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PubMed2004

Pretreatment with high-fat enteral nutrition reduces endotoxin and tumor necrosis factor-alpha and preserves gut barrier function early after hemorrhagic shock.

Gram-negative sepsis is a potentially fatal clinical syndrome characterized by a proinflammatory response (tumor necrosis factor-alpha) to bacterial (endo)toxins and gut barrier function loss. Recently, we found that high-fat enteral nutrition protects against late bacterial translocation in a model of hemorrhagic shock in rats. However, the basis for this protection is unknown. We hypothesized that the observed protection is the result of an early inhibition of endotoxin and the subsequent inflammatory response resulting in a preserved gut barrier function. Sprague-Dawley rats were divided into a group that was starved overnight (HS-S), fed with a low-fat enteral diet (HS-LF) or fed wih a high-fat enteral diet (HS-HF), and subsequently subjected to a nonlethal hemorrhagic shock. Ninety minutes after hemorrhage, arterial endotoxin significantly decreased in HS-HF rats (4.0 +/- 0.6 pg/mL) compared with HS-LF rats (10.7 +/- 0.9 pg/mL, P = 0.002) and HS-S rats (15.2 +/- 2.2 pg/mL P = 0.001). Interestingly, arterial tumor necrosis factor-alpha was also decreased in HS-HF rats (17.9 +/- 10.4 pg/mL) compared with HS-LF (83.5 +/- 16.7 pg/mL, P < 0.01) and HS-S rats (180.9 +/- 67.9 pg/mL, P < 0.02). Loss of tight junction structure (ZO-1) observed in ileum and colon of control hemorrhagic shock rats was prevented in HS-HF rats. In parallel, intestinal barrier function was preserved in HS-HF rats, evidenced by a reduced permeability to horseradish peroxidase (P < 0.05), less bacterial invasion, and a 10-fold reduction of bacterial translocation early after hemorrhagic shock. This report describes a new strategy to nutritionally prevent endotoxemia, the subsequent inflammatory response and gut barrier failure following hemorrhagic shock. High-fat enteral nutrition requires further evaluation as an intervention to prevent a potentially fatal systemic inflammatory response in patients at risk for sepsis.

Animal Feed↗
PubMed1982

Permeability of adolescent rat intestine to pancreatic ribonuclease.

There are indications that exocrine pancreatic enzymes may undergo an enteric recirculation. Ribonuclease (RNase) is present in considerable quantities in pancreatic exocrine secretions. Therefore we studied the intestinal transport of pancreatic RNase using everted gut sacs from duodenum, midgut, and ileum of young rats. Gut sacs were incubated aerobically at 37 degrees C, 22 degrees C, and 0 degrees C, and anaerobically at 37 degrees C. Measurable amounts of RNase crossed the intestinal barrier, but neither duodenum, midgut nor ileum absorbed RNase preferentially. The experimental data favor simple diffusion of RNase across rat small bowel. However, the amounts of pancreatic RNase absorbed were small. Thus, while our data do not negate the concept of an enteropancreatic recirculation in the rat, only a minor quantity of luminal, pancreatic RNase could recirculate.

Animals↗
PubMedDate not supplied

Protein immobilization in crosslinked alginate microparticles.

Oral administration of peptide and protein drugs requires their protection from the acidic and enzymatic degradation in the gastro-intestinal environment and their targeting to the absorption zone. For this purpose, an alginate microsystem, as a carrier of bovine serum albumin (BSA), as a model protein, was developed using a spray-drying technique. A hardening process with Ca2+ and chitosan (CS) provided a system with resistance to the gastro-intestinal barriers and of appropriate size for targeting to the Peyer's patches. The present work aims to evaluate the effects of the ratio of sodium alginate (Na-A) and BSA as well as the pH of the crosslinking medium on the microsystem properties. Microparticle morphological and dimensional characteristics did not change significantly with the formulation variables. BSA loading at a pH value less than the protein isoelectric point (pI) was higher than that at a pH similar to the pI owing to an electrostatic interaction between the charged protein and the polyanionic alginate. The maximum encapsulation efficiency was obtained at the highest Na-A/BSA ratio. Protein release in a simulated gastro-intestinal fluid was not affected by the preparative variables, but was controlled by the pH-dependent nature of the polymer material. Polyacrylamide gel electrophoresis (PAGE) demonstrated the stability of the protein to both the preparative conditions and the gastro-intestinal pH values.

