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PubMed1995

Outcome analysis of 71 clinical intestinal transplantations.

OBJECTIVE: The aim of the study was to determine risk factors associated with graft failure and mortality after transplantation of the intestine alone or as part of an organ complex. SUMMARY BACKGROUND DATA: Even with modern immunosuppressive therapies, clinical intestinal transplantation remains a difficult and unreliable procedure. Causes for this and solutions are needed. METHODS: Between May 1990 and February 1995, 71 intestinal transplantations were performed in 66 patients using tacrolimus and low-dose steroids. The first 63 patients, all but one treated 1 to 5 years ago, received either isolated grafts (n = 22), liver and intestinal grafts (n = 30), or multivisceral grafts (n = 11). Three more recipients of allografts who recently underwent surgery and one undergoing retransplantation were given unaltered donor bone marrow cells perioperatively as a biologic adjuvant. RESULTS: Of the first 63 recipients, 32 are alive: 28 have functioning primary grafts and 4 have resumed total parenteral nutrition after graft enterectomy. Thirty-five primary grafts were lost to technical and management errors (n = 10), rejection (n = 6), and infection (n = 19). Regression analysis revealed that duration of surgery, positive donor cytomegalovirus (CMV) serology, inclusion of graft colon, OKT3 use, steroid recycle, and high tacrolimus blood levels contributed to graft loss. All four intestine and bone marrow recipients are alive for 2-3 months without evidence of graft-versus-host disease. CONCLUSION: To improve outcome after intestinal transplantation with previous management protocols, it will be necessary to avoid predictably difficult patients, CMV seropositive donors, and inclusion of the graft colon. Bone marrow transplantation may further improve outcome by ameliorating the biologic barriers of rejection and infection and allowing less restrictive selection criteria.

Adult↗

PubMed1983

[Further studies on the practicability of fattening and slaughtering pigs free from Salmonella].

Attempts were made to fatten pigs free from Salmonella on a piggery which was initially contaminated with Salmonella. A specially adapted pig house was thoroughly cleaned and disinfected and efforts were made to keep out birds, insects and rodents during this experiment. Attempts were also made to purchase piglets free from Salmonella. Clean clothes, special footwear and disinfectants were used on entering the pig house. Infection with serotypes of Salmonella similar to those detected immediately prior to the experiment on the ancillary breeding farm occurred in the experimental pig house during the experiment. Other serotypes of Salmonella present on the piggery did not penetrate into the experimental pig house so that it can be concluded that all hygienic barriers functioned adequately after the piglets had been brought in. The experiment showed that the hygienic procedures had a positive effect on economic results, even though efforts to keep out Salmonella had not been completely successful. The pigs were slaughtered in two groups after the fattening period. Group one was slaughtered as usual. The pigs of group two were scalded individually with every care after slaughter and the guts were carefully removed. Examination of the carcases after slaughter showed that 46 per cent of the pigs of group one were contaminated with Salmonella, against 7 per cent of group two. It can be concluded from this finding that slaughtering does not necessarily result in further contamination by the Salmonella organisms present in the intestine but that a careful slaughtering procedure may even reduce the number of Salmonella organisms on the surfaces of the carcases of pigs.

Abattoirs↗

PubMed1994

Capsaicin-like effect of resiniferatoxin in the rat stomach.

Neurochemical and functional studies were performed to investigate and to compare the effects of resiniferatoxin and capsaicin in the rat stomach. Neonatal administration of resiniferatoxin (0.6-1.6 mumol/kg subcutaneously (s.c.)) produced a marked decrease in gastric calcitonin gene-related peptide-like immunoreactivity in both secretory and non-secretory region of the stomach. Almost complete depletion of the peptide was determined by neonatal administration of capsaicin (164 mumol/kg s.c.). Vasoactive intestinal polypeptide-like immunoreactivity was concomitantly unaffected by resiniferatoxin or capsaicin, thus showing the selectivity of action of the neurotoxins on gastric afferent fibers. Oral administration of an equimolar dose (0.3 nmol/kg) of resiniferatoxin or capsaicin together with 50% ethanol reduced at a similar extent gastric haemorrhagic lesions produced by the mucosal barrier-breaker agent. These findings provide evidence that resiniferatoxin and capsaicin may act on a common neuronal target in the rat stomach and that the acute exciting (protective) effect is of the same magnitude.

