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PubMed2005

Place of probiotics.

PURPOSE OF REVIEW: This review reports on the recent progress understanding mechanisms of action and clinical applications of probiotics. RECENT FINDINGS: New insights on regulating mechanisms of intestinal commensal bacteria to prevent and treat different gastrointestinal diseases have been reported. Some probiotics, though not all, exert beneficial effects by modulating the mucosal barrier function and immune activity. It seems that a combination of different probiotics is more effective than a single strain. It was demonstrated that not only viable bacteria administered to the intestinal tract but also isolated probiotic DNA is active, even if injected subcutaneously. There is reasonable evidence to recommend probiotics in infectious diarrhoea for prevention and treatment (mainly in children) and to prevent antibiotic-induced gastrointestinal side effects. Furthermore, probiotics are effective in maintaining remission in ulcerative colitis and preventing and treating pouchitis. Promising positive effects were published in major surgery patients (gastric resection, pancreatic resection, liver transplantation) and in severe necrotising acute pancreatitis. SUMMARY: Increasing knowledge on probiotics is exciting, but in the near future it must be defined which probiotics (single strains or a combination) are most effective in specific diseases. Well-designed, randomized clinical trials are still required to further define the role of probiotics as preventive and therapeutic agents.

Colitis, Ulcerative↗
PubMed1997

Molecular events in neutrophil transepithelial migration.

Neutrophil transepithelial migration is a central component of many inflammatory diseases of the gastrointestinal, respiratory and urinary tracts, and correlates with disease symptoms. In vitro modeling with polarized intestinal epithelial monolayers has shown that neutrophil transepithelial migration can influence crucial epithelial functions, ranging from barrier maintenance to electrolyte secretion. Studies have also demonstrated a dynamic involvement of the epithelium in modulating neutrophil transepithelial migration. Characterization of the molecular interactions between neutrophils and epithelial cells has revealed that transepithelial migration is dependent on the neutrophil beta 2 integrin CD11b/CD18, and does not appear to involve adhesive interactions with the selectins or intercellular adhesion molecule-1. Recent studies have implicated another transmembrane glycoprotein, CD47, as a crucial component of the transepithelial migration response. While the precise function of CD47 is not known, current evidence suggests that CD47-dependent events occur after CD11b/CD18-mediated neutrophil adhesion to the epithelium. This review will highlight key features of the current understanding of the molecular events important in neutrophil migration across epithelial surfaces.

Animals↗
PubMed1984

Small intestine transplantation in the rat--immunology and function.

Heterotopic, vascularized small intestine transplants were performed in inbred strains of rats to investigate the structural, functional, and immunologic consequences of intestinal transplantation with and without immunosuppression with cyclosporine (CyA). Lewis X Brown Norway F1 intestine was rejected by untreated Lewis recipients in 7 to 10 days. Structurally, rejected intestine was characterized by shortened crypts and villi lined by damaged attenuated epithelial cells. Functionally, rejection was associated with impaired epithelial active ion transport as indicated by decreased potential difference and with diminished epithelial barrier function as reflected by decreased transepithelial resistance. Administration of CyA for 7 days prevented clinical rejection and partially prevented the structural and functional defects. Lewis intestine transplanted into Lewis X Brown Norway F1 recipients caused fatal graft versus host disease (GVHD) in 9 to 17 days. Treatment with CyA for 7 days failed to prevent GVHD routinely, but prolonged administration delayed fatal GVHD until CyA was discontinued. Intestine from Lewis "B" rats made deficient of T cells by thymectomy, irradiation, and reconstitution with syngeneic T cell-depleted bone marrow failed to cause GVHD in Lewis recipients. Reconstitution of the "B" rats with T cells before transplantation restored the GVHD response. These results may be relevant in the consideration of clinical small intestinal transplantation.

Animals↗
PubMed2005

Bombesin and neurotensin reduce endotoxemia, intestinal oxidative stress, and apoptosis in experimental obstructive jaundice.

