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PubMed2000

Characterization of M cell development during indomethacin-induced ileitis in rats.

BACKGROUND: M cells play an important role in the intestinal immune system as they have a high capacity for transcytosis of a wide range of microorganisms and macromolecules. However, little is known about the role of M cells during intestinal inflammation. AIM: We studied M cell development during indomethacin-induced intestinal inflammation in rats. METHODS: Ileitis in rats was induced by two subcutaneous injections with indomethacin (7.5 mg/kg) given 24 h apart. Rats were sacrificed after 14 days and tissue was analysed by fluorescence microscopy and electron microscopy. M cells could be visualized by using the FITC-labelled mAb anti-cytokeratin (CK)-8 (clone 4.1.18), which was recently identified as specific M cell marker in rats. The number of cytokeratin-8 positive M cells was related to the surface of the follicle associated epithelium. For morphological studies, we used both transmission electron microscopy (T.E.M.) and scanning electron microscopy (S.E.M.). RESULTS: In non-inflamed ileum M cells were scarce. Only 4% of the follicle associated epithelium were M cells, whereas an increase of M cells up to 11% was found in inflamed follicle associated epithelium (P < 0.001). The rate of M cell induction depended on the macroscopic degree of inflammation. T.E.M./S.E.M. studies showed that in inflamed tissue most M cells underwent apoptosis with typical morphological signs. In contrast to apoptotic M cells, the neighbouring enterocytes usually appeared intact. The number of mononuclear cells below the follicle associated epithelium was significantly increased. S.E.M. studies revealed that during induced ileitis mononuclear cells migrated from the lamina propria into the gut lumen by passing through apoptotic M cells. CONCLUSIONS: During indomethacin-induced ileitis in rats the increase in M cell number in association with apoptosis of M cells may alter the intestinal barrier function. These observations may play a pivotal role in the pathogenesis of chronic intestinal inflammation, e.g. in inflammatory bowel disease.

Animals↗
PubMed2002

Cloning of the human claudin-2 5'-flanking region revealed a TATA-less promoter with conserved binding sites in mouse and human for caudal-related homeodomain proteins and hepatocyte nuclear factor-1alpha.

Claudin-2 is a structural component of tight junctions in the kidneys, liver, and intestine, but the mechanisms regulating its expression have not been defined. The 5'-flanking region of the claudin-2 gene contains binding sites for intestine-specific Cdx homeodomain proteins and hepatocyte nuclear factor (HNF)-1, which are conserved in human and mouse. Both Cdx1 and Cdx2 activated the claudin-2 promoter in the human intestinal epithelial cell line Caco-2. HNF-1alpha augmented the Cdx2-induced but not Cdx1-induced transcriptional activation of the human claudin-2 promoter. In mice, HNF-1alpha was required for claudin-2 expression in the villus epithelium of the ileum and within the liver but not in the kidneys, indicating an organ-specific function of HNF-1alpha in the regulation of claudin-2 gene expression. Tight junction structural components, which determine epithelial polarization and intestinal barrier function, can be regulated by homeodomain proteins that control the differentiation of the intestinal epithelium.

3T3 Cells↗
PubMed2004

[Intestinal permeability in patients with viral and alcoholic liver disease].

BACKGROUND/AIMS: Increased intestinal permeability has been possible contributing factors to the pathogenesis of alcoholic liver disease. Moreover, it can contribute to the development of bacterial infection and intestinal endotoxemia in patients with liver cirrhosis. This study aimed to examine the difference of intestinal barrier dysfunction between alcoholic and viral liver disease patients through the comparison of the intestinal permeabilities of patients with clinical characteristics. METHODS: Intestinal permeabilities were measured in 18 healthy controls, 41 patients with alcoholic liver disease (17 cases of alcoholic liver disease without cirrhosis and 24 cases of alcoholic liver cirrhosis) and 46 patients with viral liver disease (14 cases of chronic viral hepatitis and 32 cases of viral liver cirrhosis) by measuring 24 hour urine excretion of 51Cr-EDTA. RESULTS: The intestinal permeability was significantly increased in the patients with alcoholic liver disease without cirrhosis (5.62 +/- 2.80%), alcoholic liver cirrhosis (5.29 +/- 2.48%) and viral liver cirrhosis (3.15 +/- 1.39%) compared with that in control subjects (1.99 +/- 0.53%). On the contrary, it was not increased in the patients with chronic viral hepatitis (2.05 +/- 0.57%) versus controls. The significant correlation was not found between intestinal permeability and clinical and laboratory findings. CONCLUSIONS: The intestinal permeability was elevated in patients with alcoholic liver disease compared to those with viral liver cirrhosis. The pathophysiology of liver injury secondary to intestinal epithelial damage may be different between alcoholic and viral liver diseases.

