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Results for “Intestinal Barrier Function”

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PubMed1991

The effect of elemental diet on intestinal permeability and inflammation in Crohn's disease.

This study examines whether treatment of acute Crohn's disease with an elemental diet improves intestinal integrity and inflammation as assessed by a 51Cr-labeled ethylenediaminetetraacetatic acid (EDTA) permeability test and the fecal excretion of 111In-labeled autologous leukocytes, respectively. Thirty-four patients with active Crohn's disease completed a 4-week treatment course with an elemental diet. Active disease was characterized by increased intestinal permeability [24-hour urine excretion of orally administered 51Cr-EDTA, 6.4% +/- 0.6% (mean +/- SE); normal, less than 3.0%] and by high fecal excretion of 111In-labeled leukocytes (14.2% +/- 1.1%; normal, less than 1.0%). Twenty-seven (80%) went into clinical remission, usually within a week of starting treatment. After 4 weeks of treatment, there was a significant decrease in both the urine excretion of 51Cr-EDTA (to 3.4% +/- 0.5%; P less than 0.01) and the fecal excretion of 111In (to 5.7% +/- 1.0%; P less than 0.001), indicating that such treatment is not just symptomatic. A framework for the mechanism by which elemental diet works, centering around the importance of the integrity of the intestinal barrier function, is proposed, and also appears to provide a logical explanation for some relapses of the disease.

Acute Disease↗
PubMed1991

[Intestinal permeability in patients with acquired immunodeficiency syndrome (AIDS)].

Intestinal permeability has been assessed as a parameter of the small intestinal barrier function in 33 patients with AIDS (WR 6), in 25 healthy volunteers, 32 patients with Crohn's disease, 18 patients with ulcerative colitis and in 12 patients with untreated coeliac disease. Permeability was measured by means of the 5 hour urinary excretion of lactulose and rhamnose after administration of these sugars (1 g rhamnose, 10 g lactulose) which allowed to calculate the urinary lactulose/rhamnose--ratio (L/R-r) as an index of intestinal permeability. Compared to the controls (L/R-r = 0.014 +/- 0.010) patients with AIDS had significantly increased lactulose/rhamnose--ratios (0.189 +/- 0.164; p less than 0.01) indicating abnormal permeation both of lactulose and rhamnose. This alteration of intestinal permeability was more pronounced than the significant increase of the L/R-r in the patients with either Crohn's disease or coeliac disease. However, intestinal permeability was not altered in the patients with ulcerative colitis. Among the patients with AIDS, the most abnormal permeability ratios were observed in two subjects with intestinal cryptosporidiosis. This investigation demonstrates by means of the "double sugar ratio", that intestinal permeability in patients with AIDS is highly abnormal, the impairment being even more abnormal than in patients with other small intestinal disease.

Acquired Immunodeficiency Syndrome↗
PubMed1990

The route of feeding influences injury responses.

The balance of current clinical data suggests that the route by which patients are fed during the postinjury phase may influence immunologic and metabolic responses to subsequent insults. The mechanisms underlying such amplification processes are presumed to be generated by loss of intestinal barrier function. The resulting host exposure to toxins is hypothesized to induce regional production of inflammatory mediators which serve to alter organ-specific and systemic responses. The cytokine class of mediators appears capable of altering splanchnic tissue function in a manner consistent with observed clinical responses. The breadth of tissue activity influenced by the cytokines spans those benefitting tissue homeostasis and repair to an exaggerated response which may induce tissue injury and organ failure. Data are presented from both clinical and experimental studies to suggest that a lack of intestinal nutrient provision, such as that induced by parenteral feeding, appears to predispose to enhanced cytokine mediator production in hepatic tissues. Thus alterations in the route of antecedent feeding may influence immunologic and metabolic function in a manner which will amplify responses to a subsequent inflammatory challenge.

Animals↗
PubMed1992

[Experimental damage of the epithelial layer of the ileum by dietary fats: transmission electron microscopy findings and their comparison with cell pathology in Crohn disease].