OBJECTIVE: To evaluate the effect of bombesin (BBS) and neurotensin (NT) on intestinal histopathology, intestinal oxidative stress, and endotoxemia in experimental obstructive jaundice. SUMMARY BACKGROUND DATA: Obstructive jaundice compromises gut barrier function, resulting in endotoxemia. BBS and NT, exerting various biologic actions on gastrointestinal tissues, preserve gut mucosal integrity in cases of injury or atrophy. METHODS: Seventy male Wistar rats were randomly divided into 5 groups: I = controls, II = sham operated, III = bile duct ligation (BDL), IV = BDL + BBS (30 microg/kg/d), V = BDL + NT (300 microg/kg/d). By the end of the experiment, on day 10, endotoxin was measured in portal and aortic blood. Tissue sections of the terminal ileum were examined histologically, and villus density, mucosal thickness, mitotic activity and apoptosis in crypts were assessed. In addition, ileal mucosa was analyzed for DNA and protein content. To estimate intestinal oxidant/antioxidant equilibrium, lipid peroxidation, protein oxidation, and thiol redox state (reduced glutathione [GSH], oxidized glutathione [GSSG], total nonprotein mixed disulfides [NPSSR], protein thiols [PSH], and protein disulfides [PSSP]) were determined on tissue homogenates from the terminal ileum. RESULTS: BBS or NT administration significantly reduced portal and systemic endotoxemia observed in obstructive jaundice. Both factors reversed obstructive jaundice-induced morphologic features of intestinal atrophy, increasing villus density and mucosal thickness. This effect was accompanied by induction of mitoses and reduction of apoptosis in intestinal crypts. Mucosal DNA and protein content were reduced, although not to significant levels, in BDL animals and restored to control levels after BBS or NT treatment. Moreover, BBS or NT administration protected the intestine in jaundiced rats against oxidative stress, as demonstrated by reduction of intestinal lipid peroxidation, increase of the antioxidant GSH, and decrease of the oxidized forms GSSG and NPSSR, while BBS additionally reduced protein oxidation as well. CONCLUSIONS: Administration of BBS or NT in bile duct-ligated rats exerts beneficial effects on intestinal oxidative stress, cell proliferation, apoptosis, and endotoxemia. This observation might be of potential value in patients with extrahepatic cholestasis.

Animals↗
PubMedDate not supplied

Insulin-like growth factor-I prevents gut atrophy and maintains intestinal integrity in septic rats.

BACKGROUND: The effects of insulin-like growth factor-I (IGF-I) on gut metabolism, structure, and barrier function as well as its general anabolic effects were investigated in septic rats. METHODS: Thirty-three male Wistar rats that underwent cecal ligation were randomly divided into one of the following two groups: (1) received only total parenteral nutrition (control group) or (2) received total parenteral nutrition with IGF-I (IGF group) at a dose of 4 mg/kg/d for 3 days. RESULTS: During the 3-day period, the body weight of rats in the IGF group increased significantly over that of rats in the control group (17.1 +/- 2.6 vs 5.8 +/- 4.6 g, p < .01). The total and free IGF-I plasma concentrations were significantly higher in the IGF group than in the control group. The cumulative nitrogen balance was significantly more positive for the IGF group (423.9 +/- 24.3 mg of nitrogen) than for the control group (290.8 +/- 26.0 mg of nitrogen). The weights of thymus, spleen, and kidneys were significantly increased in the IGF group compared with weights in the control group. Treatment with IGF-I improved the gut mucosal weight in all regions of the gut examined, including duodenum, jejunum, ileum, and colon. Histologic and biochemical analyses of the jejunum showed greater villus height and crypt depth and higher mucosal DNA and protein content in the IGF group. The arterial concentration of endotoxin was not significantly different between the two groups, whereas its level in portal blood was significantly lower in the IGF group (23.2 +/- 9.9 pg/mL) than in the control group (95.5 +/- 37.9 pg/mL), an indication that IGF-I treatment decreased the amount of endotoxin that traversed the gut barrier. CONCLUSIONS: These results indicate that IGF-I can improve gut metabolism and reduce mucosal atrophy and that it may play a role in maintaining the gut barrier function in sepsis.

Amino Acids↗
PubMed2006

Disrupted barrier function through epithelial cell apoptosis.

