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PubMed1979

Intestinal barriers to water-soluble macromolecules.

Neonates of some species of mammals absorb water-soluble macromolecules from the lumen of the gut to the circulation. This is a means for providing the neonate with passive immunological protection. The accepted model for absorption of macromolecules, particularly immunoglobulin G (IgG), has at least three phases: adherence of the macromolecule to the brush border on enterocytes; internalization of the macromolecule within the enterocytes; and egress of the macromolecule into the lamina propria. With regard to the absorption of IgG, adherence is thought to be a specific reaction of ligand (IgG) with a plasmalemma binding site. Pinocytosis is activated and internalization follows. Egress into the lamina propria occurs at the basal-lateral membrane by a process of reverse pinocytosis. Unbound (unprotected) macromolecules that are internalized in the pinocytosic fluid are shunted off to lysosomes and either digested or stored therein. Neonatal rodents fit this model for macromolecular absorption. However, in another group of neonates (e.g., pig, cow, horse), nonselected absorption takes place, in that IgG and other macromolecules are transported from the gut lumen to the blood. In a third group of neonates, (e.g., human, guinea pig) absorption of IgG is either of low order or nonexistent. Since neonatal mammals possess a mechanism for absorbing macromolecules, there is the potential for internalizing toxic macromolecules if the toxin is presented to the neonate's enterocytes in competitive amounts. Adults retain remnants of the neonatal absorptive mechanism.

Adult↗
PubMed1996

A critical role for nitric oxide in intestinal barrier function and dysfunction.

There is growing evidence that endogenous nitric oxide (NO) regulates mucosal barrier integrity under physiological conditions and counters the increase in mucosal permeability associated with acute pathophysiological states. The potential mechanisms of action for the protective effects of NO are discussed. These include maintenance of blood flow, inhibition of platelet and leukocyte adhesion and/or aggregation within the vasculature, modulation of mast cell reactivity, and scavenging of reactive oxygen metabolites such as superoxide. On the basis of the data presented, we conclude that both constitutive nitric oxide synthase (cNOS)-derived endogenous NO and exogenous NO (from NO donors) appear to reduce the sequelae of acute inflammation. The second section of this review summarizes the data germane to prolonged (chronic) inflammatory conditions associated with the overproduction of NO from the inducible form of NOS (iNOS). Some emphasis is placed on the role of NO in sepsis and inflammatory bowel disease (IBD), and data to suggest that NO, or more specifically a NO-derived mediator, is involved in these disorders are summarized. These studies are compared with recent publications suggesting that inhibition of NO synthesis with nonspecific inhibitors of NOS or selective iNOS inhibitors may not protect in models of sepsis or IBD. Overall, the review highlights the potential importance of the type of NOS enzyme involved in the particular inflammatory process being studied.

Animals↗
PubMed2026

Kefir and Its By-Products Supplementation Reduces Inflammation and Oxidative Stress, Improves Intestinal Barrier Integrity, and Modulates the Gut Microbiota in Animal Models of Inflammatory Bowel Disease: A Systematic Review.

UNLABELLED: Kefir is a beverage obtained by fermenting milk or sugary solutions with a symbiotic community of bacteria and yeasts, presenting promising antimicrobial, antioxidant, and immunomodulatory properties. This systematic review aimed to synthesize evidence from preclinical studies evaluating the effects of kefir or its by-products on biomarkers of inflammation, oxidative stress, and gut health in animal models of IBD. A systematic review was conducted in accordance with PRISMA guidelines, utilizing the PubMed/MEDLINE, Web of Science, Embase, and Scopus databases. The quality of the studies was assessed using SYRCLE’s Risk of Bias tool. Sixteen experimental studies were included, comprising 585 rodents with chemically induced colitis. The interventions included traditional milk kefir, rice and water kefir, as well as isolated microorganisms and kefir-derived supernatants. Most studies reported reductions in inflammatory cytokines (TNF-α, IL-1β, IL-6) and inflammatory enzymes (iNOS, COX-2, MPO), along with increases in anti-inflammatory cytokines (IL-10, IL-4). Reductions in MDA and H₂O₂ were reported, supporting the antioxidant effects of kefir and its derivatives. Changes in antioxidant enzyme activity, including SOD, were also observed. In addition, kefir modulated gut microbiota composition, upregulated the expression of tight junction proteins, and influenced immune and molecular signaling pathways. Improvements were also observed in clinical parameters of IBD models, including disease activity index, rectal bleeding, and histological damage. Kefir and its derivatives exhibit beneficial effects on inflammation, oxidative stress, gut permeability, and immune modulation in animal models of IBD, suggesting a potential alternative for treating these diseases in humans. Although the findings are promising, heterogeneity among study protocols and methodological limitations highlight the need for further studies. Registration PROSPERO number: CRD420251062931. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s12602-026-10948-5.

Animal model↗
PubMed2002

Ethanol impairs intestinal barrier defense by modulation of immunoglobulin A transport.