Aged↗
PubMed1989

Evolution of the caecal epithelial barrier during Clostridium difficile infection in the mouse.

The most striking effect of Clostridium difficile infection is its degrading of the intestinal barrier. The aim of this study is to establish whether the cellular or paracellular constituent of the barrier is the initial target of the toxins produced by C difficile. Accordingly, the caecal epithelium of C3H/He mice was challenged under three experimental conditions with the C difficile strain VPI 10463: (1) by in vivo inoculation of axenic mice, (2) by adding the toxins to ligated caeca in vivo, and (3) by adding them to the mucosal side of isolated caeca in Ussing chambers. Under all three conditions, the epithelial barrier was tested in caeca mounted in these chambers. The transepithelial potential difference (PD), electrical conductance (G), and intact and degraded Horseradish peroxidase (HRP) fluxes were used as indexes of permeability. Results were as follows: (1) In axenic mice, C difficile caused severe infection, produced toxins A and B, reduced PD, and enhanced G and intact HRP fluxes without changing degraded HRP fluxes, (2) four hours after the toxins were added to ligated caeca in vivo, PD was relatively unaltered, but G, and intact and degraded HRP fluxes increased, and (3) when toxins were added to caeca during two hours in the Ussing chambers, the only modification observed was an increase in degraded-HRP fluxes. These results indicate that the C difficile toxins gradually cause intestinal lesions. After an apparent resistance, they stimulate the endocytotic process and then increase paracellular permeability and finally cause loss of cell viability.

Animals↗
PubMed1996

Influence of macrophage depletion on bacterial translocation and rejection in small bowel transplantation.

Rejection and sepsis can be intimately related following small bowel transplantation when rejection compromises normal intestinal barrier mechanisms and bacterial translocation results. Macrophages play a role in controlling the egress of intestinal luminal bacteria--and they have also been implicated in allograft rejection. In this study, the role of macrophages in rejection and bacterial translocation was evaluated by depleting macrophages in donors and/or recipients of rat small bowel allografts with injection of liposome-encapsulated dichloromethylene diphosphonate (CL2MDP). In preliminary studies, we demonstrated that a single intraperitoneal injection of liposome-encapsulated CL2MDP (350 mg/kg) depleted ED2-positive macrophages by > 90% in the liver mesenteric lymph nodes and proximal and distal small bowel, and by approximately 50% in the spleen. ED1-positive macrophages were depleted by > 90% in the liver and by approximately 50% at the other sites. ED3-positive macrophages were completely depleted. Dendritic cells were > 90% depleted in the spleen and mesenteric lymph nodes, but were not depleted in the small bowel. Macrophage depletion in the donor resulted in increased translocation of bacteria to the peritoneal cavity (P = 0.03) if recipient macrophages were present. With histopathologic analysis, a significantly milder rejection with less arteritis was seen in the allografts of the recipient macrophage-depleted group compared with nondepleted controls (P = 0.045). This suggests that recipient macrophages play an important role in rejection. With macrophage depletion in both the donor and the recipient, graft survival was prolonged significantly (13.2 +/- 1.9 days) compared with non-macrophage-depleted controls (9.2 +/- 1.3 days) (P = 0.003). These studies suggest that strategies targeting recipient macrophages may be useful in controlling small bowel allograft rejection without increasing bacterial translocation.

Animals↗
PubMed2006

IL-22 is increased in active Crohn's disease and promotes proinflammatory gene expression and intestinal epithelial cell migration.