Administration, Oral↗

PubMed2004

Altered immune system glycosylation causes colitis in alpha1,2-fucosyltransferase transgenic mice.

BACKGROUND AND AIMS: Altered glycosylation of the mucosal barrier has been proposed as a primary defect in the pathogenesis of IBD. Glycosylation defects however may also have a profound influence on immune function. Mice transgenic for human alpha1,2-fucosyl-transferase (hFUT1) have widespread disturbances in cell surface glycosylation and spontaneously develop colitis. The aims of this study were to characterize colitis in hFUT1 mice and to determine whether glycosylation-induced changes of the mucosal barrier or the immune system were critical for its pathogenesis. METHODS: The pathologic features of hFUT1 transgenic mice were characterized. The mucosal barrier was assessed by lectin binding and permeability studies. T-cells and the thymus were assessed by FACS analysis and histology. To isolate the hFUT1 mucosal barrier from the hFUT1 immune system, bone marrow chimeras were generated. RESULTS: Seventy percent of hFUT1 mice raised in SPF conditions developed histologic evidence of colitis. The mucosal barrier demonstrated altered glycosylation but intestinal permeability was preserved. HFUT1 mice were profoundly lymphopenic, with aberrant T-cell markers and thymic medullary hypoplasia. Reconstitution with wild type bone marrow restored thymic morphology and prevented colitis in hFUT1 mice. CONCLUSION: Altered glycosylation in hFUT1 mice has a profound influence on T-cell development and this defect, rather than a mucosal barrier defect, is crucial for the development of colitis.

Animals↗

PubMed2004

NF-kappaB- and AP-1-mediated induction of human beta defensin-2 in intestinal epithelial cells by Escherichia coli Nissle 1917: a novel effect of a probiotic bacterium.

Little is known about the defensive mechanisms induced in epithelial cells by pathogenic versus probiotic bacteria. The aim of our study was to compare probiotic bacterial strains such as Escherichia coli Nissle 1917 with nonprobiotic, pathogenic and nonpathogenic bacteria with respect to innate defense mechanisms in the intestinal mucosal cell. Here we report that E. coli strain Nissle 1917 and a variety of other probiotic bacteria, including lactobacilli--in contrast to more than 40 different E. coli strains tested--strongly induce the expression of the antimicrobial peptide human beta-defensin-2 (hBD-2) in Caco-2 intestinal epithelial cells in a time- and dose-dependent manner. Induction of hBD-2 through E. coli Nissle 1917 was further confirmed by activation of the hBD-2 promoter and detection of the hBD-2 peptide in the culture supernatants of E. coli Nissle 1917-treated Caco-2 cells. Luciferase gene reporter analyses and site-directed mutagenesis experiments demonstrated that functional binding sites for NF-kappaB and AP-1 in the hBD-2 promoter are required for induction of hBD-2 through E. coli Nissle 1917. Treatment with the NF-kappaB inhibitor Helenalin, as well as with SP600125, a selective inhibitor of c-Jun N-terminal kinase, blocked hBD-2 induction by E. coli Nissle 1917 in Caco-2 cells. SB 202190, a specific p38 mitogen-activated protein kinase inhibitor, and PD 98059, a selective inhibitor of extracellular signal-regulated kinase 1/2, were ineffective. This report demonstrates that probiotic bacteria may stimulate the intestinal innate defense through the upregulation of inducible antimicrobial peptides such as hBD-2. The induction of hBD-2 may contribute to an enhanced mucosal barrier to the luminal bacteria.

Binding Sites↗

PubMed2000

Introduction: a brief history of capillaries and some examples of their apparently strange behaviour.

