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PubMed1996

[Measurement of intestinal permeability].

The intestinal epithelium has the dual functions of being an absorptive organ and acting as a barrier to the permeation of potentially harmful compounds and organisms. The theory behind measurement of intestinal permeability in human studies as well as selected studies of intestinal permeability are presented. Intestinal permeability studies as diagnostic, prognostic, sequential and screening parameters are illuminated- and the importance of changed intestinal permeability in the pathogenesis and maintenance of disease is discussed. Measuring of intestinal permeability can be used as both a prognostic and diagnostic tool, and maybe also as a screening parameter. The method may in the future turn out to be an important tool in the management of various diseases.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1995

[The intestine: a central organ in the pathogenesis of septic complications in acute pancreatitis].

Despite the array of new diagnostic and therapeutic tools, acute pancreatitis remains a critical condition with a high rate of septic morbidity and mortality. To date the main cause of death is still the occurrence of septic complications. In 80% the cases, the microorganisms responsible for infection are of enteric origin and in 30% of the patients with septic shock, no evident focus of infection is recognized. Bacterial translocation is increasingly accepted as the main cause of infection, sepsis and multiple organ failure in these critically ill patients. The mechanisms facilitating the loss of gut barrier function are overgrowth of enteric bacteria and damage to the intestinal mucosa. Pancreatitis-induced immunosuppression may allow the systemic spread of translocated organisms and subsequent severe septic sequelae.

Acute Disease↗
PubMed1995

Differential cloning of novel intestine-specific genes whose expression is altered under conditions of villus atrophy.

Atrophy of the small intestinal villi occurs in a variety of disease states and is associated with diarrhea, malabsorption, and impaired barrier function. We have previously demonstrated that villus atrophy is associated with an increase in lactase and a decrease in intestinal alkaline phosphatase gene expression. Given these changes in enterocyte phenotype with villus atrophy, we speculated that there may be other intestine-specific genes whose expression is altered as a function of epithelial growth state. We have employed two molecular techniques in order to identify and clone complementary DNAs (cDNA) which are differentially expressed in atrophic compared to normal small intestinal mucosa. In differential cDNA library (+/-) screening, duplicate filters of a normal jejunal cDNA library are hybridized with radiolabeled cDNA probes from either atrophic or control tissues. Comparisons of the intensities of hybridized clones allows for the identification of differentially expressed gene products. In the mRNA differential display system, RT-PCR is used to randomly amplify mRNA species. Similar to cDNA library screening, comparisons of radiolabeled bands on a polyacrylamide sequencing gel allow for the identification of differentially expressed genes. Using these methods, we have identified a novel cDNA, called D9, which appears to be expressed exclusively in the intestinal mucosa. Northern analyses have confirmed that the expression of the D9 mRNA is dramatically decreased under conditions of villus atrophy, suggesting an underlying relationship with epithelial growth state. DNA sequence analysis (GenBank) reveals no identity to previously cloned genes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

Intestinal permeability and genetic determinants in patients, first-degree relatives, and controls in a high-incidence area of Crohn's disease in Southern Italy.

OBJECTIVE: A defect of gastrointestinal barrier function is considered to represent an important step in the pathogenesis of Crohn's disease (CD) but the mechanisms leading to an increased intestinal permeability (IP) are poorly understood. Since IP is influenced by pro-inflammatory mediators, it seems likely that a genetically determined abnormal immune response may lead to a loss of barrier function. METHODS: In a geographic area in Southern Italy with high incidence of CD we investigated IP (lactulose/mannitol testing) together with the three main mutations of the NOD2/CARD15 and the D299G polymorphism of the toll-like receptor (TLR)-4 gene in 23 families of CD patients (patients and first-degree relatives). RESULTS: Forty-eight percent of CD patients and 40% of their healthy relatives were found to have an abnormal IP compared to 5% of an appropriate control population (p < 0.0001). IP, however, was not associated with the L1007finsC mutation of the NOD2/CARD15 or the D299G variant of the TLR-4 gene. Allele frequency of the only L1007finsC mutation of CARD15 was significantly increased in patients (8.7%, p < 0.003) and in relatives (8.3%, p < 0.024) compared with controls (2.4%), whereas the D299G variant of the TLR-4 gene was found to be increased only in relatives (8.3%, p < 0.022), but not in patients (4.3%) compared with the control population (1.7%). CONCLUSIONS: There was no association between IP and genetic markers. Our findings showed a very high proportion of healthy first-degree relatives to bare alterations suggested to constitute determinants of CD. Mutations of NOD2/CARD15 or TLR-4, however, do not lead to permeability defects emphasizing the importance of additional environmental and/or genetic factors for pathogenesis.

