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PubMed1997

Early functional effects of Clostridium difficile toxin A on human colonocytes.

BACKGROUND & AIMS: Previous in vitro studies have shown that Clostridium difficile toxin A is able to directly affect the intestinal epithelial barrier function. The aim of this study was to examine the early effects of toxin A on mucin exocytosis and determine whether this toxin can induce the production of the chemokine interleukin 8 (IL-8) from human colonic epithelial cells. METHODS: Two model systems were used: the HT29-CI.16E colonic goblet cell line and primary cultures of human normal colonocytes. RESULTS: Toxin A exerted a rapid and dose-related inhibition of stimulated mucin exocytosis without altering baseline (constitutive) mucin exocytosis from HT29-CI.16E cells. Toxin A was also able to induce the secretion of IL-8 from both HT29-CI.16E cells and primary cultures of human normal colonocytes, as early as 2-3 hours of incubation. CONCLUSIONS: The results show that while toxin A is able to down-regulate stimulated mucin exocytosis, it is able to up-regulate the secretion of an important chemoattractant chemokine, IL-8. These modifications illustrate the ability of colonocytes to recruit inflammatory and immune cells that will eventually bring about major mucosal damage.

Bacterial Toxins↗
PubMed2006

Implication of TNF-related apoptosis-inducing ligand in inflammatory intestinal epithelial lesions.

BACKGROUND & AIMS: Few data exist on the molecular events causing intestinal epithelial destruction during inflammatory processes, such as inflammatory bowel disease (IBD). In this work, we analyzed the potential implication of tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) in these inflammatory lesions. METHODS: TRAIL and TRAIL-receptor expression were analyzed in normal, inflammatory ileum/colon and human intestinal epithelial cell (IEC) lines (HIEC), Caco-2, and HT-29 using RNase protection assay, real-time and reverse-transcription polymerase chain reaction (RT-PCR), immunohistochemistry, and Western blot analysis. TRAIL-induced activation of NF-kappaB was determined by electrophoretic mobility shift assay. Caspase-recruitment domain (CARD)15 expression and interleukin-(IL)8 production were studied by RT-PCR and enzyme-linked immunosorbent assay. Apoptosis was monitored using Annexin-V/caspase-3 assays. RESULTS: Normal mature IEC expressed low TRAIL levels, whereas, in inflammatory lesions, TRAIL messenger RNA and protein were markedly up-regulated in IEC and lamina propria lymphocytes at levels comparable with trinitrobenzene sulfonic acid-induced colitis. Interferon-gamma and TNF-alpha potently induced TRAIL in IEC. In vitro analyses revealed a dual biologic effect of TRAIL on HIEC: Under noninflammatory conditions, TRAIL up-regulated via nuclear factor-kappaB CARD15 and IL-8, whereas, under inflammatory conditions, TRAIL became a potent inducer of apoptosis in HIEC, which was confirmed ex vivo using ileal organ cultures. TNF-alpha markedly increased the expression of the proapoptotic receptor TRAIL-R2. TRAIL-induced IEC apoptosis required a functional caspase cascade. CONCLUSIONS: TRAIL is a new inflammatory mediator implicated in the homeostasis of intestinal epithelial barrier functions. TRAIL is highly up-regulated in IEC in inflammatory ileum and colon. It may augment in an auto-/paracrine fashion the elimination of IEC via apoptosis.

Animals↗
PubMed2005

Gut bacterial translocation and postoperative infections: a prospective study in schistosomotic patients.