1. Over the past decade, evidence has accumulated challenging the notion that the smallest blood vessels, the capillaries, are static, uniform, semipermeable pipes with no function except as a passive barrier marking the boundary between the vascular compartments from the tissue compartment. 2. Instead, capillaries are dynamic structures that participate in the active regulation of water, waste and nutrient exchange, the formation and destruction of exchange vessels and the sites for initiation of signals to regulate the flow of blood into the exchange vascular network. 3. The following papers will provide insight into the expanded appreciation of the varied nature of capillaries and how their functions are co-ordinated to achieve 'whole organ' exchange.

Capillaries↗

PubMed2005

Effect of bacterial chemotactic peptides on intestinal inflammation in animal models of acute and chronic "relapsed" colitis.

It is known that bacterial chemotactic peptides such as formyl-methionyl-leucyl-phenylalanine (fMLP) exacerbate colitis during the acute phase, but the precise role of fMLP during chronic "relapse" is unknown. In this study we examined the effect of bacterial peptides in animal models of acute and chronic "relapsed" colitis. Different parameters were evaluated, such as tissue damage, myeloperoxidase activity, and mucosal function. In acute trinitrobenezene sulfonic acid colitis, fMLP had significant adverse effects on mucosal function and worsened several parameters. In contrast, in chronic "relapsed" colitis the ability of fMLP to exacerbate the inflammation was dependent on whether it was confined to the lumen of the colon. Bacterial peptides such as fMLP appear to play a different role in the acute phase of inflammation compared with the chronic phase, depending on the integrity of the mucosal barrier.

Acute Disease↗

PubMed2026

Functional analysis of Candida albicans protein kinases identifies Crk1 as a modulator of epithelial cell damage.

UNLABELLED: The commensal and pathogenic lifestyles of the opportunistic fungal pathogen Candida albicans require complex signaling networks regulated by protein kinases. To investigate the role of C. albicans protein kinases at the intestinal epithelial interface, we screened a comprehensive protein kinase deletion library for the capacity of the mutants to damage intestinal epithelial cells (IEC). Mutants showing altered IEC cytotoxicity relative to the wild type were further analyzed for their growth and morphology, focusing on hyper-damaging strains to identify kinases that rather prevent host cell damage. Deletion of CRK1 caused increased IEC-specific damage, despite slower growth, reduced hyphal length, and reduced adhesion as compared to wild-type cells. While tissue invasion levels and the formation of transcellular tunnels of the crk1Δ/Δ mutant were increased, the translocation capacity through the IEC barrier was reduced. Transcriptional and metabolic profiling suggested a role for Crk1 in metabolic adaptation to carbon and nitrogen sources, which was validated by showing that high glucose and amino acids are required for crk1Δ/Δ to cause increased IEC damage. Deletion of CRK1 rendered C. albicans more susceptible to cell wall and membrane stressors, but caused higher resistance to a catalase-specific and histidine biosynthesis inhibitor. This phenotypic pattern of medium- and epithelial cell type-specific cytotoxicity displayed by a C. albicans protein kinase mutant suggests that Crk1 regulates processes linked to carbon and amino acid metabolism that are relevant to interactions with intestinal epithelial cells. IMPORTANCE: Microbial signal transduction pathways regulate adaptation to changing environmental conditions and facilitate the success of many microbes during interactions with their hosts. The fungal pathobiont Candida albicans exists as a harmless commensal on mucosal surfaces of most humans but can also cause superficial and invasive infections under certain circumstances. Both lifestyles require complex signaling networks, predominantly regulated by protein kinases. The C. albicans genome was predicted to encode 108 protein kinases, yet nearly 50% remain uncharacterized. We aimed to dissect the role of C. albicans protein kinases during the transition from commensal to pathogen. We showed that multiple protein kinase genes are involved in epithelial cell damage. Particularly, the protein kinase gene Crk1 was of interest because deletion of CRK1 caused increased damage to intestinal epithelial cells under distinct conditions. Our study links Crk1 with regulation of metabolic processes relevant for commensalism and pathogenicity of C. albicans.