Adult↗
PubMed2006

Enterogenesis in a clinically feasible model of mechanical small-bowel lengthening.

BACKGROUND: Recent work indicates that mechanical force induces small-bowel growth, although methods reported do not have direct clinical application. We report a clinically feasible technique of enterogenesis and describe intestinal function in this model. METHODS: Using a pig model (n = 11), we stretched isolated small intestinal segments mechanically for 7 days in vivo with an intraluminal device. Control segments were not stretched. Morphology, histology, and epithelial proliferation were assessed. Absorption and epithelial barrier function were examined in an Ussing chamber. RESULTS: Stretch segments were significantly longer than Control segments and had nearly 2-fold greater surface area (P < .001). Mucosal thickness was much greater in Stretch than Control segments (772 +/- 134 vs. 647 +/- 75 microm, P = .02). Although villus height was reduced in Stretch and Control segments (353 +/- 76 vs. 324 +/- 76 microm, P = .6) versus native jejunum (522 +/- 87, P < .0005), crypt depth was increased dramatically in Stretch (450 +/- 95 microm) versus Control segments (341 +/- 64, P = .005). This observation was accompanied by a 2-fold increase in cellular proliferation (26.3 +/- 3.8 vs 12.1 +/- 6.6 % bromodeoxyuridine+, P < .05). Barrier function was intact ([3H]-mannitol permeation, 0.16 +/- 0.08%, vs native jejunum, 0.17 +/- 0.08%, P = .81). Glucose-mediated sodium transport was similar in Stretch versus native jejunum segments (60.0 +/- 23.5 vs 82.3 +/- 47.3 microA/cm2, P = .31), as was carbachol-induced chloride transport (82.4 +/- 72.2 vs 57.2 +/- 33.4 microA/cm2, P = .54) and alanine absorption (16.46 +/- 12.94 vs 23.53 +/- 21.31 microA/cm2, P = .53). CONCLUSIONS: Mechanical stretching induces small intestinal growth, while maintaining function. Epithelial architecture does change, such that a decrease in villus height is offset by a marked increase in crypt depth and a 2-fold increase in epithelial proliferation. Epithelial barrier and absorptive functions remain intact. The device described may have direct clinical applicability.

Animals↗
PubMed1992

Logistics and technique for combined hepatic-intestinal retrieval.

During a 13-month period, en bloc liver-small bowel cadaveric grafts were procured for seven children and one adult. All liver grafts functioned immediately, and all but one of the recipient patients recovered. Return of absorptive small bowel function was slow, but the integrity of the bacterial intestinal barrier was not disrupted. The described technique allows the procurement of other abdominothoracic organs, with the exception of the whole pancreas.

Adolescent↗
PubMed2001

Modulation of colonic barrier function by the composition of the commensal flora in the rat.

BACKGROUND AND AIMS: Altered intestinal permeability is a key pathogenetic factor of idiopathic bowel inflammation. We investigated in the rat if changes in the composition of the bowel flora can alter colonic permeability. METHODS: A colonic segment was surgically excluded from faecal transit and brought out as a loop to the abdominal wall through two colostomies. The loop was used for colonisation with specific bacterial strains after eradication of the native flora with antibiotics. Lumen to blood clearance of dextran (molecular weight 70 000) and mannitol (molecular weight 182) was measured in rats recolonised with a single bacterial strain from rat colonic origin, and in control rats whose colonic loop was kept free of bacteria by antibiotics. Actual colonisation was confirmed by culture of segment effluents. RESULTS: Colonisation with Escherichia coli, Klebsiella pneumoniae, and Streptococcus viridans significantly increased lumen to blood clearance of mannitol. Colonisation with Lactobacillus brevis had the opposite effect and reduced permeability to mannitol. Bacteroides fragilis did not induce significant changes. Permeability to dextran was not altered by any of the strains tested. CONCLUSIONS: Certain commensal bacteria can modify colonic wall permeability to luminal substances.

Analysis of Variance↗
PubMed2002

Effects of recombinant human growth hormone on rat septic shock with intraabdominal infection by E. coli.