Regarding the unknown pathogenesis of Crohn's disease repeatedly the importance of diet has been accentuated. Epidemiological, biochemical and animal experimental results have focused on a possible relationship between the consumption of chemically processed, partial hydrogenated fats and the development of regional enteritis. In this context an experimental animal model in pigs was designed to analyze, whether transmission electron microscopic alterations of ileal mucosa could be induced by forage of chemically processed fats. By creation of a retroperistaltic ileal segment the contact time between chyme and intestinal mucosa was prolonged. Our underlying question was to what extent disorders of the intestinal barrier function could be compared to Crohn's disease. Present study concentrates on the epithelial-cell-layer. It was shown that in comparison to the control animals the lamina epithelialis mucosae of all animals after fat-feeding was characterized by: sublethal lesion of the enterocytes/crypt-epithelial cells (shortening and alteration of the microvilli, degeneration of mitochondria, formation of autophagocytic vacuoles); goblet cell hyperplasia and increased production of mucus; focal appearance of intraepithelial lymphocytes as well as presence of polymorphonuclear granulocytes in the epithelium; widening of the intercellular-space locally up to total loss of the functional structure of the epithelial-cell-layer. In total the picture can be evaluated as an inflammatory process of the ileal mucosa. It can be concluded, that chemically processed fats as used in the described experimental conditions could induce this process. The feature of mucosal damage shows obvious similarities to ultrastructural findings in Crohn's disease if compared.

Animals↗
PubMed1989

Interferon-gamma directly affects barrier function of cultured intestinal epithelial monolayers.

Although epithelia, which often are in intimate contact with lymphoid cells, may bear receptors for various cytokines, it is unclear whether cytokines directly effect epithelial function. We examine the effects of the cytokine interferon (IFN) on barrier function of cultured monolayers of the T84 human intestinal epithelial cell line. Gamma IFN, in concentrations and exposures required to show its other biological effects, directly affects such monolayers. Monolayer resistance is substantially diminished by gamma IFN. Such effects were not due to cytotoxicity as judged morphologically and by LDH assays. Solute fluxes and dual Na+-mannitol flux analysis indicate that the resistance decrease is due to an effect of gamma IFN on tight junction permeability. The effects of gamma IFN on monolayer barrier function were not duplicated by the cytokines interleukin 1, interleukin 2, or tumor necrosis factor. We speculate that such products of activation of lymphoid cells might influence barrier function of intestinal, and perhaps other epithelia in disease states.

Cell Line↗
PubMed2025

Recent evolution of the developing human intestine affects metabolic and barrier functions.

Diet, microbiota, and other exposures make the intestinal epithelium a nexus for evolutionary change; however, little is known about genomic changes associated with adaptation to a distinctly human environment. In this work, we interrogate the evolution of cell types in the developing human intestine by comparing tissue and organoids from humans, chimpanzees, and mice. We find that recent changes in primates are associated with immune barrier function and lipid and xenobiotic metabolism and that human-specific genetic features affect these functions. Enhancer assays, genetic deletion, and in silico mutagenesis resolve evolutionarily important enhancers of lactase (LCT) and insulin-like growth factor binding protein 2 (IGFBP2). Altogether, we identify the developing human intestinal epithelium as a rapidly evolving system and show that great ape organoids provide insight into human biology.

Animals↗
PubMed1987

Effects of polymorphonuclear leukocyte transmigration on the barrier function of cultured intestinal epithelial monolayers.

We describe a model to study the effects of polymorphonuclear leukocyte (PMN) transmigration on the intestinal epithelial barrier. Human PMN were induced to transmigrate across high resistance monolayers of a cultured human intestinal epithelial cell line (T84 cells) by chemotactic gradients produced by formyl methionyl leucyl phenylalanine (FMLP). With maximal transmigration monolayer resistance decreased by 48 +/- 12.6% in 15 min and by 83 +/- 1.6% in 60 min. This response was dependent on the size of the FMLP gradient and the density of PMN transmigration. The decrease in resistance correlated with number of PMN migrating across monolayers, and was accompanied by increases in flux of paracellular tracers. Macromolecular tracer studies localized the leak sites to foci at which PMN impaled the epithelium. Removal of the chemotactic gradient led to restoration of baseline resistance within 18 h. PMN transmigration across intestinal epithelial monolayers occurs via intercellular occluding junctions and may be associated with a reversible increase in epithelial permeability.