Candida albicans↗

PubMed1998

Rapid and prolonged impairment of gut barrier function after thermal injury in mice.

Loss of gut barrier function after burn injury can be important in the pathogenesis of systemic infections and organ dysfunction. The purpose of this study was to determine how rapidly impairment of gut barrier function occurs after burn injury and how long it persists. BALB/c mice were gavaged with 10(10) (111)In-oxine-labeled Escherichia coli 3 h before inflicting a 20% total body surface area burn. They were then killed at 5, 15, 30, 60, 120, or 240 min post-burn. Additional mice were given a 20% or 30% burn injury and were randomized into eight groups, which were killed at either 4 h or 1, 2, 4, 7, 14, or 21 days post-burn. Each mouse was gavaged with 10(10) (111)In-oxine-labeled E. coli 4 h before sacrifice to determine the magnitude of translocation. Gut barrier function was impaired as early as 5 min post-burn and was maximal by 4 h. Rapid improvement was observed by 24 h, followed by slow improvement, but with persistent abnormality through 21 days post-burn. Killing of translocated bacteria was impaired at 4 h and day 7 post-burn, according to the percentage of viable E. coli that remained alive in the tissues. The magnitude of gut dysfunction following burn injury is temporally related.

Animals↗

PubMed2000

Hepatic encephalopathy in liver cirrhosis: pathogenesis, diagnosis and management.

The pathogenesis of hepatic encephalopathy (HE) is unknown. Many theories have been proposed. Most established therapies are based on such theories but since no theory has have ever been proved, therapies have to be considered empiric. The spectrum of HE ranges from minimal cerebral functional deficits, which can only be found by sensitive psychometric tests, to coma with signs of decerebration. HE has arbitrarily been divided into stages. A number of precipitating factors are known and the first line of therapy should always be the elimination of these factors. The differential diagnosis includes all states of impaired consciousness and deficits in cerebral function in patients with chronic liver disease, and clinical and biochemical tests to differentiate are indicated. The therapeutic options for HE include: protein restriction only for a limited time in comatous patients; nonabsorbable antibiotics (aminoglycosides), which because of adverse effects are also limited to higher grades of HE: intestinal cleansing which is applicable in all degrees of HE; lactulose, branched chain aminoacids and ornithin aspartate which have been proven to be effective and can be applied long term in patients with lower grades of HE.

Anti-Bacterial Agents↗

PubMed1982

Malabsorption in giardiasis: presence of a luminal barrier (mucoid pseudomembrane). A scanning and transmission electron microscopic study.

Investigations of the small bowel mucosa by scanning and transmission electron microscopy are reported in two coetaneous children with giardiasis. Serum immunoglobulins and mucosal architecture by light microscopy were normal in both, as well as activities of lactase, sucrase, and maltase. One of the children had suggestive evidence of malabsorption. Scanning and transmission electron microscopic examination of biopsied mucosa of the child with malabsorption suggested the following: increased secretory activity in crypts and increased cell damage, producing excess mucus containing extruded cytoplasm. It is hypothesized that the physicochemical properties of the mucoid material permitted ready interaction with the mucosal surface, the biochemical qualities of which could have been altered by the presence of the parasites. Close adherence of this mucoid layer to the surface gave it the aspect of a pseudomembrane which, by covering wide areas of the mucosal surface, probably functioned as an effective luminal barrier for nutrients. This pseudomembrane was not seen by light microscopy. Excessive secretion of mucus, its physicochemical and immunologic properties, and mucus-mucosal surface interaction could have been engendered by genetic and environmental factors, which need further study. Although some mucus was present in the mucosa of the other child, it was confined to the base of the villi, and did not cover the mucosal surface. The presence of a luminal barrier (mucoid pseudomembrane) may be added to the list of mechanisms implicated in causing malabsorption in giardiasis.

