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PubMed2005

Exogenous interleukin 7 affects gut-associated lymphoid tissue in mice receiving total parenteral nutrition.

In the absence of enteral nutrient delivery, gut-associated lymphoid tissue (GALT) mass and function are reduced. The purpose of this study was to examine whether exogenous interleukin (IL)-7 treatment reverses intravenous (IV)-total parenteral nutrition (TPN)-induced changes in GALT, immunoglobulin (Ig) A levels, and gut barrier function. Eighty-nine mice were randomized to chow, TPN, or TPN + IL-7 (1 microg/kg, administered IV twice a day) and treated for 5 days. The entire small intestine was harvested and lymphocytes were isolated from Peyer's patches (PPs), intraepithelial (IE) spaces, and the lamina propria (LP). Small intestinal and bronchoalveolar IgA levels were measured. Proximal and distal small intestinal levels of IgA-stimulating (IL-10) and IgA-inhibiting (IFNgamma) cytokines were determined with enzyme-linked immunoabsorbant assay. Moreover, 1 x 10 live Pseudomonas aeruginosa were delivered by gavage and survival was observed. TPN decreased total cell yields from PPs, IE spaces, and the LP compared with the chow group. IL-7 treatment restored cell numbers. PP CD4+, PP CD8+, IE gammadeltaTCR+, and LP CD4+ cell numbers were higher in the TPN + IL-7 group than in the TPN group. Secretory IgA levels were lower in the TPN and TPN + IL-7 than in the chow group. In the distal small intestine, IFNgamma levels were similar in the three groups, whereas IL-10 levels were reduced in the TPN and TPN + IL-7 groups relative to the chow group. Survival times were reduced in the TPN compared with the chow group, but IL-7 treatment significantly improved survival. Thus, exogenous IL-7 does not improve secretory IgA levels, nor are there any remarkable effects on levels of gut IgA-mediating cytokines. However, IL-7 treatment during TPN reverses TPN-induced GALT atrophy and improves survival in a gut-derived sepsis model.

Animals↗

PubMed2006

[The dynamics of parameters of interstitial space of small intestinal naps during absorbing process in rat].

There are several works about interstitial space of small intestinal naps in white rats; but there are not discussions about dynamics of parameters of interstitial space of small intestinal naps during absorbing process. The aim of our research was focused on this issue. The trial was carried out on 20 white rats of both sexes. Treisterial method was used for the study of the barrier functions. The macromolecular penetration was studied using reddish peroxidase. The obtained material was studied by electron microscopy. We were measuring the absolute size of nap stroma in series of half-thin slices for the estimation of the interstitial volume modification during absorption. On the electrograms we took in the account the part (the fraction) of the volume, which is composed of extracellular component of the connective tissue. The results of the stereological analyses have shown hat extension of nap stroma is due to the expansion of the interstitial space. That fraction, which falls to than shear of whole volume of the stroma, distinctly estimates the active absorption.

Animals↗

PubMed2005

Alteration of intestinal epithelial function by intraepithelial lymphocyte homing.

BACKGROUND: Intimate cross-talk may take place between intestinal epithelial cells and intraepithelial lymphocytes (IEL). The purpose of this study was to analyze the influence of lymphocyte migration into the epithelium on epithelial function, using an in vitro "IEL homing" model. METHODS: Molecular expression on epithelial cells was analyzed by flow cytometry. The barrier function of the epithelial monolayer was assessed by transepithelial electrical resistance. Cytokine production was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: (1) IEL homing into the epithelia induced significant phenotypic changes in epithelial cells; upregulation of MHC class I, and II, intercellular adhesion molecule (ICAM)-1, and CD44. IEL-derived interferon-gamma (IFN-gamma) could partially account for this alteration, as a neutralizing antibody (Ab) against IFN-gamma inhibited the upregulation of these molecules, except for CD44. (2) A marked fall in transepithelial electrical resistance was observed 4 h after IEL homing started, and Ab against IFN-gamma slightly inhibited this fall in resistance. (3) The production of interleukin (IL)-8 and IFN-gamma inducible protein-10 (IP-10), but not transforming growth factor (TGF)-beta1 or tumor necrosis factor (TNF)-alpha, in the epithelial monolayer was markedly induced after IEL homing in a basolaterally polarized fashion. IEL-conditioned media also induced the production of these cytokines in epithelial cells, thus suggesting that IEL-derived soluble factor(s) induce epithelial chemokine production. CONCLUSIONS: Under inflammatory conditions, IEL obviously interact with epithelial cells and upregulate adhesion molecules, alter barrier function, and enhance chemokine production. Because such alterations may increase epithelial permeability to luminal antigens or accelerate the migration of other inflammatory cells, our results suggest that IEL have a critical role in mucosal immunity.