IL-22 is produced by activated T cells and signals through a receptor complex consisting of IL-22R1 and IL-10R2. The aim of this study was to analyze IL-22 receptor expression, signal transduction, and specific biological functions of this cytokine system in intestinal epithelial cells (IEC). Expression studies were performed by RT-PCR. Signal transduction was analyzed by Western blot experiments, cell proliferation by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay and Fas-induced apoptosis by flow cytometry. IEC migration was studied in wounding assays. The IEC lines Caco-2, DLD-1, SW480, HCT116, and HT-29 express both IL-22 receptor subunits IL-22R1 and IL-10R2. Stimulation with TNF-alpha, IL-1beta, and LPS significantly upregulated IL-22R1 without affecting IL-10R2 mRNA expression. IL-22 binding to its receptor complex activates STAT1/3, Akt, ERK1/2, and SAPK/JNK MAP kinases. IL-22 significantly increased cell proliferation (P = 0.002) and phosphatidylinsitol 3-kinase-dependent IEC cell migration (P < 0.00001) as well as mRNA expression of TNF-alpha, IL-8, and human beta-defensin-2. IL-22 had no effect on Fas-induced apoptosis. IL-22 mRNA expression was increased in inflamed colonic lesions of patients with Crohn's disease and correlated highly with the IL-8 expression in these lesions (r = 0.840). Moreover, IL-22 expression was increased in murine dextran sulfate sodium-induced colitis. IEC express functional receptors for IL-22, which increases the expression of proinflammatory cytokines and promotes the innate immune response by increased defensin expression. Moreover, our data indicate intestinal barrier functions for this cytokine-promoting IEC migration, which suggests an important function in intestinal inflammation and wound healing. IL-22 is increased in active Crohn's disease and promotes proinflammatory gene expression and IEC migration.

Cell Movement↗
PubMed2000

Inducible nitric oxide synthase gene knockout mice have increased resistance to gut injury and bacterial translocation after an intestinal ischemia-reperfusion injury.

OBJECTIVE: Intestinal ischemia-reperfusion after severe shock states is often associated with bacterial translocation and intestinal barrier dysfunction. Our previous studies showed that inducible nitric oxide synthase (iNOS) gene knockout mice were resistant to endotoxin-induced bacterial translocation and ileal mucosal damage. The goal of this study was to test whether iNOS mediates bacterial translocation after intestinal ischemia-reperfusion, using iNOS knockout mice (iNOS-/-) and their wild-type littermates (iNOS+/+). DESIGN: Prospective animal study with concurrent controls. SETTING: Small animal laboratory. SUBJECTS: Thirty-eight iNOS knockout mice and 51 wild-type littermates. INTERVENTIONS: iNOS+/+ mice or iNOS-/- mice were subjected to a sham operation or 30 mins of superior mesenteric artery occlusion followed by reperfusion. Twenty-four hours after reperfusion, bacterial translocation to mesenteric lymph nodes, ileal villous damage, and cecal bacterial population were evaluated. MEASUREMENTS AND MAIN RESULTS: Sham operation did not induce bacterial translocation, change cecal bacterial population levels, or cause ileal villous damage. Intestinal ischemia-reperfusion caused bacterial translocation in 72% of the iNOS+/+ mice but only 28% of the iNOS-/- mice. Both iNOS+/+ and iNOS-/- mice subjected to superior mesenteric artery occlusion (SMAO) in which bacterial translocation occurred had cecal bacterial population levels that were three logs higher than mice subjected to sham SMAO or mice subjected to SMAO in which bacterial translocation did not occur. The magnitude of villous injury was less in the iNOS-/- mice than the iNOS+/+ mice after SMAO, although the incidence of ileal villous damage was significantly higher in both the iNOS+/+ and iNOS-/- mice in which bacterial translocation occurred after SMAO than in the mice in which bacterial translocation did not occur after SMAO. iNOS+/+ mice subjected to SMAO had increased plasma concentrations of nitrite (NO2-) and nitrate (NO3-), and the plasma concentrations of NO2- and NO3- were highest in the mice in which bacterial translocation had occurred. CONCLUSION: iNOS knockout mice were more resistant to intestinal ischemia-reperfusion-induced bacterial translocation and mucosal injury than wild-type mice, suggesting that iNOS might play a role in intestinal ischemia-reperfusion-induced loss of gut barrier function.

