by Sijunzi decoction in scalded rats].

OBJECTIVE: To explore the effects of traditional Chinese herbal medicine Sijunzi decoction on amelioration of postburn intestinal injury in scalded rats. METHODS: One hundred and eighty Wistar rats were randomly divided into 3 groups, i.e. scald and treatment (T), scald control (S) and normal control (C) groups. The rats in T group were gavaged with the decoction consisting of tangshen, tuckahoe, large head atractylodes rhizome, glycyrrhizic and rhubarb in a dose of 2 ml twice daily, while the rats in C group were just gavaged with the same amount of distilled water. The rats were sacrificed according to the scheduled postburn observation timepoints. The contents of TNF, NO, MDA and ATPase activity in rat plasma and the intestinal mucosa and the S-IgA content in the intestinal mucus were determined respectively. The changes in histopathology of intestinal mucosa were observed. The samples from internal organ tissue and blood were obtained for bacterial culture. RESULTS: The contents of TNF, NO and MDA in the intestinal mucosa tissue and the rat plasma in scalded rats were lowered significantly by Sijunzi decoction. Furthermore, S-IgA secretion from intestinal mucous cells was maintained by Sijunzi decoction. T cell count was recovered and intestinal mucous barrier injury were lessened, and the bacterial positive rate in the internal organs was decreased. CONCLUSION: Traditional Chinese herbal medicine Sijunzi decoction might be helpful in alleviation of postburn intestinal injury and in the prevention of intestinal bacterial translocation.

Animals↗

PubMed1994

The concept and diagnosis of multiple systems organ failure.

There are still controversies concerning the concept and diagnosis of multiple systems organ failure (MSOF), since the term does not precisely define its true nature, and its differential diagnosis with other irrelevant clinical conditions, such as senile dysfunction of organs, agonal state, etc, remains unclarified. Our studies on both human burn patients and rat model by means of electron spin resonance (ESR) showed that there was an excessive generation of free oxygen radicals resulting in lipid peroxidation of cell membrane of various tissues. The intestine seemed to be particularly sensitive to hypoperfusion-reperfusion injury, as diamine oxidase activity of the ileum was lowered and translocation of bacteria occurred, indicating failure of intestinal mucosal barrier function. Concomitant determinations of plasma endotoxin (LPS) and tumor necrosis factor alpha (TNFa) levels showed significant elevation, especially in patients who finally developed MSOF. The data suggested that intestinally derived bacteria and/or LPS exacerbate the systemic responses initiated by ischemia reperfusion injury and the presence of large amounts of devitalized tissue. Early diagnosis is important in order to improve the prognosis. However, current criteria of diagnosis for MSOF do not conduce to an early diagnosis, as they only describe the end stage manifestations, while our therapeutic strategy should be directed against different levels of initiators, systemic mediators, and effectors of injury. Therefore, it is important to emphasize the role of septic responses in the development of the syndrome. We propose that the name of the syndrome be changed to "sepsis with organ dysfunction" or "mediator injury of organs".

Animals↗

PubMed2001

Man the barrier! Strategic defences in the intestinal mucosa.

Immunologists typically study the immune responses induced in the spleen or peripheral lymph nodes after parenteral immunization with antigen and poorly defined experimental adjuvants. However, most antigens enter the body through mucosal surfaces. It is now clear that the microenvironment in these mucosal barriers has a marked influence on the immune response that ultimately ensues. Nowhere is the microenvironment more influential than in the gut-associated lymphoid tissue (GALT). The GALT must constantly distinguish harmless antigens that are present in food or on commensal bacteria from pathogenic assault by microbes. It is perhaps not surprising, then, that the GALT contains more lymphocytes than all of the secondary lymphoid organs combined.

Animals↗

PubMed2002

Delayed consequences of protein deficiency during lactation for the development of enzyme systems of digestive and nondigestive organs in offspring.

Suboptimal protein nutrition during lactation has a negative impact on the digestive function of the small intestine and trophic barrier functions of the large intestine, liver, and kidneys due to significant enzyme deficiency (disaccharidase, peptidase, alkaline phosphatase) in 6-month-old offspring. Changes in enzyme activity in digestive and nondigestive organs play an important role in metabolic disorders promoting the development of "risk diseases" and reducing lifespan.

Animals↗

PubMed2026

Distal Recirculation of Enteral contents Augmented Mechanically (DREAM) Promotes Intestinal Adaptation and Restores Enterohepatic Signaling in Short Bowel Syndrome.