Cell Line↗
PubMed1985

Macromolecular transport in the fetal rat intestine.

Macromolecular barrier function of the fetal rat small intestine and colon was analyzed from 16 to 22 days gestation (birth). During this period the epithelium is converted from stratified to simple columnar. To assess permeability, horseradish peroxidase (HRP) was introduced by microinjection into the lumen or into the umbilical circulation. Proximal small intestine, distal small intestine, and colon were examined after 10-20 min. Paracellular passage of HRP through occluding junctions was not observed after either intraluminal or intravascular injection. After intraluminal injection, transepithelial transport of HRP from lumen to blood occurred in all regions at all ages studied. Horseradish peroxidase was present in cytoplasmic vesicles of most cells in the primitive stratified epithelia, during epithelial conversion, and in simple columnar epithelia. After intravascular injection, HRP was present in the lamina propria and in intercellular spaces of the epithelium, but HRP did not enter tight junctions. Tracer was taken up into cytoplasmic vesicles of both stratified and simple columnar epithelial cells, but was only rarely seen in the lumen. We conclude that there is rapid transcellular, vesicle-mediated transport from lumen to blood across both stratified and simple columnar epithelia of fetal rat small intestine and colon; after intravascular injection, macromolecules may be taken up into vesicles at basolateral epithelial cell surfaces but are not rapidly transported into the lumen; paracellular passage does not occur in the fetal ages studied.

Animals↗
PubMed1976

[Epithelial barriers of the intestine. Significance and function in defense against infection].

The epithelial surface of the intestinal tract provides for an important barrier between the organism and its environment. However, it permits the passage into the tissues of limited amounts of macromolecules and/or particles, especially bacteria. These functions are age- and species-dependent, and they are closely related to nonspecific and specific immune reactions. Continuous and intimate contact between antigenic material from the gut lumen and immunocompetent cells takes place in gut-associated lymphoid tissues.

Bacterial Infections↗
PubMed1990

Structure and function of the intestinal epithelial barrier in health and disease.

The major and rate-limiting barrier to transepithelial permeation in the intestine is the intercellular tight junction. Tight junction structure is often cell type specific and general but imperfect correlates between tight junction structure and permeability exist. The structure and permeability of this key barrier is not static and can be regulated physiologically. The means of regulation appears to involve the cytoskeleton of neighboring epithelial cells (particularly absorptive cells). Meal-related solutes--nutrients such as glucose--can reversibly enhance the permeability of absorptive cell tight junctions. Although this may substantially enhance the ability of the small intestine to harvest meal-related nutrients, it is conceivable that this may also result in transient exposure of the subepithelial compartment to potentially noxious lumenal compounds. Some features found in many intestinal disease states such as PMN migration across the epithelium may also result in transient barrier defects. With PMN transmigration it is clear that even macromolecules may permeate junctions being impaled by PMNs. When disease processes finally result in focal epithelial denudation, the epithelium has the potential of resealing such defects with remarkable efficiency. The preceding discussion highlights how dynamic the tight junction is and sets the stage for future work aimed at understanding the initial signaling events and intracellular cascade(s) that allow this major barrier to demonstrate such plasticity.

Epithelial Cells↗
PubMed1979

Intestinal structure and function related to toxicology.

The study of toxic effects on small intestinal function is complicated by the integration of the activity of the small intestine with the activities of other regions of the GI tract. Also, the barrier and portal functions of the intestine are not as clearly defined as sometimes assumed. The intestinal surface functions as a barrier to the ingress of large quantities of large water soluble molecules. Lipidic substances enter the body quite readily as do small water-soluble molecules. The small intestinal surface is more a portal than a barrier, with its portal functions divided between nonspecific diffusional entry, which depends on physical properties and electric charge, and entry by specific membrane transport, which depends upon chemical structure. The implications of these properties of the small intestine for toxicological studies are stressed.