Epithelial barrier function is determined by trans- and paracellular permeabilities, the latter of which is mainly influenced by tight junctions (TJs) and apoptotic leaks within the epithelium. The present article aims to present experimental evidence for a functional role of epithelial apoptoses by means of cell culture models as well as in tissues from patients with inflammatory bowel disease. It is shown that epithelial apoptoses are sites of elevated conductance within the intestinal epithelium and that proinflammatory cytokines like TNF-alpha upregulate both the apoptotic rate and single apoptotic conductivity, making cytokine-induced apoptosis functionally far more relevant than is spontaneous apoptosis. In ulcerative colitis and Crohn's disease (CD), but not in collagenous colitis, apoptotic rates are increased to about 5%, in mild-to-moderately inflamed colon specimens, where as the control apoptotic rate is about 2%. Thus, epithelial apoptoses lead to a loss of ions and water into the intestinal lumen, causing leak flux diarrhea and enabling small antigens of <4,000 Da in the intestinal lumen to enter the intestinal mucosa, thereby perpetuating inflammatory responses. In addition to TNF-alpha, interleukin (IL)-13 is an important inductor of epithelial apoptosis in Th2 immune responses. Therapeutically,TNF-alpha-antibodies (infliximab) can restore barrier function in Crohn's disease by downregulating epithelial apoptoses, while epithelial TJs are unaffected.

Apoptosis↗
PubMed2003

Intracellular survival of Staphylococcus aureus within cultured enterocytes.

BACKGROUND: Little is known about the mechanisms involved in bacterial translocation from the intestinal lumen to extraintestinal sites. Because Staphylococcus aureus can colonize the intestinal tract, and because the intestinal tract is a reservoir for antibiotic resistant S. aureus, experiments were designed to clarify the interactions of S. aureus with cultured intestinal epithelial cells, and assays included measurements of bacterial internalization, enterocyte apoptosis, and epithelial barrier function. METHODS AND RESULTS: Mature, confluent enterocytes were incubated 1 h with S. aureus, and the gentamicin protection assay was used to quantify intracellular bacterial survival at various time intervals up to 120 h later. Enterocyte apoptosis was assessed using Annexin V, and the permeability of confluent enterocyte cultures was measured by transepithelial electrical resistance and by transmigration of Escherichia coli across confluent enterocytes.S. aureus was internalized by cultured enterocytes and remained viable for up to 120 h within both HT-29 and Caco-2 enterocytes. S. aureus intracellular survival was associated with enterocyte apoptosis and with decreased transepithelial electrical resistance across confluent Caco-2 enterocytes. S. aureus intracellular survival over time was also associated with increased E. coli transmigration across confluent Caco-2, but not HT-29, enterocytes. CONCLUSIONS: S. aureus appeared to survive within cultured enterocytes for prolonged time periods, up to several days. Survival of S. aureus within host eukaryotic cells, such as enterocytes, might facilitate persistence of S. aureus in infected tissue despite appropriate antibiotic therapy.

Apoptosis↗
PubMed2003

Peroxynitrite inhibits epidermal growth factor receptor signaling in Caco-2 cells.

Intestinal mucosa serves as an important barrier that may be disrupted by inflammation. A complex system of cellular and humoral factors, including epidermal growth factor (EGF), maintains the integrity of this barrier. We hypothesized that peroxynitrite, generated in inflamed intestinal epithelium, can alter the EGF receptor function by nitrating tyrosine residues and blocking ligand-activated tyrosine autophosphorylation. Caco-2 cells or A431 cell membranes were treated with peroxynitrite or its decomposed form. Cell proliferation was measured by [3H]thymidine uptake. Immunoblot and immunoprecipitation were used to assess the tyrosine phosphorylation and nitration. Binding of epidermal growth factor to its receptor was detected by affinity labeling with 125I-EGF. Peroxynitrite inhibited EGF-induced Caco-2 cell proliferation and binding of EGF to its receptor in a concentration-dependent manner. Peroxynitrite abolished EGF-stimulated receptor autophosphorylation and nitrated EGF receptor tyrosine residues. Peroxynitrite generated during inflammation may disrupt the EGF-induced signaling in intestinal epithelial cells.

Caco-2 Cells↗
PubMed2001

Strategies to overcome simultaneous P-glycoprotein mediated efflux and CYP3A4 mediated metabolism of drugs.

Cytochrome P450 3A4 (CYP3A4), abundant in both the liver and upper intestinal enterocytes, limits the systemic bioavailability of xenobiotics. P-glycoprotein (P-gp), the MDR1 gene product, is also known to reduce the oral bioavailability of the drug molecules. High cellular expression of P-gp and CYP3A4 in mature intestinal enterocytes and their similar substrate specificity suggest that the function of these proteins may be complementary and may form a co-ordinated intestinal barrier. Various ongoing preclinical and clinical studies have demonstrated that the oral bioavailability of various P-gp and/or CYP3A4 substrates can be increased by simultaneous administration of P-gp and/or CYP3A4 inactivators. The current review describes the background and summarises several proposed hypotheses in modifying oral bioavailability by various drug-inhibitor interactions.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Interferon-gamma decreases barrier function in T84 cells by reducing ZO-1 levels and disrupting apical actin.