Alginates↗
PubMed2001

Evaluation of residual and therapeutic doses of tetracycline in the human-flora-associated (HFA) mice model.

In order to evaluate an in vivo model system for assessing the effect of therapeutic and residue levels of tetracycline on human intestinal microflora, tetracycline was administered via drinking water (1, 10, and 100 mg/liter) to human-flora-associated (HFA) male and female mice. The effects of the antibiotic on fecal aerobic and anaerobic populations, selection of bacteria resistant to tetracycline, metabolic parameters of the microflora, and maintenance of the intestinal barrier against exogenous Salmonella (resistance to colonization) were recorded. In both sexes of mice, tetracycline exposure at 10 and 100 mg/liter induced the selection of several resistant bacterial species (Gram-positive anaerobes, Bacteroides fragilis, enterobacteria, and enterococci). This effect was also observed at the lowest dose (1 mg/liter) in female mice and indicates the potential sensitivity of this endpoint for evaluating the microbiological risk of tetracycline residues. The resistance to colonization was impaired at 100 mg/liter, a concentration corresponding to about half of the therapeutic doses in humans and animals. Metabolic parameters of the microflora were not affected by tetracycline at all levels. In this study, the no-observed-effect level (NOEL) of tetracycline on intestinal flora in this study was less than 1 mg of tetracycline per liter of drinking water. This concentration in the mouse corresponds to 0.125 mg of tetracycline per kilogram of body weight per day. Within the constraints of the experimental design employed here, the HFA mice model proved to be acceptable for studying dose-related effects of tetracycline on human intestinal microflora.

Animals↗
PubMed1998

IL-1beta and TNF-alpha, but not IFN-alpha, IFN-gamma, IL-6 or IL-8, are secretory mediators in human distal colon.

Inflammatory bowel disease (IBD) and HIV infection can cause diarrhoea which is accompanied by elevated cytokine levels. To elucidate a pathogenic role of cytokines, their effect on ion secretion was studied in human distal colon using the Ussing technique. Interluekin 1beta (IL-1beta) dose dependently increased short-circuit current (ISC). An ISC maximum of 2.5+/-0.3 micromol. h-1.cm-2 was reached at 20 ng/ml within 43+/-4 min. 22Na+ and 36Cl- fluxes were not altered and residual flux increased by 2.4+/-1.0 micromol.h-1.cm-2 indicating that the IL-1beta-induced ISC is based on electrogenic bicarbonate secretion. IL-1beta had no effect on HT-29/B6 epithlial monolayers suggesting that IL-1beta does not act directly on the epithelium. Furthermore, in human colon the effect was not attenuated by removal of the submucosa (total stripping) pointing to a mediation step via subepithlial cells in the lamina propria. While tetrodotoxin and the 5-lipoxygenase inhibitor ICI-230487 had no effect, indomethacin completely blocked IL-1beta action. Prostaglandin determination by RIA revealed an increased production of PGE2. At half maximum effective concentrations an additive action of tumour necrosis factor alpha (TNF-alpha) could be demonstrated on IL-1beta-induced secretion. Interferon alpha (IFN-alpha), IFN-gamma, IL-6, and IL-8 had no seretory effect in human distal colon. None of the investigated cytokines altered the intestinal barrier function. By their secretory effects IL-1beta and TNF-alpha, but not IFN-alpha, IFN-gamma, IL-6, and IL-8, may contribute to diarrhoea in IBD and AIDS.

Chlorides↗
PubMed2002

Induction of intestinal inflammation in mouse by activation of proteinase-activated receptor-2.