AIM: To investigate the therapeutic effects of recombinant human growth hormone (rhGH) on rat septic shock with intraabdominal infection by E. coli and its possible mechanism. METHODS: 76 SD rats were divided into 3 groups randomly: control group (group C, n=16) without any special treatment, septic shock group (group S, n=30) received bolus injection of E.coli (1X10(10) cfu x L(-1), 15 ml x kg(-1), ip), treated group (group T, n=30) received bolus injection of E.coli, and then followed by rhGH injection (2.25 U x k g(-1) x d(-1), im). Group S and group T were further divided into 1d and 3d subgroups, respectively (n=15 each). Mean arterial pressure (MAP), levels of plasma TNFalpha and endotoxin and leukocyte count were determined on 1st day and 3rd day after E.coli injection. Another 39 SD rats were divided into groups C, S and T (n=13 each) just for observing survival rate within 1 week. RESULTS: (1) On 1st and 3rd day, MAP in group S decreased markedly, and MAP on 1st day lowered more than that of 3rd day (P<0.01), while MAP in group T just decreased slightly. The survival rate within 1 week was much higher in group T (84.6 %) than in group S (46.2 %) (P<0.01). (2)On 1st day, plasma TNFalpha and endotoxin elevated significantly in group S and group T (P<0.05), and endotoxin in group S had more increase (P<0.01). On 3rd day, TNFagr in group S returned to the level of group C (P>0.05),while TNFagr in group T went down below the level of group C(P<0.01). On 3rd day, endotoxin in group S declined, but was still higher than that of group C (P<0.01), endotoxin in group T returned to the level of group C (P>0.05). (3) On 1st day, neutrophil ratio in total leukocyte count in both group S and group T increased significantly (P<0.05 vs group C). CONCLUSION: rhGH showed beneficial effects on rat septic shock. The possible mechanisms may involve the attenuation of bacteria/endotoxin translocation and decreased systemic endotoxin level; inhibition of the production and release of TNFalpha; improved circulatory function; improved systemic host defenses and maintenance of intestinal mucosa barrier.

Abdomen↗
PubMedDate not supplied

[Enteral feeding. Importance in clinical practice].

The gut is the most important organ for the final digestion, absorption and metabolizing of the nutrients ingested. When the gut is available, it must be used as the ideal way to provide nutrients to the body tissues, either orally or by using a feeding tube to help delivering the nutrients. This type of nutrition has important advantages: One of them is the stimulation of the intestinal cells to preserve its integrity and the guts barrier function; it is economic, safe, efficient and it has been associated to improve the patient's outcome. Nowadays, there are many industrialized formulas available for tube feeding use, as well as a great variety of tubes designed for administrating this formulas, depending on the age, size, and time in which the patient will be using them. The future directions for some cases like its use in critically ill patients or the molecular effects of providing nutrients enterally is still under investigation, and there are still questions to be answered in this broad field.

Enteral Nutrition↗
PubMed2000

Technology evaluation: Valspodar, Novartis AG.

Valspodar (PSC-833) is a derivative of cyclosporin but devoid of the immunosuppressive and nephrotoxic properties seen in cyclosporin A. It exhibited high affinity binding to Mdr1 P-glycoprotein (P-gp) and demonstrated multidrug resistance-reversing activity superior to cyclosporin A and verapamil both in vitro and in vivo. Preclinical and phase I/II clinical data have indicated that plasma levels of PSC-833 with multidrug resistance-reversing activities are achievable. Potent inhibition of intestinal, hepatobiliary and blood-brain barrier P-gp function has been demonstrated. Since valspodar is also a substrate of cytochrome P450 3A (CYP3A), dual interactions of this compound with P-gp and CYP3A are the basis for the pharmacokinetic interactions seen in preclinical and clinical studies. A new formulation of the drug has recently been developed with better oral bioavailability (60%) and less interindividual variability. The toxicity profiles of valspodar are acceptable and dose-limited by transient and reversible cerebellar ataxia. It has shown multidrug resistance-modulating activities towards acute myeloid leukemia, multiple myeloma and ovarian cancer in phase I/II clinical trials. Phase III studies with respect to these three diseases are ongoing.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

ATP-binding cassette transporters in the heart.

Members of the ATP-binding cassette (ABC) protein superfamily are integral membrane proteins involved in energy-dependent transport of a wide variety of substrates across biologic membranes. ATP-binding cassette transporters serve as functional barriers against the entry of xenobiotics, for example, in the intestine or at the blood-brain barrier, or contribute to drug excretion, for example, in the kidney or the liver. Many human ABC transporters, such as ABCB1 (P-glycoprotein), ABCC5 (MRP5), or ABCC9 (SUR2), are expressed in the heart, suggesting an important role of these transporters in cardiac drug effects or physiology. Interestingly, mutations in ABCC9, a constituent of cardiac K(ATP) channels, can cause dilated cardiomyopathy in humans, providing evidence that dysfunction of cardiac ABC transporters might have clinical implications. This review aims to give insights into the possible functions of ABC transporters in the heart, their role in drug disposition, as well as control of intracellular cyclic nucleotide levels or regulation of K(ATP) channel conductivity.