Child, Preschool↗

PubMed2004

Design and evaluation of cyclodextrin-based drug formulation.

The pharmaceutically useful cyclodextrins (CyDs) are classified into hydrophilic, hydrophobic, and ionic derivatives. Because of the multi-functional characteristics and bioadaptability, these CyDs are capable of alleviating the undesirable properties of drug molecules through the formation of inclusion complexes or the form of CyD/drug conjugates. This review outlines the current application of CyDs in design and evaluation of CyD-based drug formulation, focusing on their ability to enhance the drug absorption across biological barriers, the ability to control the rate and time profiles of drug release, and the ability to deliver a drug to a targeted site.

Animals↗

PubMed2003

The effect of hypoxia on permeability and bacterial translocation in Caco-2 adult and I-407 fetal enterocyte cell culture models.

Hypoxia has been implicated in the breakdown of the intestinal epithelial barrier in animals, leading to bacterial translocation (BT); however, the mechanism of this hypoxic insult is unknown. To determine the effects of hypoxic injury in vitro on epithelial membrane integrity, transepithelial electrical resistance (TEER), mannitol permeability (Ma-Pm), and BT were measured in both an adult (Caco-2) and fetal (I-407) intestinal epithelial cell culture model. Caco-2 adult and I-407 fetal epithelial cell monolayers were treated with or without bacteria (1 x 10(7) Escherichia coli. C-25), and then incubated under either normoxic (5% CO(2) in room air) or hypoxic (5% CO(2) and 95% N(2)) conditions at 37 degrees C for 6 h. Hypoxia caused a 10% increase in Ma-Pm in the I-407 fetal cell model independent of the bacterial challenge. In contrast, a bacterial challenge in the Caco-2 adult model caused a 485% increase in Ma-Pm independent of hypoxia. Neither hypoxia, nor C-25 bacteria, for 6 h caused BT in either cell culture model. In the adult cell culture model, bacteria appear to mediate changes in epithelial barrier function, with hypoxia having no effect. On the other hand, hypoxia is the major factor in the loss of epithelial barrier function in fetal epithelium, but has no effect on adult epithelium. The data suggest that the breakdown of barrier function caused by a hypoxic insult is the primary stimulus for subsequent BT in neonates.

Bacterial Translocation↗

PubMed1989

Edgar J. Poth lecture. The surgeon and gut maintenance.

The gastrointestinal tract is metabolically active, requires specific nutrients, and is important both for substrate redistribution and barrier function. The provision of optimal support can be expected to obviate the stress-related response associated with increased gut permeability and bacterial translocation. Enteral feeding is the preferable technique whenever it is possible. It should be used to provide whatever level of nutrients the gut will accommodate, even when it may not immediately support full feeding. Parenteral administration of gut-specific nutrients may be an option in the near future. Judicious consideration of the effects of antibiotics and other drugs on indigenous flora is also important.

Animals↗

PubMed1985

Neuronal control of brain microvessel function.

Cerebral capillary endothelium forms a barrier limiting and controlling the movement of ions and solutes between blood and brain. Recent anatomical, physiological and biochemical studies have suggested the possibility that capillary function may be directly controlled by neuronal structures. Alterations in neuronal systems involved in the regulation of microcirculation may account for microvascular dysfunctions which occur in different pathologic conditions.

Acetylcholine↗

PubMed1995

Neurotensin receptors: binding properties, transduction pathways, and structure.