Proteinase-activated receptor (PAR)-2, a G-protein-coupled receptor for trypsin and mast cell tryptase, is highly expressed in the intestine. Luminal trypsin and tryptase are elevated in the colon of inflammatory bowel disease patients. We hypothesized that luminal proteinases activate PAR-2 and induce colonic inflammation. Mice received intracolonically PAR-2 agonists (trypsin, tryptase, and a selective PAR-2-activating peptide) or control drugs (boiled enzymes, inactive peptide) and inflammatory parameters were followed at various times after this treatment. Colonic administration of PAR-2 agonists up-regulated PAR-2 expression and induced an inflammatory reaction characterized by granulocyte infiltration, increased wall thickness, tissue damage, and elevated T-helper cell type 1 cytokine. The inflammation was maximal between 4 and 6 hours and was resolved 48 hours after the intracolonic administration. PAR-2 activation also increased paracellular permeability of the colon and induced bacterial trans-location into peritoneal organs. These proinflammatory and pathophysiological changes observed in wild-type mice were not detected in PAR-2-deficient mice. Luminal proteinases activate PAR-2 in the mouse colon to induce inflammation and disrupt the integrity of the intestinal barrier. Because trypsin and tryptase are found at high levels in the colon lumen of patients with Crohn's disease or ulcerative colitis, our data may bear directly on the pathophysiology of human inflammatory bowel diseases.

Animals↗
PubMed1981

Passage of molecules through the wall of the gastrointestinal tract. Increased passive permeability in rat ileum after exposure to lysolecithin.

The interaction between lysolecithin and mucosal cells in the distal ileum has been studied. Using a rat experimental model, we determined the intestinal permeability to fluorescent dextran 3000 after exposure to different amounts of lysolecithin. At pH 7.3, lysolecithin, 10 mg/ml, significantly enhanced the transmural passage, and at pH 3.5, even 1 mg/ml markedly increased the permeability. However, when lysolecithin was incubated with homogenized mucosal cells, a rapid disappearance of the compound occurred; this was accompanied by formation of free fatty acids and minor formation of lecithin. It appears, therefore, that high concentrations of lysolecithin can impair the intestinal barrier function in the distal part of ileum but that the mucosal cells are well equipped with activities for the rapid removal of such high concentrations. This could be physiologically significant, since the mucosal cells could otherwise be faced with large amounts of lysolecithin that might facilitate the absorption of potentially antigenic and toxic compounds.

Animals↗
PubMed2006

Effect of steroid on mitochondrial oxidative stress enzymes, intestinal microflora, and bacterial translocation in rats subjected to temporary liver inflow occlusion.

Protective effects of steroids against ischemia-reperfusion (I/R) injury are well known, but there is little information about the influence of temporary inflow occlusion on intestinal barrier function or bacterial translocation. The aim of this experimental study was to investigate the effects on liver, kidney, spleen, ileal mitochondrial stress enzymes, and bacterial translocation of methylprednisolone (MP) in rats undergoing temporary liver inflow occlusion. Twenty-seven pathogen-free Wistar albino rats were randomized into three groups: group A: I/R (n = 10); group B: I/R + MP (n = 10); and group C: sham (n = 7). Rats in groups A and B were subjected to 20 minutes of portal vein and hepatic artery occlusion with 3 mg/kg MP injected into group B animals intraperitoneally during the occlusion. Twenty-two hours later, all rats were sacrificed to measure mitochondrial oxidative stress enzymes in liver, kidney, spleen, and ileum. We evaluated intestinal bacterial counts, intestinal mucosal histopathology, bacterial translocation to mesenteric lymph nodes (MLN), liver, spleen, and kidney. Decreased levels of malondialdehyde and increased levels of glutathione were observed in all examined tissues of group B compared to those of group A rats. Statistically significant increases in the intestinal counts of Klebsiella spp and Proteus spp and of bacterial translocation to liver, kidney, spleen, and MLN were measured in group B with respect to group A.