Cells, Cultured↗

PubMed2003

Escherichia coli endotoxin enhances acute renal failure in rats after thermal injury.

This study was designed to evaluate the burned rat model to determine whether there are any differences in endotoxin-sensitive kidney functions between an infant rat (10-day-old pup) and an adult rat (10-week-old rat). Renal failure was observed in the infant burned rat and histological changes showed the adhesion of inflammatory cells in the glomerular capillaries and vacuolar changes in the renal proximal tubular cell. A horseradish peroxidase (HRP) tracer experiment suggested that the intestinal barrier damage of the infant burned rat was more severe than that of the adult burned rat. Therefore, more bacterial translocation of the intestinal flora, rich in endotoxin, might be expected in the infant versus the adult rats. Renal failure was not observed in the adult burned rat, so we investigated to determine the effects of endotoxin on the kidney function of the adult burned rat with low lethal lipopolysaccharide (LPS) or carrageenan (CAR). CAR is known to increase sensitivity to the lethal effects of endotoxin in rodents. Our present data demonstrated that renal failure was observed in the LPS- or CAR-treated adult burned rat and LPS- and CAR-treated adult rat (non-burned). These results show the possibility that endotoxin enhances renal failure in a burned rat model and provide additional support for the hypothesis that postburn renal failure is mediated, in part, by endotoxin associated with bacterial translocation.

Acute Kidney Injury↗

PubMedDate not supplied

Glutamine peptide does not improve gut barrier function and mucosal immunity in total parenteral nutrition.

In two separate experiments, three groups of 10 (first experiment) and 12 (second experiment) rats each were catheterized for the long term via the right jugular vein and fed one of the following dietary regimens for 7 days while in individual metabolism cages. The rat food control groups were fed powdered rat food. The total parenteral nutrition (TPN) formula for one group was enriched with the stable dipeptide L-alanyl-L-glutamine (ALA-GLN) equivalent to a 1% or 2% glutamine concentration. For the control TPN groups, the dipeptide was replaced by isonitrogenous amounts of alanine (ALA). In both experiments, bacterial translocation was promoted to a similar extent by the ALA-GLN and ALA TPN formulas compared with the rat food groups. Bacterial overgrowth in the cecum and intestinal atrophy, quantitated by the mucosal protein content, did not differ between ALA-GLN and ALA groups. The nitrogen balances of the three groups showed similar values in the second experiment. The secretory immunoglobulin A was measured in washings of the jejunum and ileum (soluble fraction) and in the homogenates of the gut mucosa (insoluble fraction). The secretory immunoglobulin A values of both fractions showed no difference between the ALA and ALA-GLN groups, irrespective of whether they were normalized for gut segment length or corrected for mucosal protein content. In conclusion from these results, the supplementation of TPN with glutamine does not seem to improve gut barrier function or mucosal immunity in unstressed rats.

Alanine↗

PubMed2004

Weaning induces both transient and long-lasting modifications of absorptive, secretory, and barrier properties of piglet intestine.