BACKGROUND: Bacterial translocation (BT) across the intact intestinal mucosal barrier has been postulated as a source of sepsis in susceptible patients, including those with cirrhosis and portal hypertension. This condition has not been studied in hepatosplenic schistosomiasis, wherein portal hypertension and the presence of an immune deficiency state associated with the parasitic disease could predispose to BT into mesenteric lymph nodes (MLN). A study was conducted to determine the prevalence of aerobic bacteria in MLN (bacterial translocation) of patients with hepatosplenic schistosomiasis, and establish a possible association with postoperative infections. METHODS: In a series of 51 patients submitted to surgical treatment of schistosomotic portal hypertension with splenectomy and gastric devascularization, MLN were obtained from each patient at the beginning (MLN1) and at the end (MLN2) of the surgical procedure, and sent for bacteriological analysis. Prospective patient evaluation during the postoperative period correlated positive MLN cultures with infectious complications. RESULTS: The prevalence of aerobic bacteria was 17.6% at MLN1 and 27.5% at MLN2, however, this difference was non-significant (p = 0.24). Bacterial translocation to all MLN was 22.5%. Escherichia coli was the most frequent organism (26.1%, 6/23). The overall incidence of postoperative infections was 19.6% (10/51), with a significant association with the presence of positive cultures of MLN (p = 0.043). CONCLUSIONS: The findings of this study suggest that the presence of aerobic bacteria on MLN as a consequence of BT may play a role in the development of postoperative infectious complications, particularly in schistosomotic patients.

Adult↗
PubMed1980

Metabolism of orally and intravenously administered purines in rats.

One experiment was conducted in which radioactively labeled purine bases (adenine, guanine, hypoxanthine and xanthine) were individually given intravenously to young adult rats and the recovery of radioactivity in urine and gut, gut content and liver was measured at the end of the next 24 hours. The total recovery of radioactivity from orally and intravenously administered adenine was measured in experiment 2. A third experiment measured the recoveries of radioactivity from oral and intravenous adenine in a wider variety of tissues and organs than in experiment 1. The chemical identities of the urinary end products of the metabolism or orally and intravenously administered adenine were compared in a fourth experiment. When purines were given intravenously, significantly more of the administered radioactivity was recovered in urine from rats given guanine, hypoxanthine or xanthine compared with those given adenine. The greater recoveries of radioactivity in urine were associated with smaller recoveries in tissues. A larger proportion of intravenously compared to orally administered radioactivity from adenine was incorporated into all body tissues, and this was most pronounced in glandular and lymphoid tissues. The primary urinary end product of both orally and intravenously administered adenine was allantoin. The absorption of individual purines from isolated rat gut sacs was evaluated in a fifth experiment. A significant proportion of unaltered adenine crossed the mucosal to serosal barrier of intestinal sacs whereas unaltered guanine, hypoxanthine or xanthine did not cross into the serosal fluid. These results show that the intestinal metabolism of dietary adenine is uniquely different from that of guanine, hypoxanthine or xanthine.

Adenine↗
PubMed1994

The role of calcium intake in preventing bone fragility, hypertension, and certain cancers.

This paper examines the evidence that connects calcium intake and vitamin D status to bone fragility, hypertension, colon cancer, and breast cancer. Human calcium physiology, with an intestinal absorptive barrier and inefficient conservation, reflects the abundance of calcium in the primordial human food supply. The calcium intake of stone-age adults is estimated at 50 to 75 mmol/d, three to five times the median calcium intake of present-day U.S. adults. Long-term calcium restriction and/or insufficient vitamin D may promote the development of bone fragility, high blood pressure, colon cancer, and breast cancer in susceptible individuals. Conversely, improvement in calcium intake and/or in vitamin D status may help to prevent these serious health problems. At least 12 intervention studies have established the skeletal benefit of increased calcium intake among women in the late postmenopause. Other reports suggest that adequate calcium may protect against salt-sensitive and pregnancy-associated hypertension. High intakes of both dietary calcium and vitamin D are associated with reduced development of precancerous changes in colonic mucosa. Preliminary findings also suggest that vitamin D has a protective effect against breast cancer.

Bone and Bones↗
PubMed2000

Role of neutrophils in burn-induced microvascular injury in the intestine.