Animals↗
PubMed2024

Deficiency of IL-22-binding protein enhances the ability of the gut microbiota to protect against enteric pathogens.

Interleukin 22 (IL-22) promotes intestinal barrier integrity, stimulating epithelial cells to enact defense mechanisms against enteric infections, including the production of antimicrobial peptides. IL-22 binding protein (IL-22BP) is a soluble decoy encoded by the Il22ra2 gene that decreases IL-22 bioavailability, attenuating IL-22 signaling. The impact of IL-22BP on gut microbiota composition and functioning is poorly understood. We found that Il22ra2-/- mice are better protected against Clostridioides difficile and Citrobacter rodentium infections. This protection relied on IL-22-induced antimicrobial mechanisms before the infection occurred, rather than during the infection itself. Indeed, the gut microbiota of Il22ra2-/- mice mitigated infection of wild-type (WT) mice when transferred via cohousing or by cecal microbiota transplantation. Indicator species analysis of WT and Il22ra2-/- mice with and without cohousing disclosed that IL22BP deficiency yields a gut bacterial composition distinct from that of WT mice. Manipulation of dietary fiber content, measurements of intestinal short-chain fatty acids and oral treatment with acetate disclosed that resistance to C. difficile infection is related to increased production of acetate by Il22ra2-/--associated microbiota. Together, these findings suggest that IL-22BP represents a potential therapeutic target for those at risk for or with already manifest infection with this and perhaps other enteropathogens.

Animals↗
PubMed1999

Mechanisms and impact of enteric infections.

The increased recognition of both old and new enteric pathogens and their potential impact requires an improved understanding of pathogenesis and effective interventions. While the overwhelming mortality (> 3 million children per year) due to diarrheal diseases is well-recognized, the potential long-term impacts of enteric infections and early childhood diarrhea morbidity are just beginning to be appreciated. Furthermore, several enteric infections are now being recognized as causes of growth shortfalls with or without diarrhea; i.e., malnutrition may be one of the greatest yet of the "emerging infectious diseases." The increased appreciation of this extended impact calls for further quantification and improved understanding of the deranged physiology. In particular, persistent diarrheal illnesses exhibit common themes of blunted villi, disruption of intestinal barrier function and varying degrees of sub-mucosal inflammation for which lactulose/mannitol permeability and fecal lactoferrin provide respective quantification. Finally, such improved understanding will allow targeted interventions among those most vulnerable, which will enable further documentation of cost effectiveness and the potential for improved human development which is critical to reducing the widening disparity and population overgrowth which increasingly threaten our global security.

Animals↗
PubMed1996

The relationship between gut-derived bacteria and the development of the multiple organ dysfunction syndrome.

Abnormal colonisation, infections of gut origin and bacterial translocation are all signs of gut failure that have been hypothesised as being implicated in the pathogenesis of the multiple organ dysfunction syndrome (MODS). We have summarised published experimental and clinical studies that have tried to correlate the occurrence or prevention of these phenomena with the development of MODS. We conclude that in some patients loss of intestinal barrier function or the onset of infection precedes the development of MODS. In other patients, however, this relationship is not so clear and it seems that these are epiphenoma of critical illness and may reflect a failure of the host's immune and mechanical defence systems. The causal relationship between these phenomena and the development of MODS is complex and needs further clarification.

Animals↗
PubMed2002

Attenuation of internal organ damages by exogenously administered epidermal growth factor (EGF) in burned rodents.