ATP-Binding Cassette Transporters↗
PubMed1987

The anatomical basis for the immune function of the gut.

The barrier function of the gut wall can be divided into different histotopographically defined lines of defence. These consist not only of lymphoid cells but also of goblet cells, entero-endocrine cells, macrophages and mast cells. Subsets of lymphoid cells are found preferentially within the epithelium (T suppressor) or in the lamina propria (T helper). Most plasma cells produce IgA. Peyer's patches are described in detail as typical organized lymphoid structures of the gut. In man, they are present well before birth and are found in large numbers even in old age. They are not only typical for the ileum but are also present in the duodenum and jejunum. The four compartments in Peyer's patches, i.e. follicle, corona, interfollicular area and the dome, are defined by the typical localization of lymphocyte subsets and by their different functions. Typical features of the epithelium of the dome are the lack of villi and goblet cells and the presence of specialized epithelial cells (M cells) which are important for the uptake of particulate antigen from the gut lumen. Precursor cells of IgA producing plasma cells leave the intestinal wall via the lymphatics and return preferentially to the gut mucosa, and this is summarized by the term gut-associated lymphoid tissue (GALT). Other organs with mucous membranes, such as mammary and salivary glands, bronchial and genital tract, are also included in this circulatory route and this is expressed by the term mucosa-associated lymphoid tissue (MALT). Mast cells in the gut mucosa can be classified as connective tissue or mucosa mast cells. These differ in their sensitivity to formaldehyde as a fixative, contain different granules and mediators, have different origins, and show major differences in the effectiveness of antiallergic compounds on the stabilizing of the cell membrane. Mucosa mast cells have also been demonstrated in the human gut. The histotopographical relationship of many cell types such as goblet and M cells in addition to cells of the immune system such as lymphoid cells, macrophages and mast cells, is essential in the understanding of the barrier function of the gut wall.

Animals↗
PubMed2006

Chronic psychological stress in rats induces intestinal sensitization to luminal antigens.

There is increasing evidence that stress plays a role in the pathophysiology of chronic intestinal disorders, but the mechanisms remain unclear. Previous studies in rats have revealed that stress decreases gut barrier function and allows excessive uptake of luminal material. Here, we investigated whether chronic psychological stress acts to induce sensitization of intestinal tissues to oral antigens. Rats were subjected to 1 hour per day of water avoidance stress or sham stress daily for 10 days, and horseradish peroxidase (HRP) was delivered by gavage on day 5. Studies to determine sensitization were conducted on day 20. All stressed rats developed HRP-specific IgE antibodies, antigen-induced intestinal secretion, and increased numbers of inflammatory cells in gut mucosa. Luminal HRP was absorbed more readily by enterocytes of stressed animals. In addition, stressed rats had increased expression of interleukin-4 and decreased expression of interferon-gamma in gut mucosa, a cytokine profile that is typical of allergic conditions. Treatment of stressed rats with an antagonist to corticotropin-releasing hormone (previously shown to inhibit stress-enhanced gut permeability) eliminated the manifestations of intestinal hypersensitivity. Our results indicate that the presence of oral antigen during chronic psychological stress alters the immune response (to sensitization rather than oral tolerance) and causes subsequent antigen-induced gut pathophysiology.

Animals↗
PubMedDate not supplied

Gastrointestinal host defence: importance of gut closure in control of macromolecular transport.