The present study evaluated burn-induced vascular permeability alterations of rat small intestine in vivo and assessed the effect of neutrophil depletion in burn-injured rats on the altered intestinal microvascular permeability. 125I-labeled bovine serum albumin (125I-BSA) was injected intravenously, and its leakage from circulation into the intestinal tissue was determined by measuring tissue counts of 125I-BSA. Compared with sham, vascular albumin permeability increased 1.7-fold on day 1 post-burn and 3.0-fold on day 3 post-burn in ileum. In the jejunum, albumin permeability increased 1.8- and 2.5-fold on day 1 and day 3 post-burn, respectively. Intestinal tissue edema, determined as increases in tissue water contents, was noted in both intestinal segments on day 1 post-burn; no further increase in edema was found on day 3 post-burn. Neutrophil depletion before burn injury prevented the vascular leakage of albumin and edema in the ileum and jejunum on day 1 post-burn. On day 3 post-burn, the effect of prior neutrophil depletion on vascular permeability was less marked, and edema formation was not affected at all. These findings indicate that an absence of neutrophils prevents the loss of intestinal vascular barrier properties only in the initial periods after burns.

Animals↗
PubMed2006

Early internal fracture fixation prevents bacterial translocation.

The aim of our study was to determine whether early internal fixation of major bone fractures helps prevent bacterial translocation in patients with multitrauma. Thirty-seven Sprague-Dawley rats were divided into three groups: (1) anesthesia only (n = 12); (2) the trauma group: tibia and femur fractures and moderate head trauma under anesthesia (n = 14); and (3) the fixation group: fixation of tibia and femur fractures and moderate head trauma under anesthesia (n = 11). After 24 hours, mesenteric lymph nodes, liver, spleen, and systemic blood samples were quantitatively cultured. The terminal ileum was assessed histopathologically. The incidence of bacterial translocation was less in the anesthesia group (two of 12 rats) and the fixation group (two of 11 rats) than in the trauma group (10 of 14 rats). The number of organs containing viable bacteria was significantly lower in the fixation group than in the trauma group. Histopathologically, villous architecture was preserved mostly in the fixation group; however, marked mucosal damage was detected in the trauma group. Our data suggest early internal fixation of long bone fractures in polytraumatized experimental animals with head injury results in preservation of the intestinal mucosal barrier and decreased bacterial translocation from the gut.

Animals↗
PubMed2003

Decreased lymphocyte apoptosis by anti-tumor necrosis factor antibody in Peyer's patches after severe burn.

Severe burn results in immunosuppression, with increased lymphocyte apoptosis in both the central and peripheral immune system. As atrophy of the small intestine has been described in mouse models and intestinal lymphocytes have been implicated in the burn inflammatory response, we examined the effects of burn and tumor necrosis factor (TNF)-alpha on lymphocytes in intestinal Peyer's patches. Anesthetized C57BL6 mice received a 30% full-thickness scald burn on the upper back. Sham-burned animals served as controls. Anti-TNF or control immunoglobulin (Ig) G antibody (200 microg) was given immediately after the burn. The animals were initially resuscitated with 2 mL of normal saline, and were then sacrificed 12 h postburn. Terminal deoxyuridine nick-end labeling (TUNEL) and proliferative cell nuclear antigen (PCNA) staining was performed. Apoptosis was quantified as apoptotic lymphocytes/high-powered field (hpf). Results, expressed as mean +/- SEM, were compared using analysis of variance (ANOVA) and the Student-Newman-Keuls test. All mice survived the burn. An initial time-course experiment demonstrated maximal Peyer's patch apoptosis 12 h after the burn. Sham mice had 25 +/- 7 TUNEL-stained cells/hpf in Peyer's patches, whereas burned mice had 93 +/- 18 cells/hpf (P < 0.05). In contrast, burned mice receiving anti-TNF antibody had 28 +/- 8 TUNEL-stained cells/hpf (P < 0.05 vs. burn), whereas sham mice receiving anti-TNF antibody had 20 +/- 4 cells/hpf. There were no significant differences in PCNA staining between the groups. Scald burn results in lymphocyte apoptosis in Peyer's patches. This apoptosis can be abrogated by the addition of anti-TNF antibody. Apoptotic changes may lead to the failure of the intestinal immunological barrier and increased risk of sepsis.

Animals↗
PubMed1977

Studies on the pathogenicity of Yersinia enterocolitica. II. Interaction with cultured cells in vitro.