Major burns are associated with multiple internal organ damages, including necrosis of the gastrointestinal mucosa. Failure of the intestinal barrier is a serious complication in burned patients. Epidermal growth factor (EGF) is a mitogenic polypeptide that stimulates wound repair and affords protection to the gastric mucosa. We examined whether a single systemic intervention with EGF prevents organ systems damages, following full-thickness scalds (25-30%) in rodents. Animals were randomly assigned to receive an intraperitoneal injection of EGF (30 microg/kg in mice, 10 microg/kg in rats) or saline solution, 30 min prior thermal injury in mice or after the cutaneous injury in rats. General clinical condition and mortality during 24h were recorded. Animals were autopsied and histopathological and histomorphometric studies were conducted. Mice treated with EGF exhibited a milder clinical evolution and acute lethality was significantly reduced as compared to saline counterparts (P<0.01). Histopathological and morphometric analysis showed that EGF significantly reduced intestinal necrosis and contributed to preserve jejunoileal architecture in mice (P<0.05) and rats (P<0.01). The onset of renal hemorrhagic foci was significantly reduced in EGF-treated groups (P<0.01). Lung damages appeared attenuated in EGF-treated animals. These data indicate the salutary effects of EGF by attenuating internal complications associated to thermal injuries. Further studies are warranted to fully elucidate the usefulness of this therapy.

Animals↗
PubMed2004

Preservation of intestinal structural integrity by zinc is independent of metallothionein in alcohol-intoxicated mice.

Intestinal-derived endotoxins are importantly involved in alcohol-induced liver injury. Disruption of intestinal barrier function and endotoxemia are common features associated with liver inflammation and injury due to acute ethanol exposure. Zinc has been shown to inhibit acute alcohol-induced liver injury. This study was designed to determine the inhibitory effect of zinc on alcohol-induced endotoxemia and whether the inhibition is mediated by metallothionein (MT) or is independent of MT. MT knockout (MT-KO) mice were administered three oral doses of zinc sulfate (2.5 mg zinc ion/kg body weight) every 12 hours before being administered a single dose of ethanol (6 g/kg body weight) by gavage. Ethanol administration caused liver injury as determined by increased serum transaminases, parenchymal fat accumulation, necrotic foci, and an elevation of tumor necrosis factor (TNF-alpha). Increased plasma endotoxin levels were detected in ethanol-treated animals whose small intestinal structural integrity was compromised as determined by microscopic examination. Zinc supplementation significantly inhibited acute ethanol-induced liver injury and suppressed hepatic TNF-alpha production in association with decreased circulating endotoxin levels and a significant protection of small intestine structure. As expected, MT levels remained undetectable in the MT-KO mice under the zinc treatment. These results thus demonstrate that zinc preservation of intestinal structural integrity is associated with suppression of endotoxemia and liver injury induced by acute exposure to ethanol and the zinc protection is independent of MT.

Alanine Transaminase↗
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↗
PubMed1984

[Duodenal absorption of a low molecular weight heparin in rabbits].

Commercial heparin cannot practically cross the intestinal barrier. Meanwhile, because of the theoretical interest in oral heparin therapeutics, we applied our studies to a low molecular weight heparin fraction (3 000 to 4 000 D). This fraction was directly injected into anaesthetized rabbit duodenum. For an equal anticoagulant activity (expressed in international units), commercial heparin is not absorbed whereas the low molecular weight fraction mainly induces an early plasmatic anti-Xa activity which remains over the fifth hour.

Animals↗
PubMed1995

[Systemic enzyme therapy: problems of resorption of enzyme macromolecules].

Systemic enzyme therapy represents a special therapeutic approach consisting in the oral application of high doses of hydrolytic animal and plant enzyme combinations. The originally empirical method was by detailed experimental analyses and successful clinical studies transformed into a widely appreciated therapeutic method of various pathologic processes. In spite of this fact systemic enzyme therapy has been repeatedly questioned by referring to an almost hundred year old dogma claiming the unabsorbality of enzymes in the macromolecular form. The authors present arguments denying the unexceptional validity of this dogma. The histological, radiological, biochemical (chromatographical, enzymological), immunological and biological methods have convincingly proven that a part of swallowed enzymes may pass the intestinal barrier in an undamaged macromolecular form and realize their activities in the body. The most important elements able to absorb macromolecules seem to be so called "M-cells" (FAE) which cover lymphoid foci of the organized gut lymphoid tissue. Other mechanisms of enzyme resorption are under discussion. The absorbed enzymes are rapidly complexed with naturally occurring blood antiproteases. In these complexes the potential immunogenicity of enzymes is restricted and they are concentrated into pathologically affected areas of the body. Complexes in addition display important immunoregulatory activities.