Animals↗
PubMed1997

Dual role for AlF4(-)-sensitive G proteins in the function of T84 epithelial cells: transport and barrier effects.

T84 monolayers were studied to determine the effect of AlF4, an activator of heterotrimeric G proteins, on Cl-secretion and intestinal barrier function. Basolateral (but not apical) addition of AlF4- increased short-circuit current (I(sc)) and decreased transepithelial resistance. Preincubation with the heavy metal chelator deferoxamine showed that both effects were dependent on Al3+. The effect on I(sc) was abolished by the intracellular Ca2+ chelator 1,2-bis(2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid or in Cl(-)-free solutions, whereas the decrease in resistance was unaffected. AlF4- also increased intracellular Ca2+, as assessed via fura 2 fluorometry. AlF4- had no effect on adenosine 3',5'-cyclic monophosphate (cAMP) or guanosine 3',5'-cyclic monophosphate (cGMP) levels in T84 cells. The effect of AlF4- on transepithelial resistance was accompanied by a decrease in cellular F-actin as well as increased transepithelial fluxes of the paracellular markers mannitol and inulin. The results indicate that AlF4(-)-sensitive G proteins regulate both epithelial secretory and barrier functions, but via different pathways. AlF4- increases Cl- secretion via a Ca2+-dependent and cAMP- and cGMP-independent mechanism in T84 cells, whereas the decrease in resistance is independent of Ca2+.

Actins↗
PubMed1991

Iron absorption by intestinal epithelial cells: 1. CaCo2 cells cultivated in serum-free medium, on polyethyleneterephthalate microporous membranes, as an in vitro model.

Iron absorption by intestinal epithelial cells, passage onto plasmatic apotransferrin, and regulation of the process remain largely misunderstood. To investigate this problem, we have set up an in vitro model, consisting in CaCo2 cells (a human colon adenocarcinoma line, which upon cultivation displays numerous differentiation criteria of small intestine epithelial cells). Cells are cultivated in a serum-free medium, containing 1 microgram/ml insulin, 1 ng/ml epidermal growth factor, 10 micrograms/ml albumin-linoleic acid, 100 nM hydrocortisone, and 2 nM T3 on new, transparent, Cyclopore polyethyleneterephthalate microporous membranes coated with type I collagen. Cells rapidly adhere, grow, and form confluent monolayers; after 15 days, scanning electron microscopy reveals numerous uniform microvilli. Domes, which develop on nonporous substrata, are absent on high porosity membranes. Culture medium from upper and lower compartments of microplate inserts and cell lysates were immunoprecipitated after labeling with [3H]glucosamine and leucine; analysis was done by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), followed by autoradiography. [3H]transferrin is found mainly in the lower compartment and in cells; [3H]apolipoprotein B is released in both compartments, and fibronectin almost entirely recovered in the lower compartment; [3H]transferrin receptors and ferritin are only present in cell lysates. Binding experiments also show that transferrin receptors are accessible from the lower compartment. These results suggest that CaCo2 cells, cultivated in synthetic medium on membranes of appropriate porosity, could provide an in vitro model of the intestinal barrier, with the upper compartment of the culture insert corresponding to the apical pole facing the intestinal lumen and the lower one to the basal pole in contact with blood.

Adenocarcinoma↗
PubMed2006

TFF3-peptide increases transepithelial resistance in epithelial cells by modulating claudin-1 and -2 expression.

TFF3 plays an important role in the protection and repair of the gastrointestinal mucosa. The molecular mechanisms of TFF function, however, are still largely unknown. Increasing evidence indicates that apart from stabilizing mucosal mucins TFF3 induces cellular signals that modulate cell-cell junctions of epithelia. In transfected HT29/B6 and MDCK cells stably expressing FLAG-tagged human TFF3 we have recently shown that TFF3 down-regulates E-cadherin, impairs the function of adherens junctions and thus facilitates cell migration in wounded epithelial cell layers. Here we investigate TFF3-induced effects on the composition and function of tight junctions in these cells. TFF3 increased the cellular level of tightening claudin-1 and decreased the amount of claudin-2 known to form cation-selective channels. Expression of ZO-1, ZO-2 and occludin was not altered. The change in claudin-1 and -2 expression in TFF3-expressing HT29/B6 cells was accompanied by an increase in the transepithelial resistance in confluent monolayers of these cells. These data suggest that TFF3 plays a role in the regulation of intestinal barrier function by altering the claudin composition within tight junctions thus decreasing paracellular permeability of the intestinal mucosa.