This study investigated intestinal physiology of piglets at weaning. Piglets (n = 60) weaned at 21 d were food deprived for 2 d and then tube-fed using 2 different diets (a conventional diet vs. a wheat-enriched diet). They were slaughtered at d 0, 2, 5, 8, or 15 postweaning. Jejunum, ileum, and colon were mounted in Ussing chambers. In addition, segments of the proximal jejunum of 4 growing pigs were studied 35 d after weaning. Secretory function was assessed by basal short-circuit current (Isc) and secretagogue-stimulated Isc. Glucose absorption was measured by the increase in Isc after the addition of glucose. Epithelial barrier function was measured by transmucosal resistance (R) and horseradish peroxidase (HRP) fluxes across the epithelium. There were no significant differences between the pigs fed the 2 diets for any of the parameters studied. As already reported, a transient villous atrophy was observed. At the same time, we observed an increased basal Isc in jejunum and colon, increased glucose absorption and a dramatic drop of R in jejunum. These parameters had returned to preweaning values by d 5. Weaning was also followed by long-lasting modifications. In jejunum, responses to the secretagogues and glucose absorption were decreased at wk 2 after weaning and were not different between d 15 and 35. Ileal transmucosal resistance increased on d 5 and was stable thereafter. HRP flux in jejunum declined on d 2 and stayed at this low level throughout the experiment. We conclude that weaning induces transient dramatic changes in intestinal physiology but is also a period of maturation of the intestine.

Aging↗

PubMed1998

Poly (ADP-ribose) synthetase activation mediates pulmonary microvascular and intestinal mucosal dysfunction in endotoxin shock.

Endotoxin shock is known to impair critical cellular functions and is associated with the development of multiple organ dysfunction. Recent in vitro and in vivo studies demonstrated that oxidants produced during shock and inflammation trigger the activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS), resulting in intracellular energetic failure and tissue dysfunction. Here we examined the role of PARS activation in the development of barrier dysfunction of the intestine and lung during endotoxemia in rats. Ileal mucosal permeability was assessed by the measurement of the lumen to plasma directional passage of the hydrophil solute sodium fluorescein. Microvascular permeability in the lung was examined by the measurement of the extravasation of Evans blue. Inhibition of PARS was achieved by treating the animals with 3-aminobenzamide 30 min prior and 3 hr after lipopolysaccharide injection (10 mg/kg). Endotoxemia (E. coli bacterial lipopolysaccharide, 5-10 mg/kg) resulted in an increased epithelial permeability in the ileum and a microvascular hyperpermeability and neutrophil accumulation in the lung in 6 hr. The PARS inhibitor 3-aminobenzamide significantly reduced the lipopolysaccharide-induced hyperpermeability in both organs, without affecting neutrophil deposition. Thus, PARS activation plays a role in mediating endothelial and epithelial dysfunction and hyperpermeability during endotoxin shock.

Animals↗

PubMedDate not supplied

Glutamine: an essential amino acid for the gut.

Glutamine is a non-essential amino acid which is produced in sufficient amount by the healthy human body. From experimental work it is known that glutamine is an important nutrient for rapidly dividing cells such as cells from the immune system and the gut. During several conditions a lack of glutamine may occur. This will result in functional disturbances of the immune system and/or the gut. Glutamine is produced mainly by the muscle tissue. A decrease in muscle mass during nutritional depletion may result in decreased glutamine production capacity. Furthermore during critical illness, there is an increased demand for glutamine probably as a result of an increased utilization by the immune system. In addition, patients receiving standard parenteral nutrition do not receive glutamine, until recently, commercial parenteral nutrition did not contain glutamine because of instability of this amino acid during prolonged storage. One of the important functions of the gut is to prevent migration of bacteria and/or toxins from the gut lumen into the systemic circulation. A lack of glutamine may result in deterioration of this intestinal barrier. Supplementation of glutamine to certain patients could be essential. The relation between glutamine and the gut in several situations (nutritional depletion, critical illness, parenteral nutrition) is discussed in this paper.