The effects of interferon-gamma (IFN-gamma) on tight junctions in T84 human intestinal epithelial cells were investigated. Treatment of T84 cells with IFN-gamma caused a dose- and time-dependent increase in monolayer permeability as assessed by transepithelial electrical resistance measurements. Examination of specific proteins associated with tight junctions by immunoblotting and confocal microscopy revealed changes in the expression levels and localization of some of these proteins after exposure of the cells to IFN-gamma. Specifically, IFN-gamma treatment resulted in an almost total loss of zonula occludens (ZO)-1, whereas the levels of ZO-2 and occludin showed relatively modest decreases compared with untreated cells. Loss of ZO-1 was associated with the altered localization of ZO-2 and occludin. In IFN-gamma-treated cells, ZO-2 and occludin were diffusely distributed, whereas, in control cells, they, along with ZO-1, were predominantly localized to the tight junctions. Analysis of ZO-1 protein and RNA by pulse chase and RT-PCR, respectively, showed an increase in protein turnover, a decrease in protein synthesis, and a reduction in RNA levels following IFN-gamma treatment. In contrast to ZO-1, ZO-2 and occludin did not show any major changes in these parameters. In addition, the organization of actin in the apical and tight junction regions, but not in the mid- or basal regions, of the cells was also perturbed by IFN-gamma treatment of cells. Time-course analysis of IFN-gamma-induced alterations in ZO-1 expression and apical actin perturbation indicated that these two effects were intimately linked and could not be dissociated. These results suggest that IFN-gamma affects barrier function in T84 cells by decreasing the levels of ZO-1 and perturbing apical actin organization, which leads to a disorganization of the tight junction and an increase in paracellular permeability.

Actins↗
PubMed2001

Microbes and microbial toxins: paradigms for microbial-mucosal interactions. VII. Enteropathogenic Escherichia coli: physiological alterations from an extracellular position.

Enteropathogenic Escherichia coli (EPEC) is primarily associated with infantile diarrhea in developing countries. This intriguing pathogen exerts numerous physiological effects on its host target tissue, the intestinal epithelium, all from an extracellular location. Expression of a type III secretory apparatus allows this organism to transfer bacterial effector molecules directly into host cells. As a result of EPEC attachment to and/or translocation of proteins into intestinal epithelial cells, many signaling cascades are activated. Ultimately, host functions are perturbed, including alteration of ion transport, disruption of the tight junction barrier, and activation of the inflammatory response.

Diarrhea↗
PubMed1994

Reconstitution of cultured intestinal epithelial monolayers with a mucosal-derived T lymphocyte cell line. Modulation of epithelial phenotype dependent on lymphocyte-basolateral membrane apposition.

In vivo, epithelial cells which line the intestine are intimately associated with lymphocytes, termed intraepithelial lymphocytes. Previous studies have demonstrated that intraepithelial lymphocytes are present in the uninflamed mucosa, and become especially prominent in various human enteropathies including coeliac disease, tropical sprue, dermatitis herpetiformis, and giardiasis. Using the intestinal crypt cell line T84, and a previously well-defined human mucosa-derived lymphocyte (MDL) line with phenotypic features similar to (but not specific for) intraepithelial lymphocytes, we describe a co-culture model to study the functional sequellae of MDL-T84 cell interactions in vitro. A co-culture method was defined which permitted reconstitution of the paracellular spaces of physiologically confluent epithelial monolayers with MDL. Such co-cultures thus mimicked the correct geometry of intraepithelial lymphocytes-epithelial cell interactions. The presence of physiologically positioned MDL brought about specific and dramatic effects on intestinal epithelial monolayer function. In a dose-dependent fashion, the presence of MDL significantly attenuated barrier function (expressed as a decrease in monolayer resistance), decreased epithelial electrogenic Cl- secretion, and modulated epithelial-neutrophil interactions. Such effects were not reproduced in monolayers similarly reconstituted with inert polystyrene beads equivalent in size to MDL. These MDL-elicited effects on epithelial function specifically required direct MDL apposition to the epithelial basolateral membrane. Furthermore, this specific form of MDL-epithelial basolateral contact released soluble factors which were able to confer the MDL-reconstituted phenotype on virgin epithelial monolayers in the absence of MDL. We have previously shown that many aspects of the MDL converted epithelial phenotype described here can be induced by IFN-gamma. While IFN-gamma, a cytokine produced by many lymphocytes including intraepithelial lymphocytes, was detectable in conditioned supernatants from co-cultures, it existed at concentrations insufficient to fully explain the physiologic effects observed here.