Animals↗
PubMed2003

Glutamine supports recovery from loss of transepithelial resistance and increase of permeability induced by media change in Caco-2 cells.

Recent evidence suggests that the conditionally essential amino acid glutamine is important for intestinal barrier function. However, the mechanism remains undefined. To determine the effects of glutamine on permeability of intestinal epithelial cell monolayers, Caco-2 cells were grown on membrane filters and exposed to 4 mmol/L sodium butyrate in order to rapidly achieve high levels of alkaline phosphatase and high transepithelial resistance as seen in functionally mature enterocytes. A standard method of medium exchange consisting of removal and replacement resulted in a catastrophic loss of transepithelial resistance and increase of mannitol and dextran fluxes that required 2-4 hrs and protein synthesis to recover. The effect was attributed to exposure of the upper monolayer surface to atmosphere and could be avoided by refeeding by incremental perfusion. Spontaneously-differentiated Caco-2 monolayers were resistant to this stress. This novel stress test was employed as a sensitive assay for the requirement of glutamine for monolayer transepithelial resistance and mannitol permeability. Pre-stress glutamine availability was more important than Gln-availability during the recovery phase. Thus the transepithelial resistance and permeability of butyrate-induced monolayers is dynamically-regulated in response to atmospheric exposure, by a mechanism that depends on threshold levels of glutamine availability.

Alkaline Phosphatase↗
PubMed2005

Exogenous acid fibroblast growth factor inhibits ischemia-reperfusion-induced damage in intestinal epithelium via regulating P53 and P21WAF-1 expression.

AIM: To detect the effect of acid fibroblast growth factor (aFGF) on P53 and P21WAF-1 expression in rat intestine after ischemia-reperfusion (I-R) injury in order to explore the protective mechanisms of aFGF. METHODS: Male rats were randomly divided into four groups, namely intestinal ischemia-reperfusion group (R), aFGF treatment group (A), intestinal ischemia group (I), and sham-operated control group (C). In group I, the animals were killed after 45 min of superior mesenteric artery (SMA) occlusion. In groups R and A, the rats sustained for 45 min of SMA occlusion and were treated with normal saline (0.15 mL) and aFGF (20 mug/kg, 0.15 mL), then sustained at various times for up to 48 h after reperfusion. In group C, SMA was separated, but without occlusion. Apoptosis in intestinal villi was determined with terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling technique (TUNEL). Intestinal tissue samples were taken not only for RT-PCR to detect P53 and P21WAF-1 gene expression, but also for immunohistochemical analysis to detect P53 and P21WAF-1 protein expression and distribution. RESULTS: In histopathological study, ameliorated intestinal structures were observed at 2, 6, and 12 h after reperfusion in A group compared to R group. The apoptotic rates were (41.17+/-3.49)%, (42.83+/-5.23)%, and (53.33+/-6.92)% at 2, 6, and 12 h after reperfusion, respectively in A group, which were apparently lower than those in R group at their matched time points (50.67+/-6.95)%, (54.17+/-7.86)%, and (64.33+/-6.47)%, respectively, (P<0.05)). The protein contents of P53 and P21WAF-1 were both significantly decreased in A group compared to R group (P<0.05) at 2-12 h after reperfusion, while the mRNA levels of P53 and P21WAF-1 in A group were obviously lower than those in R group at 6-12 h after reperfusion (P<0.05). CONCLUSION: P53 and P21WAF-1 protein accumulations are associated with intestinal barrier injury induced by I-R insult, while intravenous aFGF can alleviate apoptosis of rat intestinal cells by inhibiting P53 and P21WAF-1 protein expression.

Animals↗
PubMed1995

The intestinal response to critical illness.