Amino Acids, Essential↗

PubMed2001

Pulmonary and gastric surfactants. A comparison of the effect of surface requirements on function and phospholipid composition.

Surfactant is present in the alveoli and conductive airways of mammalian lungs. The presence of surface active agents was, moreover, demonstrated for avian tubular lungs and for the stomach and intestine. As the surface characteristics of these organs differ from each other, their surfactants possess distinct biochemical and functional characteristics. In the stomach so-called 'gastric surfactant' forms a hydrophobic barrier to protect the mucosa against acid back-diffusion. For this purpose gastric mucosal cells secrete unsaturated phosphatidylcholines (PC), but no dipalmitoyl-PC (PC16:0/16:0). By contrast, surfactant from conductive airways, lung alveoli and tubular avian lungs contain PC16:0/16:0 as their main component in similar concentrations. Hence, there is no biochemical relation between gastric and pulmonary surfactant. Alveolar surfactant, being designed for preventing alveolar collapse under the highly dynamic conditions of an oscillating alveolus, easily reaches values of <5 mN/m upon cyclic compression. Surfactants from tubular air-exposed structures, however, like the conductive airways of mammalian lungs and the exclusively tubular avian lung, display inferior compressibility as they only reach minimal surface tension values of approximately 20 mN/m. Hence, the highly dynamic properties of alveolar surfactant do not apply for surfactants designed for air-liquid interfaces of tubular lung structures.

Animals↗

PubMed2002

[Probiotics in gastroenterology].

Probiotics are defined as live microorganisms of human origin. Their use may favorably influence human health and ameliorate or prevent certain diseases. Prebiotics are non-digestible foodstuffs (fiber, oligofructans - "colonic foods"), which enter the colon and are metabolized by the probiotics. Probiotics should fulfill the following criteria: Phenotypic and genotypic classification, no pathogenic properties, human origin, application in the living state, resistance to gastric acid and bile, ability to adhere to colonocytes, ability to colonize the gut, clinically proved favorable health-effect, and safety. Experimental and clinical studies supplied evidence of the possible use of probiotics in the following diseases: Traveler's diarrhea, antibiotic-associated diarrhea, relapsing Clostridium difficile colitis, infantile diarrhea, rotavirus enteritis, inflammatory bowel disease, irritable bowel syndrome, colon cancer, peritonitis, acute pancreatitis, and diarrhea associated with HIV infection. Probiotics displayed the following effects in these studies: Involvement in production of essential nutrients of the colonic mucosa, beneficial effect on intestinal immunity, recovery of the disturbed gut mucosal barrier and prevention of microbial translocation, elimination of toxins and eradication of microbial pathogens, production of steroids from cholesterol and reduction of its pool in circulation, participation in regulation of intestinal functions, reduced incidence of chemically induced colon tumors in rodents. Probiotics open new therapeutic modalities in a number of diseases and it may be expected that their importance will increase with growing knowledge and experience.

Colitis↗

PubMed1997

Human jejunal effective permeability and its correlation with preclinical drug absorption models.

This review focuses on intestinal permeability measurements in humans and various aspects of in-vivo transport mechanisms. In addition, comparisons of human data with preclinical models and the blood-brain barrier is discussed. The regional human jejunal perfusion technique has been validated by several crucial points. One of the most important findings is that there is a good correlation between the measured human effective permeability values and the extent of absorption of drugs in humans determined by pharmacokinetic studies. We have also shown that it is possible to determine the effective permeability (Peff) for carrier-mediated transported compounds, and to classify them according to the proposed Biopharmaceutical Classification System (BCS). Furthermore, it is possible to predict human in-vivo permeability using preclinical permeability models, such as in-situ perfusion of rat jejunum, the Caco-2 model and excized intestinal segments in the Ussing chamber. The permeability of passively transported compounds can be predicted with a particularly high degree of accuracy. However, special care must be taken for drugs with a carrier-mediated transport mechanism, and a scaling factor has to be used. It is also suggested that it is possible to roughly estimate the permeability of the blood-brain barrier using measurements of intestinal permeability, even if the quantitative role of efflux of P-glycoprotein(s) in-vivo still remains to be clarified. Finally, the data obtained in-vivo in humans emphasize the need for more clinical studies investigating the effect of physiological in-vivo factors and molecular mechanisms influencing the transport of drugs across the intestinal and as well as other membrane barriers. It is also important to study the effect of anti-transport mechanisms, such as efflux by P-glycoprotein(s), and gut wall metabolism, for example CYP 3A4, on the bioavailability.