Analysis of the pathogenicity of Yersinia enterocolitica was performed by means of cell culture studies on the interaction of the organisms with HeLa cells and rabbit peritoneal macrophages based on observations of the pathogenic behavior of the organisms in vivo (II). The pathogenic strains, which successfully produced experimental enterocolitis in rabbits (II), had the ability to penetrate HeLa cells and to survive or multiply within the macrophages. The nonpathogenic strains, lacking the ability to produce pathological changes in rabbits (II), failed to penetrate HeLa cells, except for one strain, and also to survive totally or multiply within the macrophages. It was evident that the abilities of the organisms to penetrate epithelial linings which serve as the barrier of intestinal mucosa and to survive or multiply within the host cells appears to be closely related to the pathogenicity of Y. enterocolitica.

HeLa Cells↗
PubMed2000

Salmonella typhimurium induces apoptosis in human monocyte-derived macrophages.

Salmonella species represent a leading cause of gastroenteritis worldwide. More recently, they have been proposed as putative vaccine delivery vehicles in humans. Oral infection with Salmonella leads to invasion of the intestinal epithelial barrier and subsequent interaction with mucosal macrophages. In this study, we investigated the fate of Salmonella typhimurium-infected human macrophages differentiated from blood monocytes by GM-CSF. Wild type S. typhimurium strain SL1344 induced macrophage surface blebbing and caused the release of host cytoplasmic lactate dehydrogenase beginning 30 min post-infection. Three hours later more than 80% of the macrophages in the culture were killed. In contrast, during the same period, macrophages infected with the non-invasive S. typhimurium strain BJ66 remained viable. Chromatin fragmentation is a hallmark of cells undergoing apoptosis. Using TUNEL analysis, we observed chromatin fragmentation in macrophages infected with SL1344 but not in BJ66 infected cells. Consistent with this observation, we found that pretreatment of human macrophages with an inhibitor of caspase-3, a member of the pro-apoptotic enzyme family shown to be involved in S. typhimurium-induced killing of mouse macrophages, reduced SL1344-mediated cytotoxicity by 40%. Our study provides the first evidence that invasive S. typhimurium induces apoptosis in human macrophages that were differentiated from blood monocytes by GM-CSF, and that cell death is a caspase-dependent phenomenon.

Apoptosis↗
PubMed2005

BapA, a large secreted protein required for biofilm formation and host colonization of Salmonella enterica serovar Enteritidis.

In environmental settings, biofilms represent the common way of life of microorganisms. Salmonella enterica serovar Enteritidis, the most frequent cause of gastroenteritis in developed countries, produces a biofilm whose matrix is mainly composed of curli fimbriae and cellulose. In contrast to other bacterial biofilms, no proteinaceous compound has been reported to participate in the formation of this matrix. Here, we report the discovery of BapA, a large cell-surface protein required for biofilm formation by S. Enteritidis. Deletion of bapA caused the loss of the capacity to form a biofilm whereas the overexpression of a chromosomal copy of bapA increased the biofilm biomass formation. We provide evidence that overproduction of curli fimbriae and not cellulose can compensate for the biofilm deficiency of a bapA mutant strain. BapA is secreted through a type I protein secretion system (BapBCD) situated downstream of the bapA gene and was found to be loosely associated with the cell surface. Experiments with mixed bacterial populations positive or negative for BapA showed that BapA minus cells are not recruited into the biofilm matrix. The expression of bapA is coordinated with that of genes encoding curli fimbriae and cellulose, through the action of csgD. Studies on the contribution of BapA to S. Enteritidis pathogenesis revealed that orally inoculated animals with a bapA-deficient strain survived longer than those inoculated with the wild-type strain. Also, a bapA mutant strain showed a significantly lower colonization rate at the intestinal cell barrier and consequently a decreased efficiency for organ invasion compared with the wild-type strain. Taken together, these data demonstrate that BapA contributes both to biofilm formation and invasion through the regular Salmonella infection route.

Amino Acid Sequence↗
PubMed1997

Preoperative glutamine loading does not prevent endotoxemia in cardiac surgery.