Animals↗
PubMed1991

[Structural bases of the barrier-protective function of the stomach and small intestine].

The gastrointestinal tract acts as a barrier-protective tool in addition to its digestive and transport functions. The structural bases of the barrier protective function of the stomach and small intestine were shown in health, duodenal ulcer (DU), experimental gastroduodenal ulcers (GDU), vagotomy, and peritonitis in case of the interaction of these structures with parietal microflora (PM) which may be a valid criteria for assessing the barrier-protective function. PM increases in number in DU, GDU, vagotomy, and peritonitis. Various modifying interventions can normalize this parameter. Identifying the components of protective levels makes it possible to differentiate the affect of protective levels and makes it possible to differentiate affect some links of the barrier-protective function in order to restore it or prevent its disturbance.

Animals↗
PubMed1989

[The state of the gastrointestinal tract in reactive arthritis].

The gastrointestinal tract status (GIT) was evaluated in 23 reactive arthritis (RA) patients: in 17 after intestinal infection, in 2 after urogenital infection, and in 4 after mixed infection. All the examined were found to have signs of diffuse variously pronounced chronic inflammation of the small and large intestine, impaired barrier function of the stomach, liver disorders, and moderate-severe intestinal dysbacteriosis with developing transitory bacteraemia in most severe cases. The GIT changes were correlated with the severity of the RA course. In 20 control-group patients not afflicted with joint disease and operated on for cicatricial stricture of the oesophagus, no signs of chronic inflammation of the mucosa were revealed in the biopsy samples of the large and small intestine. The obtained results may be indicative of the role played by the GIT in the development of pathogenic processes in RA.

Adult↗
PubMed1990

Cutaneous thermal injury alters macromolecular permeability of rat small intestine.

The intestinal epithelium normally provides a barrier function that prevents absorption of potentially harmful materials from the intestinal lumen. It has been postulated but never demonstrated that a cutaneous thermal injury will result in increased small-intestinal permeability. In a standardized 20% body surface area full-thickness scald injury, with polyethylene glycol 3350 and horseradish peroxidase used as permeability probes, small-intestinal permeability was examined regionally in an everted intestinal sac model. In the normal animals, the upper (proximal) and lower (distal) small intestine were less permeable to these probes than the middle segment. Within 6 hours after the injury, an increase in the mucosal uptake and transmural permeability was seen in all three small-intestinal segments; the most dramatic increase in permeability occurred in the ileum, p less than 0.01. The maximum increase in permeability was seen at 18 hours, and permeability was normal by 72 hours after the injury. This increase in intestinal permeability may represent a transient failure of the intestinal barrier function and may allow absorption of potentially toxic macromolecules from the intestinal lumen into the portal circulation early after thermal injury. Absorption of these macromolecules, such as endotoxin, may be potentially harmful by direct toxic actions or potentially helpful by activation of the immune system.

Animals↗
PubMed1992

Intestinal permeability in the critically ill.

Alterations in intestinal permeability reflect one component of intestinal epithelial barrier function. The objective of this study was to assess the degree of derangement of intestinal permeability in critically ill patients and to investigate the relationship of this to markers of disease severity and sepsis. Sixteen patients admitted to the intensive care unit for a variety of problems were studied with the severity of illness and degree of sepsis recorded daily. A differential sugar absorption test, using lactulose and mannitol as markers, was performed, and in 10 patients this was repeated after an interval of between 4-11 days. The use of the lactulose/mannitol (L/M) ratio corrects for variables unrelated to permeability such as gastric emptying. The L/M ratio was significantly higher in patients (median 0.98) compared to normal controls (median 0.008). The ratios showed no relation to disease severity or sepsis. These results establish that increased intestinal permeability occurs in the general ICU patient but that it is not uniquely related to sepsis. The extent of this abnormality suggests that further study is required to show the various influences on this process.