Animals↗

PubMed1984

Small bowel function in acute lymphoblastic leukaemia.

Small bowel function before, during, and after treatment for acute lymphoblastic leukaemia was studied in 26 children. A significant impairment of D-xylose absorption was found during treatment. Permeability studies showed a significant decrease in mannitol and a significant increase in lactulose concentrations; five of 20 children tested had evidence of lactose malabsorption, three of whom were symptomatic. Intestinal function abnormalities were greater in children whose methotrexate treatments were separated by 7 day than by 16 day intervals. Only five (19%) children had no abnormal tests. Abnormalities of small bowel function may be treatment induced and this has implications for morbidity from gastrointestinal symptoms, impairment of the mucosal barrier, and malabsorption of both nutrients and drugs leading to malnutrition and suboptimal drug concentrations.

Adolescent↗

PubMed2002

Contribution of efflux pump activity to the delivery of pulmonary therapeutics.

To date, there are few in vitro models of the human lung that have been used to characterize multidrug resistant (MDR) efflux pump activity. It is expected that the presence of these protein transporter molecules, such as P-glycoprotein (Pgp) and the multidrug resistance protein associated protein-1 (MRP1), might play a role in limiting drug absorption through the pulmonary epithelium, as has been reported for other epithelial drug delivery barriers such as the intestine and brain. To date, the exact role of the lung resistance related protein (LRP) in MDR is unclear. In this article, we have summarized the biochemistry, function and in vitro/in vivo modulation of Pgp and MRP1. These topics are discussed in light of pulmonary delivery of therapeutic agents, with particular emphasis being placed on the bronchial region of human airways.

Animals↗

PubMed1993

The significance of enteral nutrition in the intensive care unit patient.

The gut and its nonimmunologic and immunologic barriers have an important role in the survival of critically ill patients. Burns, hemorrhagic shock, intestinal obstruction, protein-calorie malnutrition, and several therapies (e.g., parenteral nutrition, steroids), used in critically ill patients are known to promote the breakdown of the mucosal barrier and to permit translocation of intestinal pathogens. Enteral nutrition, in conjunction with the use of certain immunostimulatory nutrients, can now be used to prevent or minimize damage to the mucosal barrier and to enhance its immunologic function in critically ill patients.

Critical Illness↗

PubMed1989

Intestinal absorption of drugs. I: The influence of taurocholate on the absorption of dantrolene in the small intestine of the rat.

The influence of sodium taurocholate (1) on the intestinal absorption of the lipophilic drug dantrolene (2) was studied in vivo in a chronically isolated internal loop in the rat. Concentrations of 2 were kept below the saturation concentration in saline. Absorption kinetics of 2 were evaluated on the basis of steady-state blood levels, which develop during single-pass perfusions, and on the basis of the rate of disappearance of the drug from the perfusate during recirculating perfusions. Compound 1 at a concentration of 10 mM in the perfusate induced a twofold reduction of the absorption rate compared with the same concentration of 2 in saline. Pretreatment of the absorptive surface with a 10 mM solution of 1 had no detectable effect on the absorption rate of 2 in saline. After perfusions with 10 mM solutions of 1, the perfusate concentration of proteins, phosphorus, and hexoses in the effluent was increased. The reduction of the absorption rate can be ascribed mainly to a reduction of the thermodynamically active concentration of 2 as calculated from the phase-separation model. In addition, 10 mM 1 seems to temporarily increase the barrier function of the mucous layer.