BACKGROUND: The presence of endotoxemia is relatively common in cardiac surgery patients and it may modify the metabolic and hemodynamic responses peri- and postoperatively. Impaired gut fuel metabolism may contribute to the disturbed function and deterioration of the intestinal mucosal barrier and the development of bacterial translocation and endotoxemia. Glutamine may protect the gut mucosal barrier during marginal or insufficient perfusion. METHODS: We studied the effects of glutamine supplementation on endotoxemia and blood levels of tumor necrosis factor (TNF) during and after extracorporeal circulation (ECC) and the effects of endotoxemia on systemic and regional (splanchnic and leg) hemodynamics and metabolism after cardiac surgery. Nineteen elective coronary bypass patients were randomly assigned to receive preoperatively for 12 h either an infusion of glucose and a balanced amino acid solution (AA-group) or a solution containing 1/5 of total nitrogen as alanyl-glutamine (ALAGLN-group). RESULTS: Glutamine and amino acid loading before ECC did not protect from peri- or postoperative endotoxemia. Endotoxemia was detected in 5 vs. 7 of patients during ECC and 6 vs. 5 of patients postoperatively in the ALAGLN-group vs. AA-group, respectively. More than half of the patients at every measurement had an increased level of TNF. There was no consistent difference between the arterial and hepatic vein endotoxin- or TNF-concentrations. Endotoxemia did not modify systemic or regional hemodynamics and metabolism after cardiac operation. CONCLUSION: Glutamine did not prevent endotoxemia during or after cardiac surgery. An increased level of TNF was common and observed also in some patients without endotoxemia. Endotoxemia did not modify regional or whole-body metabolic patterns or hemodynamics.

Amino Acids↗
PubMed1997

Detection of Aspergillus galactomannan antigen in foods and antibiotics.

The specificity of the Pastorex Aspergillus latex agglutination test for the diagnosis of manifest aspergillosis is hampered by the occurrence of false-positive results. In order to prove whether or not the false-positive reactions may be caused by the uptake of the soluble galactomannan antigen from the environment, the presence of the antigen was tested in foods, air samples, antibiotics for therapeutic use and faeces. Reactions of the Aspergillus latex agglutination test were found in 15 (79%) out of 19 samples of meals prepared in a hospital kitchen, in five out of six canned vegetables from a supermarket, in all of six samples of pasta and rice bought in health shops, in the faeces of four bone marrow transplant (BMT) recipients and of four healthy subjects and in one and two batches of the antibiotics co-amoxyclav and piperacillin respectively. The concentration of the antigen in faecal material was calculated to be in the range of 1.2-38.4 micrograms g-1. It is concluded that the faecal galactomannan antigen may reach the circulation in patients with dysfunction of the intestinal mucosal barrier, e.g. BMT recipients, thus leading to diagnostically false-positive antigenaemia.

Air Microbiology↗
PubMed1996

[MRSA enteritis following severe gastroenteritis of salmonellosis].

A 62-year-old female patient was given cancer chemotherapy for lymph nodes metastases in the left breast cancer. She was admitted to the hospital because of severe watery diarrhea, in hypovolemic shock, and was diagnosed as suffering from not-typhoidal Salmonella by stool culture. After systemic administration of antibiotic agents, she became well in a few days, but on the 16th hospital day, she had severe watery diarrhea, hypovolemic shock and then cardiac arrest. She was resuscitated immediately. The stool culture revealed methicillin-resistant Staphylococcus aureus (MRSA), type II coagulase, producing TSST-1 and type BC staphylococcal enterotoxin. It was thought that in this case, MRSA enteritis was caused by damage of the intestinal mucosal barrier of the defense mechanism against infection due to salmonellosis and administration of multiple antibiotic agents.

Anti-Bacterial Agents↗
PubMed1999

Modified hemoglobins produce venular interendothelial gaps and albumin leakage in the rat mesentery.