Critical illness is characterized by the presence of several factors that can cause marked alterations in the structure and function of multiple organ systems (1-2). These factors include injury, ischemia, sepsis, and starvation (Fig. 1). It is common for more than one of these problems to be present in the individual patient. Our current understanding of the effect of these various factors on intestinal structure and function has increased markedly during the past decade (3). Furthermore, the patterns of intestinal dysfunction that occur in response to these conditions have also been better characterized. Although malabsorption and motility disorders have long been recognized as clinical problems, more recently loss of intestinal barrier function and immune dysfunction have gained attention. This improved understanding of the response of the intestine to critical illness may lead to prevention of intestinal failure or permit more specific therapy when it occurs. The goals of this manuscript are to describe the response of the small intestine to critical illness and to identify potential therapeutic strategies for preventing and treating intestinal failure in this setting.

Critical Illness↗
PubMedDate not supplied

Increased intestinal permeability correlates with gastrointestinal toxicity among formulations of the fluorouracil analogue tegafur in rats.

BACKGROUND: S-1 is a new antitumor agent which was developed based on biochemical modulation of fluorouracil. S-1 consists of tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1. S-1 has been reported to enhance therapeutic effects and to reduce the gastrointestinal toxicity as compared with 5-fluorouracil. In this study performed in rats, S-1 was used to assess the relationship between gastrointestinal mucosal toxicity and changes in intestinal barrier function. METHODS: Fifteen rats were equally divided into three groups: group A (untreated controls), group B (FT and CDHP mixture), and group C (FT and CDHP in combination with Oxo). The animals in groups B and C received equitoxic doses of the drugs in their food for 14 consecutive days. The intestinal permeability was determined on the basis of the urinary recovery of orally administered lactulose and mannitol (L/M). Injury to the small intestines was evaluated by light microscopy. The cell surface expression of CD44 was evaluated immunohistochemically. RESULTS: Recovery of L/M in urine (expressed as a fraction of the dose administered) was 0.15 +/- (SE) 0.08, 0.23 +/- 0.13, and 0.09 +/- 0.04 in groups A, B, and C, respectively. The intestinal permeability in group B was significantly higher than that in group C (p < 0.05). Treatment with FT and CDHP (groups B and C) induced injury to the small intestine and decreased expression of CD44 within the intestinal mucosa, but the extent of damage was reduced by coadministration of Oxo (group C). CONCLUSION: This experimental study suggested that the gastrointestinal toxicity resulting from administration of anticancer drugs is accompanied by an impaired gut barrier function measurable as an increase in intestinal permeability to L/M.

Animals↗
PubMed1999

Enhancement of ovalbumin-induced antibody production and mucosal mast cell response by mercury.

Food contaminants may contribute to the recent increased incidence of food allergies. We have investigated this hypothesis experimentally. It was our objective to determine whether toxicity to the intestinal tissue by orally applied mercury (Hg) could modulate the immune response to food allergens. Effective mechanisms were studied with functional immunological and toxicological parameters. Brown Norway rats were immunized intraperitoneally by ovalbumin (OVA). Before oral challenge with OVA, immunized and non-immunized animals were exposed to HgCl2. Immunological responses were measured by enzyme-linked immunosorbent assays [anti-OVA-IgE and-IgG, rat mast cell protease II (RMCPII), interferon-gamma, interleukin-4, lymphocyte proliferation] and by flow cytometry (lymphocyte subpopulations). Toxicity of Hg to the intestinal barrier was determined by measuring viability, DNA damage and induction of glutathione S-transferase in isolated intestinal epithelial cells and lymph node cells, and by measuring permeability, short-circuit current and tissue conductance of the intact intestinal epithelium. A single high oral dose of HgCl2 enhanced the serum concentrations of anti-OVA-IgE and IgG (P < 0.05) and of RMCPII (P < 0.05) in immunized rats. The treatment resulted in a higher number of CD4/CD25+ T cells in the lymph nodes (P < 0.05). The multiple application of low HgCl2 doses (5 x 0.2 mg/kg body weight) only resulted in an elevated RMCPII serum concentration (P < 0.05). Neither treatment schedules impaired proliferation and cytokine production of lymphocytes. In non-immunized rats only minor immunological changes were observed. Oral HgCl2 induced genotoxic damage in lymph node cells and in jejunal epithelial cells (P < 0.05). Moreover, HgCl2 increased the permeability of intestinal epithelial tissue and of Caco-2 monolayers and was genotoxic and cytotoxic to isolated intestinal epithelial cells in vitro. In conclusion, these studies indicate that the food contaminant Hg can stimulate the immune response to OVA in immunized rats. One possible mechanism could be the toxicity of Hg to the intestinal epithelial and the lymph node cells. Whether humans with allergies respond to high oral doses of Hg in a similar way needs to be investigated in further studies.