Animals↗

PubMed1986

Dietary fat content influences uptake of hexoses and lipids into rabbit jejunum following ileal resection.

After 6 weeks' feeding on a high-fat or low-fat diet, the in vitro uptake of hexoses and lipids was measured in control rabbits with an intact intestinal tract, and in animals submitted to the surgical removal of the distal half of their small intestine. Jejunal villus height, villus surface area and mucosal surface area were higher in unresected control rabbits fed the low- as compared with the high-fat diet, whereas dietary fat content had no effect on villus morphology in resected animals. Mucosal surface area was similar in control and in resected animals fed the high-fat diet, but was lower in resected than in control animals fed the low-fat diet. The active and passive transport properties of the jejunum were influenced by dietary fat manipulation. These absorption changes were qualitatively and/or quantitatively different in animals with an ileal resection from those in animals with an intact small intestine. Dietary fat manipulation had a different effect on the uptake of each lipid probe. The effective resistance of the intestinal unstirred water layer also adapted to changes in the dietary content of fat, but the changes in uptake of hexoses, fatty acids and cholesterol cannot be simply explained by alterations in this diffusion barrier, or by changes in the villus morphology. These findings indicate the importance of dietary fat on villus structure and transport function and their adaptation to ileal resection.

Adaptation, Physiological↗

PubMed1982

Neuropeptides in cerebrospinal fluid.

Most neuropeptides can now be assayed in human cerebrospinal fluid (CSF). Some, such as beta-endorphin and arginine vasopressin, seem to be secreted directly into CSF. Others may reach CSF from plasma either by passage through the blood-brain barrier or by absorption through the circumventricular organs, which lack a blood-brain barrier. The role of neuropeptides in CSF is still unclear. Thyrotropin-releasing hormone, somatostatin, arginine vasopressin, angiotensin II, substance P, vasoactive intestinal polypeptide, beta-endorphin, gastrin, and cholecystokinin are all present in assayable quantities in human CSF. Their functions in this fluid are liable to be as diverse as their functions elsewhere in the body. The release of hypothalamic releasing factors into the CSF may be part of the pathway of pituitary hormone release. Pituitary hormones may function in CSF as part of a feedback loop from the hypothalamus. Other neuropeptides may affect receptors in the central nervous system far away from their release site. Intraventricular neuropeptide injection, anatomical and physiological ablation experiments, receptor studies, and neurobiological techniques now being developed will allow a more complete understanding of CSF neuropeptide function in the future.

Animals↗

PubMed2002

Intestinal permeation and gastrointestinal disease.

The gastrointestinal tract constitutes one of the largest sites of exposure to the outside environment. The function of the gastrointestinal tract in monitoring and sealing the host interior from intruders is called the gut barrier. A variety of specific and nonspecific mechanisms are in operation to establish the host barrier; these include luminal mechanisms and digestive enzymes, the epithelial cells together with tight junctions in between them, and the gut immune system. Disruptions in the gut barrier follow injury from various causes including nonsteroidal anti-inflammatory drugs and oxidant stress, and involve mechanisms such as adenosine triphosphate depletion and damage to epithelial cell cytoskeletons that regulate tight junctions. Ample evidence links gut barrier dysfunction to multiorgan system failure in sepsis and immune dysregulation. Additionally, contribution of gut barrier dysfunction to gastrointestinal disease is an evolving concept and is the focus of this review. An overview of the evidence for the role of gut barrier dysfunction in disorders such as Crohn's disease, celiac disease, food allergy, acute pancreatitis, non-alcoholic fatty liver disease, and alcoholic liver disease is provided, together with critical insight into the implications of this evidence as a primary disease mechanism.

Acute Disease↗