Enzyme Therapy↗
PubMed2003

Effects of glutamine on intestinal permeability and bacterial translocation in TPN-rats with endotoxemia.

AIM: To evaluate the protective effect and mechanism of glutamine on the intestinal barrier function in total parenteral nutrition (TPN) rats with trauma or endotoxemia. METHODS: To perform prospective, randomized and controlled animal experimentation of rats with surgical trauma, TPN and endotoxemia, thirty-four male, adult Sprague Dawley rats were divided into four groups: control group (n=8), TPN group (n=9), trauma and endotoxemia group (LPS, n=8) and trauma plus endotoxemia supplemented with glutamine in TPN solution group (Gln.group, n=9). All groups except the control group were given TPN solutions in 7-day experimental period. For Gln group, 1 000 mg/kg/d of glutamine was added to TPN solution during day 1-6. On the 7(th) day all the animals were gavaged with lactulose (66 mg) and mannitol (50 mg) in 2 ml of normal saline. Then 24 h urine with preservative was collected and kept at -20 degrees. On day 8, under intra-peritoneal anesthesia using 100 mg/kg ketamin, the intestine, liver, mesenteric lymph nodes and blood were taken for examination. RESULTS: The body weight of LPS group decreased most among the four groups. The structure of small intestinal mucosa in TPN group, LPS group and Gln group showed impairments of different degrees, and the damage of small intestinal mucosa in Gln group was remarkably alleviated. The concentrations of interleukins in small intestine mucosa were lower (for IL-4 and IL-6) or the lowest (IL-10) in Gln group. The IgA level in the blood plasma and the mucosa of Gln group was the highest among all of the groups. The urine lactulose/mannitol test showed that the intestinal permeability in LPS group was lower than that in TPN group (P<0.001), but there was no difference between LPS group and Gln group. The rate of bacterial translocation in Gln group was lower than that in LPS group (P<0.02). CONCLUSION: Prophylactic treatment with glutamine could minimize the increments of intestinal permeability and bacterial translocation caused by trauma and endotoxemia in rats treated with TPN.

Animals↗
PubMed2007

Efflux transporters in ulcerative colitis: decreased expression of BCRP (ABCG2) and Pgp (ABCB1).

BACKGROUND: Efflux transport proteins are important components of the intestinal barrier against bacterial toxins, carcinogens, and drugs. This investigation was conducted to determine the expression of Breast Cancer Resistance Protein (BCRP/ABCG2), P-glycoprotein (Pgp/MDR1/ABCB1), and Multidrug Resistance Protein 2 (MRP2/ABCC2) in the gut mucosa of patients with ulcerative colitis (UC). METHODS: Patients were thoroughly diagnosed according to well-established clinical, endoscopic, and histologic criteria to be included in the group of patients with active UC (n = 16) or UC in remission (n = 17). Colonic and rectal mucosa from patients with UC were compared with tissues from control subjects (n = 15). The mRNA expression (TaqMan) of the efflux transporters and the proinflammatory cytokines interleukin (IL)-1beta and IL-6 was determined. Western blot was used in the analysis of protein expression and the tissue localization of BCRP was determined with confocal microscopy. RESULTS: BCRP and Pgp expression was strongly reduced in individuals with active inflammation compared with controls and was negatively correlated with the levels of IL-6 mRNA. The BCRP staining of colonic epithelium seen in healthy mucosa was diminished in inflamed tissues, with concurrent disruption of epithelial F-actin structure. CONCLUSIONS: Two of the efflux transporters of importance for the barrier function of the gut mucosa, Pgp and BCRP, are expressed at strongly reduced levels during active inflammation in patients with UC. Investigations are warranted to determine whether the low levels of efflux transporters during active UC contribute to altered transport and tissue exposure of carcinogens, bacterial toxins, and drugs.

ATP Binding Cassette Transporter, Subfamily B↗