Neurotensin is a 13-amino acid peptide (pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu) originally isolated from hypothalami (Carraway and Leeman, 1973) and later from intestines (Kitabgi et al., 1976) of bovine. The peptide is present throughout the animal kingdom, suggesting its participation to important processes basic to animal life (Carraway et al., 1982). Neurotensin and its analogue neuromedin-N (Lys-Ile-Pro-Tyr-Ile-Leu) (Minamino et al., 1984) are synthesized by a common precursor in mammalian brain (Kislauskis et al., 1988) and intestine (Dobner et al., 1987). The central and peripheral distribution and effects of neurotensin have been extensively studied. In the brain, neurotensin is exclusively found in nerve cells, fibers, and terminals (Uhl et al., 1979), whereas the majority of peripheral neurotensin is found in the endocrine N-cells located in the intestinal mucosa (Orci et al., 1976; Helmstaedter et al., 1977). Central or peripheral injections of neurotensin produce completely different pharmacological effects (Table I) indicating that the peptide does not cross the blood-brain barrier. Many of the effects of centrally administered neurotensin are similar to those of neuroleptics or can be antagonized by simultaneous administration of TRH (Table I). The recently discovered nonpeptide antagonist SR 48692 (Gully et al., 1993) can inhibit several of the central and peripheral effects of neurotensin (Table I). Like many other neuropeptides, neurotensin is a messenger of intracellular communication working as a neurotransmitter or neuromodulator in the brain (Nemeroff et al., 1982) and as a local hormone in the periphery (Hirsch Fernstrom et al., 1980). Thus, several pharmacological, morphological, and neurochemical data suggest that one of the functions of neurotensin in the brain is to regulate dopamine neurotransmission along the nigrostriatal and mesolimbic pathways (Quirion, 1983; Kitabgi, 1989). On the other hand, the likely role of neurotensin as a parahormone in the gastrointestinal tract has been well documented (Rosell and Rökaeus, 1981; Kitabgi, 1982). Both central and peripheral modes of action of neurotensin imply as a first step the recognition of the peptide by a specific receptor located on the plasma membrane of the target cell. Formation of the neurotensin-receptor complex is then translated inside the cell by a change in the activity of an intracellular enzyme. This paper describes the binding and structural properties of neurotensin receptors as well as the signal transduction pathways that are activated by the peptide in various target tissues and cells.

Amino Acid Sequence↗

PubMed2006

Metabolic learning in the intestine: adaptation to nutrition and luminal factors.

There is increasing evidence that the magnitude and potential of intestinal nutrient absorption (sugars, fatty acids, cholesterol and triglycerides) and intestinal defense function are regulated by metabolic learning phenomena, and are influenced by dietary energy content and exercise. Metabolic overload syndromes, mainly obesity, and chronic malabsorption disorders such as inflammatory bowel disease and celiac disease have been defined as extreme phenotypes. Metabolic learning processes depend on developmental and transcriptional control systems of intestinal epithelial cell differentiation. The physiological differentiation zone of enterocytes is linked to the beta-catenin system, apolipoprotein apoA-IV and the master transcription factors Cdx2, HNF1alpha, and GATA4. In addition to these developmental regulatory transcription factors, nuclear receptors including RXR, LXR, PPAR, PXR, and CAR have been implicated in the generation of more absorptive enterocytes with a more differentiated phenotype on the one hand, and dedifferentiated cells with reduced capacity of detoxification and defense causing loss of junction control and barrier defects on the other. Large-scale analysis of gene expression profiles and identification of key pathways and master regulatory transcription factors will help dissect the role of nutritional and environmental factors as well as pharmacological intervention on mucosal homeostasis and disease, with potential applications for diagnosis and therapy.

Adaptation, Physiological↗

PubMed1999

The gastrointestinal tract as a barrier in sepsis.

The gastrointestinal tract is an organ of digestion and absorption which is metabolically active and has specific nutrient requirements. In health, it has an additional function as a major barrier, protecting the body from harmful intraluminal pathogens and large antigenic molecules. In disease states, such as sepsis when the mucosal barrier is compromised, micro-organisms and their toxic products gain access to the portal and systemic circulations producing deleterious effects. Under these circumstances, systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) develop leading to deterioration and death of the patient in the intensive care unit. Therapeutic strategies for such patients in the intensive care unit aim to support general immune function and maintain the structure and function of the gastrointestinal tract. For these therapies to be successful, the underlying septic or necrotic focus must be ablated using appropriate surgical or other invasive techniques.

Digestive System↗