An important adaptation of the gastrointestinal tract to the extrauterine environment is its development of a mucosal barrier against the penetration of harmful substances (bacteria, toxins and antigens) present within the intestinal lumen. At birth, the newborn infant must be prepared to deal with bacterial colonization of the gut, with formation of toxic byproducts of bacteria and viruses (enterotoxins and endotoxins) and with the ingestion of antigens (milk proteins). These potentially noxious substances if allowed to penetrate the mucosal epithelial barrier under pathological conditions can cause inflammatory and allergic reactions which may result in gastrointestinal and systemic disease states. To combat the potential danger of invasion across the mucosal barrier the infant must develop an elaborate system of defence mechanisms within the lumen and on the luminal mucosal surface which act to control and maintain the epithelium as an impermeable barrier to uptake of macromolecular antigens. These defences include a unique immunological system adapted to function in the complicated milieu of the intestine as well as other non-immunological processes such as a gastric barrier, intestinal surface secretions, peristaltic movement and natural antibacterial substances (lysozyme, bile salts) which also help to provide maximum protection for the intestinal surface. Unfortunately, during the immediate postpartum period, particularly for premature and small-for-dates infants, this elaborate local defence system is incompletely developed. As a result of the delay in the maturation of the mucosal barrier newborn infants are particularly vulnerable to pathological penetration by harmful intraluminal substances. The consequences of altered defence are susceptibility to infection and the potential for hypersensitivity reactions and for formation of immune complexes. With these reactions comes the potential for developing life-threatening diseases such as necrotizing enterocolitis, sepsis and hepatitis. Fortunately, 'nature' has provided a means for passively protecting the 'vulnerable' newborn against dangers of a deficient intestinal defence system, namely human milk. It is now increasingly apparent that human milk contains not only antibodies and viable leucocytes but many other substances which can interfere with bacterial colonization and prevent antigen penetration.

Animals↗
PubMed1988

The use of a perfluorochemical emulsion as a vascular perfusate in drug absorption.

In-vitro simultaneous luminal and vascular perfusion using the perfluorochemical emulsion, FC-43 emulsion, as a vascular perfusate, was examined for drug absorption in rat jejunum. The intestinal membrane in this system was found to retain its normal barrier functions for drug transport, as evident from the following: (i) stable absorption clearance of tritiated water and salicylic acid at steady-state, (ii) agreement of this clearance with that by in-situ single-pass luminal perfusion, (iii) active transport of D-glucose and its inhibition by phloridzin and (iv) normal glutamate pyruvate transaminase activity in the intestinal mucosa. FC-43 emulsion gave a more normal absorption site blood flow than the usual vascular perfusate containing erythrocytes and albumin in Krebs-Henseleit bicarbonate buffer solution. Consequently, this emulsion was useful for examining the contribution of blood flow resistance toward drug absorption. The rate-limiting steps of absorption of tritiated water, antipyrine and salicylic acid were examined by perfusion using FC-43 emulsion. The absorption of tritiated water was almost completely blood flow-limited and its absorption clearance may possibly be an approximated absorption site blood flow. The contribution of blood flow resistance to total resistance for antipyrine absorption exceeded that for salicylic acid absorption.

Animals↗
PubMedDate not supplied

The small intestine as the origin of bacteremia in acute diffuse peritonitis.

Studies have demonstrated the failure of gut barrier function in all cases of experimental acute diffuse peritonitis. Histobacterioscopy and electron microscopy showed the occurrence of bacteria under the basal membrane, in lymphatic and blood capillaries of the small intestinal villi. Experimental and clinical trials with blood sampling from different regions of the circulation have demonstrated the gut origin polymicrobial bacteremia in 66% of patients and in 75% of experimental animals with acute diffuse peritonitis.

Acute Disease↗
PubMed1998

Absorption enhancement, structural changes in tight junctions and cytotoxicity caused by palmitoyl carnitine in Caco-2 and IEC-18 cells.

Palmitoyl carnitine chloride (PCC) has been shown to be an effective enhancer of intestinal transport of hydrophilic molecules. The exact mechanism by which the epithelial barrier function is decreased is not clear. In an attempt to elucidate the mechanism of action of PCC, we studied the relationship among absorption enhancement, cell viability and tight junction protein localization in the human colonic Caco-2 cell line and the rat small intestinal cell line IEC-18. Filter-grown cells were exposed to 0 to 1 mM PCC for 30 min, and the efficacy of PCC treatment was determined by assessing the transepithelial electrical resistance and the apparent permeability for mannitol and PEG-4000. Membrane lysis and cytotoxicity were assessed by measurement of lactate dehydrogenase leakage and uptake of propidium iodide and neutral red. The immunolocalization of the tight junctional protein ZO-1 was quantified using CSLM and image-processing software. In both cell lines, PCC caused a dose-dependent decrease in transepithelial electrical resistance and a concomitant increase in the permeability for mannitol and PEG-4000. The transport enhancement was accompanied by an increase in apical membrane permeability and a reduction in cell viability. At higher PCC concentrations (>/=0.4 mM), the distribution of the tight junctional protein ZO-1 was changed and cells were unable to recover viability. PCC is effective as an absorption enhancer for hydrophilic macromolecules. However, lytic effects on the cell membrane and reduced cell viability were concomitant with transport enhancement.

Animals↗