Cells, Cultured↗
PubMed2001

A transgenic model for listeriosis: role of internalin in crossing the intestinal barrier.

Listeria monocytogenes is responsible for severe food-borne infections, but the mechanisms by which bacteria cross the intestinal barrier are unknown. Listeria monocytogenes expresses a surface protein, internalin, that interacts with a host receptor, E-cadherin, to promote entry into human epithelial cells. Murine E-cadherin, in contrast to guinea pig E-cadherin, does not interact with internalin, excluding the mouse as a model for addressing internalin function in vivo. In guinea pigs and transgenic mice expressing human E-cadherin, internalin was found to mediate invasion of enterocytes and crossing of the intestinal barrier. These results illustrate how relevant animal models for human infections can be generated.

Animals↗
PubMed2006

Salmonella enterica serovar Typhimurium effectors SopB, SopE, SopE2 and SipA disrupt tight junction structure and function.

Salmonella enterica serovar Typhimurium is a major cause of human gastroenteritis. Infection of epithelial monolayers by S. Typhimurium disrupts tight junctions that normally maintain the intestinal barrier and regulate cell polarity. Tight junction disruption is dependent upon the Salmonella pathogenicity island-1 (SPI-1) type 3 secretion system but the specific effectors involved have not been identified. In this study we demonstrate that SopB, SopE, SopE2 and SipA are the SPI-1-secreted effectors responsible for disruption of tight junction structure and function. Tight junction disruption by S. Typhimurium was prevented by inhibiting host protein geranylgeranylation but was not dependent on host protein synthesis or secretion of host-derived products. Unlike wild-type S. Typhimurium, DeltasopB, DeltasopE/E2, DeltasipA, or DeltasipA/sopB mutants, DeltasopB/E/E2 and DeltasipA/sopE/E2 mutants were unable to increase the permeability of polarized epithelial monolayers, did not disrupt the distribution or levels of ZO-1 and occludin, and did not alter cell polarity. These data suggest that SPI-1-secreted effectors utilize their ability to stimulate Rho family GTPases to disrupt tight junction structure and function.

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↗
PubMed2004

Butyrate suppresses hypoxia-inducible factor-1 activity in intestinal epithelial cells under hypoxic conditions.

Interaction between the products of intestinal bacteria and the intestinal epithelial cells is a key event in understanding the biological, physiological, and pathological functions of the intestinal epithelium. Here, we examined the effect of butyrate, one of the major intestinal bacterial products, on hypoxia-inducible factor-1 (HIF-1) activity under hypoxic conditions in intestinal epithelial cells. HIF-1 activity was assessed by luciferase assay using cytoplasmic extracts of intestinal epithelial cells, Caco-2, and IEC-6 cells. These cells were transiently transfected with hypoxia response element (HRE)-luciferase reporter plasmids and cultured under hypoxic conditions in the presence or absence of sodium butyrate (NaB). The effect of NaB on HRE DNA binding activity in Caco-2 cells under hypoxic conditions was assessed by electrophoretic mobility shift assay. Expression of a hypoxia-responsive gene encoding intestinal trefoil factor (ITF) in Caco-2 cells after NaB treatment was assessed using reverse-transcription PCR. The barrier function of Caco-2 cells under hypoxic conditions was also evaluated by transepithelial electrical resistance measurement. NaB suppressed up-regulation of HIF-1 transcriptional activity under hypoxic conditions in Caco-2 and IEC-6 cells. In parallel, NaB reduced HRE DNA binding activity under the same conditions. Furthermore, NaB down-regulated enhanced transcription of ITF gene. Addition of NaB under hypoxic conditions delayed recovery of transepithelial electrical resistance of the monolayers after hypoxia-reoxygenation treatment. These findings indicate that NaB suppresses HIF-1 transcriptional activity on hypoxia-responsive genes by reducing the HRE DNA binding activity under hypoxic conditions in intestinal epithelial cells.

Animals↗