Adult↗
PubMed2026

Intestinal blood vessel-associated macrophages and gut-vascular barrier dysfunction in cirrhosis.

BACKGROUND: Bacterial translocation in cirrhosis can trigger infection and hepatic decompensation, leading to systemic inflammation, organ failure and increased mortality. These infections often originate from the gastrointestinal tract after bacteria breach the intestinal barrier and disseminate to systemic sites. OBJECTIVE: In this study, we explore the mechanisms underlying intestinal barrier dysfunction in cirrhosis using an experimental cirrhosis model and patient-derived intestinal biopsies. DESIGN: We developed a murine model of cirrhosis through chronic administration of carbon tetrachloride for up to 20 weeks. We investigated both the intestinal epithelial and vascular compartments and performed single-cell transcriptomic profiling of myeloid cells isolated from cirrhotic mice and from individuals with compensated and decompensated cirrhosis. RESULTS: Our findings indicate that bacterial translocation in cirrhosis is the result of failure at multiple checkpoints, including aberrant epithelial cell death, vascular barrier damage and dysfunction of gut-vascular macrophages. In a preclinical model of cirrhosis, macrophages exhibited increased levels of monocyte-attracting chemokines, reduced bacterial clearance and impaired interactions with blood vessels. Importantly, depleting vascular-lining macrophages resulted in bacterial translocation to systemic sites, even in the absence of experimental liver disease. Transcriptional profiling of macrophages from duodenal biopsies of patients with cirrhosis indicated similar dysregulation of pathways supporting blood vessels and elevated expression of chemokines. CONCLUSIONS: This study emphasises the critical role of intestinal macrophages in preventing the dissemination of luminal bacteria and highlights the multifaceted breakdown of the intestinal barrier in cirrhosis and the importance of the gut-vascular barrier.

Animals↗
PubMed2026

Phytolacca acinosa Roxb. induces intestinal toxicity through the histamine-MLCK-tight junction axis: Integrated evidence from proteomics, metabolomics, intestinal organoids and epithelial barrier validation.

Phytolacca acinosa Roxb. (PR) is a saponin-rich medicinal plant associated with gastrointestinal toxicity, but the mechanisms underlying PR-induced intestinal barrier injury remain unclear. In this study, raw PR extract was analytically characterized by UPLC-ZenoTOF-MS/MS, confirming triterpenoid saponins as the predominant constituents. C57BL/6 J mice were orally exposed to characterized PR extract (1.20 or 12.0 g/kg for 5 h), and Caco-2 cells and mouse intestinal organoids were used to assess epithelial toxicity and barrier disruption. Histopathology, ELISA, FITC-dextran permeability assays, immunofluorescence, CCK-8, LDH release, western blotting, DIA-based proteomics and untargeted metabolomics were integrated to define toxicological mechanisms. PR induced dose-dependent intestinal inflammation and barrier dysfunction, with the ileum as the most sensitive target. PR increased serum DAO and D-lactate and intestinal TNF-α and IL-1β, disrupted organoid morphology, enhanced epithelial permeability, and reduced ZO-1 expression. Proteomics revealed changes in inflammatory, lipid-metabolic, cytoskeletal and tight-junction pathways, including upregulation of MLCK3 and phospholipase-related proteins and downregulation of ZO-1 and ZO-2. Metabolomics identified histidine metabolism disturbance and histamine accumulation. Integrated multi-omics and pharmacological validation indicated that histamine activated the PLC/IP₃/Ca²⁺/CaM/MLCK cascade, promoting MLC phosphorylation, tight-junction disassembly and epithelial leakiness. MLCK inhibition partially restored ZO-1/ZO-2 expression and attenuated PR-induced epithelial injury. These findings identify the histamine-MLCK-tight junction axis as a key mechanism of PR-induced intestinal toxicity and support hazard identification of saponin-rich PR exposure.

Animals↗