Animals↗
PubMed2001

Oedema disease is associated with metabolic acidosis and small intestinal acidosis.

Limited information is available about the pathogenesis and pathophysiology of oedema disease (OD). Oedema disease is caused by specific enterotoxemic Escherichia coli (SLTIIv-toxin producing) strains; however, the same strains are also found in non-afflicted pigs. Furthermore, it is unclear how the 80 kDa SLTIIv-toxin can pass the intestinal barrier. In the present paper, piglets showing signs of acute OD were anaesthetised, instrumented and cardiovascular and intestinal parameters were determined at 0, 1, 2 and 3 hours. Healthy piglets from the same herd were used as a control. Cardiac output, blood pH and bicarbonate, small intestinal intramucosal pH, and (pulmonary) blood pressure were significantly lower in OD-pigs than in control pigs. It is concluded that OD is associated with metabolic and intestinal acidosis. Intestinal acidosis is known to increase macromolecular permeability. This suggests that once OD has developed, influx of SLTIIv-toxin into the blood stream is facilitated, thus perpetuating the disease. Since intestinal permeability appears to be central in OD, it is argued that post-weaning events increase intestinal permeability and predispose individuals to OD.

Acidosis↗
PubMed2000

Invasion genes are not required for Salmonella enterica serovar typhimurium to breach the intestinal epithelium: evidence that salmonella pathogenicity island 1 has alternative functions during infection.

Salmonella enterica serovar Typhimurium invasion genes are necessary for bacterial invasion of intestinal epithelial cells and are thought to allow salmonellae to enter and cross the intestinal epithelium during infection. Many invasion genes are encoded on Salmonella pathogenicity island 1 (SPI1), and their expression is activated by HilA, a transcription factor also encoded on SPI1. We have studied the role of Salmonella invasion genes during infection of mice following intragastric inoculation. We have found that strains containing a mutation in hilA or invG were recovered from the intestinal contents, intestinal tissues, and systemic tissues at a lower frequency than their parental wild-type strain. In contrast, a strain in which SPI1 is deleted was recovered from infected mice at a frequency similar to that of its parental wild-type strain. The DeltaSPI1 phenotype indicates that S. enterica does not require invasion genes to cross the intestinal epithelium and infect systemic tissues. This result has forced us to reconsider the long-held belief that invasion genes directly mediate bacterial infection of the intestinal mucosa and traversion of the intestinal barrier during infection. Instead, our results suggest that hilA is required for bacterial colonization of the host intestine. The seemingly contradictory phenotype of the DeltaSPI1 mutant suggests that deletion of another gene(s) encoded on SPI1 suppresses the hilA mutant defect. We propose a model for S. enterica pathogenesis in which hilA and invasion genes are required for salmonellae to overcome a host clearance response elicited by another SPI1 gene product(s).

Animals↗
PubMed1998

[Bacterial translocation in multiple organ failure].

Bacterial translocation has been defined as the passage of both viable and nonviable bacteria and their products (e.g., endotoxins) across the intestinal barrier to extraintestinal sites such as the mesenteric lymph nodes, liver, etc. It has been hypothesized that intestinally derived bacteria or endotoxins serve as triggers to initiate, perpetuate, or exacerbate the septic state and thereby promote the development of multiple organ failure (MOF). In various animal studies, bacterial translocation has been associated with mortality and septic complications. Although most data on translocation have been derived from animal studies, convincing evidence has been provided that translocation may occur in humans during various disease states. The question still remains, however, of whether bacterial translocation is an important pathophysiological event in human disease or simply an epiphenomenon of severe disease, since the results are variable. Recent studies have indicated that the gut can produce important amounts of immunoinflammatory factors and that intestinal injury predisposes to distant organ injury even in the absence of detectable bacteria or endotoxins in the portal blood or tissues. This hypothesis may in part explain the inconsistent causal relationship between bacterial translocation and MOF.

Animals↗