Cross-linked hemoglobin (alphaalpha-Hb) and polyethylene glycol (PEG)-conjugated Hb have both been considered as possible "blood substitutes." Previously, we showed that PEG-Hb extravasates rapidly in the intestinal mucosa and causes transient epithelial sloughing, resulting in temporary opening of the intestinal epithelial barrier. In the present study, the rat mesenteric preparation was used to quantify the effects of the two Hbs on microvascular leakage to albumin and to investigate possible changes in the integrity of the interendothelial cell junctions and the endothelial actin cytoskeleton. In anesthetized Sprague-Dawley rats, the microvasculature of a mesenteric window was perfused with HEPES-buffered saline (HBS) containing 0.5 mg/ml BSA and 2 mg/ml alphaalpha-Hb (n = 16) or PEG-Hb (n = 5) for 2 or 10 min. Controls (n = 4) just received HBS-BSA. In some experiments (n = 9 for alphaalpha-Hb; n = 5 for PEG-Hb), the perfusate was then replaced by FITC-albumin in HBS-BSA for the next 3 min. The vasculature was then perfusion fixed, stained for filamentous actin and for mast cells, and viewed microscopically. In the remaining experiments, the mesenteric microvasculature was stained with silver nitrate to determine the number of endothelial junctional gaps per length of venules. Both Hbs increased the number and area of leaks per micrometer of venular length compared with control, but alphaalpha-Hb increased to a greater extent than PEG-Hb. Formation of leaks was accompanied by changes in the endothelial actin cytoskeleton and by an increased number of endothelial gaps. Mast cell degranulation was significantly greater (P < 0.05) in Hb-treated preparations compared with controls, but there was no direct correlation between sites of degranulation and albumin leakage. These Hbs appear to induce venular leakage in the mesentery by mechanisms similar to those previously observed after treatment with histamine or nitric oxide synthase inhibitors.

Actins↗
PubMed1989

Passage of Salmonella through polarized epithelial cells: role of the host and bacterium.

Salmonella are intracellular parasites which enter their hosts by penetrating the intestinal epithelial barrier. We examined the interaction of S. choleraesuis and S. typhimurium with Madin Darby canine kidney (MDCK) and human larynx (HEp-2) epithelial cells to characterize bacterial adherence, invasion and penetration through epithelial monolayers. Epithelial cell microfilaments were required for bacterial internalization and surrounded the bacteria as they were internalized. The bacteria entered membrane-bound vacuoles inside epithelial cells where they replicated. When polarized MDCK cell monolayers were infected, we found that Salmonella could pass through this barrier and enter medium bathing the opposite surface, although most bacteria remained within the monolayer. Synthesis of several Salmonella proteins was induced by the presence of epithelial cell surfaces, and these proteins were required for bacterial adherence and invasion. This induction was stimulated by trypsin- and neuraminidase-sensitive structures on epithelial cells.

Actin Cytoskeleton↗
PubMed1999

Synthesis and evaluation of novel coumarin-based esterase-sensitive cyclic prodrugs of peptidomimetic RGD analogs with improved membrane permeability.

Earlier, we reported the development of a coumarin-based prodrug system that could be used for the preparation of cyclic prodrugs of opioid peptides. These cyclic prodrugs exhibited excellent membrane permeability characteristics. Therefore, it was of interest to determine the effects of this prodrug strategy on the membrane permeabilities of peptidomimetics which also have low membrane permeabilities. For this study, we have chosen two RGD (Arg-Gly-Asp) peptidomimetics, which have the potentials to be developed clinically as orally active antithrombotic agents. However, the clinical development of oral dosage forms of these RGD analogs has been hindered by their low intestinal mucosal permeability. Therefore, we have synthesized the corresponding coumarin-based cyclic prodrugs of these RGD peptidomimetics, which have the two most polar functional groups, a carboxyl and an amino group, masked as an ester and an amide, respectively. These cyclic prodrugs were shown to have higher membrane interaction potentials, as estimated by their partitioning between aqueous buffer and an immobilized artificial membrane, than the corresponding RGD analogs suggesting that they should exhibit good membrane permeation characteristics. Subsequently, in a separate study these cyclic prodrugs were shown to be 5 to 6-fold more able to permeate monolayers of Caco-2 cells, an in vitro cell culture model of the intestinal mucosa barrier, than the corresponding RGD peptidomimetics.

Caco-2 Cells↗