BACKGROUND & AIMS: Short bowel syndrome (SBS) leads to malabsorption and intestinal failure-associated liver disease. Intestinal adaptation (IA) driven by sustained enteral nutrition (EN) is essential, but EN delivery is limited after major resection. We developed DREAM (Distal Recirculation of Enteral contents Augmented Mechanically), which enables complete EN despite SBS, and enhances IA. We evaluated its efficacy in a translational large-animal model. METHODS: The study randomized 20 neonatal pigs to EN (control), SBS (75% resection), or DREAM. Growth, serum biochemistry, cytokines, intestinal morphology, barrier integrity, hepatic histology, and gene expression (quantitative polymerase chain reaction, RNA sequencing, Kyoto Encyclopedia of Genes and Genomes, and Gene Ontology enrichment) were analyzed. RESULTS: DREAM prevented hepatic and intestinal injury seen in SBS. Serum bilirubin (0.11 vs 5.14 mg/dL, P = .0008), γ-glutamyl transferase (23.2 vs 114.6 IU/L, P < .0001), and bile acids (9.7 vs 39 μmol/L, P = .0026) were significantly lower. Inflammatory cytokines (interferon-γ, P = .0296; interleukin 1β, P = .0349; and interleukin 6, P = .0189) and portal lipopolysaccharide (P = .0130) markedly improved. DREAM enhanced IA, increasing linear gut density (0.38 vs 0.209 g/cm, P < .0001), villus-to-crypt ratio (P = .0026), glucagon-like peptide 2 (P < .0001) and restored occludin and E-cadherin (P < .001). Hepatic bile salt export pump and cholesterol 7α-hydroxylase regulation were preserved (P = .0373 and P = .0034), and intestinal farnesoid X receptor, Takeda G-protein-coupled receptor 5, and epidermal growth factor signaling were reactivated (P < .01). Transcriptomic analysis confirmed improvements in metabolic, absorptive, and immune pathways. DREAM effluent demonstrated >80% macronutrient absorption within 6 hours (P < .0001). CONCLUSION: DREAM enables full EN in SBS, restoring absorption, mucosal integrity, and gut-liver homeostasis while preventing intestinal failure-associated liver disease. This approach represents a promising translational advance in SBS therapy.

Gut Atrophy↗

PubMed2000

Gastrointestinal effects of growth hormone.

GH receptor immunoreactivity is found throughout the gastrointestinal tract. GH has proliferative effects upon intestinal epithelium, and influences enteroendocrine cell secretion, calcium absorption, and intestinal amino acid and ion transport. The proliferative effects of GH may be reflected in the increased incidence of neoplastic colonic polyps in individuals with long-term GH excess reported by some investigators. GH also increases hepatic cytochrome P450 expression, potentially altering drug and steroid hormone metabolism. Current clinical research efforts include the use of exogenous GH as a stimulant of gut growth and adaptation in patients who have undergone massive intestinal resection. Exogenous GH is also being studied in animal models of critical illness where it appears to increase intestinal glutamine uptake, which may prevent deterioration of the intestinal mucosal barrier.

Animals↗

PubMed2004

Beta-defensin-2 expression is regulated by TLR signaling in intestinal epithelial cells.

The intestinal epithelium serves as a barrier to the intestinal flora. In response to pathogens, intestinal epithelial cells (IEC) secrete proinflammatory cytokines. To aid in defense against bacteria, IEC also secrete antimicrobial peptides, termed defensins. The aim of our studies was to understand the role of TLR signaling in regulation of beta-defensin expression by IEC. The effect of LPS and peptidoglycan on beta-defensin-2 expression was examined in IEC lines constitutively or transgenically expressing TLRs. Regulation of beta-defensin-2 was assessed using promoter-reporter constructs of the human beta-defensin-2 gene. LPS and peptidoglycan stimulated beta-defensin-2 promoter activation in a TLR4- and TLR2-dependent manner, respectively. A mutation in the NF-kappaB or AP-1 site within the beta-defensin-2 promoter abrogated this response. In addition, inhibition of Jun kinase prevents up-regulation of beta-defensin-2 protein expression in response to LPS. IEC respond to pathogen-associated molecular patterns with expression of the antimicrobial peptide beta-defensin-2. This mechanism may protect the intestinal epithelium from pathogen invasion and from potential invaders among the commensal flora.

Animals↗

PubMedDate not supplied

[The characteristics of the initial link in the intestinal lesion by opportunistic Proteus mirabilis bacteria].

Interaction of Proteus mirabilis with the intestine epithelium in white mongrel mice has been studied by means of bacteriological, toxicological and electron microscopic methods. Introduction of the agar culture of bacteria to the intestine lumen has permitted finding its general toxic action on enterocytes and other cell elements of epithelium which was accompanied by a potentiation of the striated margin membrane degradation but caused no destruction of cells. A damaging factor of protei was connected with the thermostable large-molecular fraction of cultural fluid of bacteria and its action was traced at the first hours of the bacterial contact with the mucous surface of thin intestine. Preliminary weakening of protective barriers of the intestine mucosa permitted protei to penetrate deep into the tissue through the intercellular slots. Colonization of the intestine lumen wall zone by the proteus is a necessary condition of the above-mentioned changes.

Animals↗

PubMedDate not supplied

[Environmental factors in the etiopathology of inflammatory bowel syndrome].

Inflammatory bowel syndrome (IBS) mainly includes ulcerative colitis (UC) and Crohn's disease (CD). UC and CD are chronic and recurrent conditions, with a tendency to exacerbations and remissions. The incidence of diseases worldwide has increased over the last years. Although the etiology of inflammatory bowel syndrome has been studied intensively it still remains unclear. The development and persistence of inflammation is an effect of numerous factors: proinflammatory (aggressive), regulating bowel mucosa homeostasis and protective factors. Proinflammatory factors include intestinal bacteria, bile acids, digestive enzymes, lipopolysaccharides and peptidoglycans. Protective mechanisms are impermeability of mucosa barrier, presence of intestinal mucus, activity of secretive immunoglobulins, some prostaglandins and interleukins, glutamine, somatostatin, cortisol and short-chain fatty acids. Factors modifying intestinal mucosa homeostasis consist of genetically determined immunoregulators and activity of intestinal mucosa barrier and some environmental factors (diet, smoking, infections, stress, antibiotics and others). Environmental factors are jointly responsible for IBS occurrence in case of genetically determined dysregulation leading to proinflammatory cytokines overproduction or disturbances in synthesis of cytokines regulating intestinal mucosa homeostasis.

Colitis, Ulcerative↗