BACKGROUND: Increased epithelial permeability may contribute to septic complications after alcohol intoxication. Prior ethanol (EtOH) exposure leads to structural and functional effects on cytoskeletal components important in maintaining barrier integrity. The cytoskeleton is also important in the transcellular transport of proteins including the polymeric immunoglobulin receptor (pIgR) mediated transport of immunoglobulin A (IgA) to the luminal surface of mucosal tissues. We (1) investigated the effects of acute EtOH exposure on cell monolayer barrier integrity and IgA transport and (2) assessed the importance of microtubule function on these functions in vitro. METHODS: Confluent Madin-Darby canine kidney (MDCK) epithelial cells transfected with pIgR cDNA were exposed to 1% or 5% EtOH, and transcytosis of dimeric IgA was measured. Paclitaxel was used to pretreat a subset of MDCK cells. Results. EtOH exposure resulted in a concentration and time dependent decrease in IgA transcytosis. This was associated with physical derangements in the integrity of the cell monolayer. Pretreatment with paclitaxel completely abrogated these effects. CONCLUSIONS: EtOH causes both physical and immune derangement of epithelial cell barrier function. Decreased secretory IgA at mucosal surfaces may initiate septic complications after EtOH intoxication.

Animals↗
PubMed1997

Intestinal epithelial barrier dysfunction in Crohn's disease.

Despite extensive research, the etiology of Crohn's disease remains unknown. Accumulating evidence suggests the possibility that a primary defect of intestinal barrier function may be present in Crohn's disease. In this review, the possible role of intestinal barrier defect in Crohn's disease is discussed. It has been recognized for some time that Crohn's patients have a defective intestinal epithelial barrier function manifested by an increase in intestinal permeability. Recent studies indicate that a subgroup of healthy first-degree relatives of Crohn's patients (a population at high risk for developing Crohn's disease) also have increased intestinal permeability. Additionally, this subgroup of patients have evidence of increased exposure to foreign antigens, suggesting a possible link between increase in intestinal permeability and increase in antigenic penetration. Furthermore, exacerbation of Crohn's disease is produced by agents that disrupt intestinal epithelial barrier function, while remission of active disease is induced by decreasing intestinal antigenic load. A "leaky gut" hypothesis is advanced which proposes that a preexisting disorder of intestinal permeability is responsible for the intestinal inflammation of Crohn's disease.

Crohn Disease↗
PubMed1995

Intestinal permeability measurements - a new application for water soluble contrast media?

The detection and quantification of altered intestinal barrier function (intestinal permeability) have been addressed frequently during the last year, but the tests available for determination of intestinal permeability are both flawed and have limitations. The new water-soluble roentgen contrast media (CM) of low- and iso-osmolar type have been proposed as intestinal permeability probes. In this article this possible new application for water-soluble CM is discussed in terms of their inherent properties and the experimental and clinical results obtained so far. The 2 iso-osmolar dimers, iodixanol (Visipaque) and iotrolan (Isovist), seem to be as good as the well-documented radio-labeled permeability probe (51)Cr-EDTA in detecting injury of the intestinal mucosal barrier. The CM offer the advantage of allowing direct control of bowel wall exposure with the aid of fluoroscopy. Current permeability probes lack this quality. Iodine-containing substances may be analyzed by the rapid, simple and reliable X-ray fluorescence technique, which is suitable for application in routine clinical practice. We conclude that the new water-soluble roentgen CM have properties which may be of use in the diagnosis and quantification of altered intestinal barrier function.

Animals↗
PubMed2005

Epithelial cells and their neighbors. IV. Bacterial contributions to intestinal epithelial barrier integrity.

Mammalian intestinal surfaces are in constant and intimate contact with a vast consortium of indigenous commensal bacteria. As a result, gut epithelia have evolved an array of strategies for limiting bacterial invasion into deeper tissues, helping to preserve the mutually beneficial nature of intestinal host-microbial relationships. In this review, we discuss a growing body of evidence indicating that commensal bacteria are actively involved in shaping the very barriers that confine them to the gut lumen. By modulating epithelial inflammatory responses, antimicrobial protein expression, and tissue repair functions, indigenous microbial populations are essential for the maintenance of healthy mucosal surfaces.

Animals↗
PubMed2004

A porous defense: the leaky epithelial barrier in intestinal disease.

A critical function of the intestinal mucosa is to form a barrier that separates luminal contents from the interstitium. This intestinal barrier is compromised in a number of intestinal diseases, most notably inflammatory bowel disease. In vitro studies have demonstrated that cytokines elaborated by immune cells can cause the mucosal barrier to become leaky; these cytokines are known to be increased in intestinal mucosa involved in inflammatory bowel disease. Detailed information describing the mechanisms by which altered cytokine signaling occurs is not available, but recent data implicate the cytoskeleton within epithelial cells as a critical regulator of the mucosal barrier under physiological and pathophysiological conditions. Using available data, we describe a model of intestinal disease where an initial insult to the epithelial barrier may trigger a self-amplifying cycle of immune activation, cytokine release, and further barrier dysfunction. This model is supported by the observation that pharmacological abrogation of cytokine signaling corrects both barrier defects and clinical disease in animal models and human patients, although such therapy clearly has multiple mechanisms. Other therapeutic targets that represent strategies to prevent or reverse disease processes are also considered. The overarching hypothesis is that modulation of the mucosal epithelial barrier plays a critical role in the initiation and propogation of inflammatory intestinal diseases.

Animals↗
PubMed2002

Factors regulating the effect of IL-4 on intestinal epithelial barrier function.

BACKGROUND: Inflammatory bowel disease is associated with an imbalance in cytokine production and defective intestinal barrier function. Previous studies indicate that IL-4, a cytokine increased in food allergy and in early Crohn's disease, enhances epithelial permeability. Here, we characterized the mechanism of action of IL-4 on cultured epithelial cells and examined if the anti-inflammatory cytokines, TGF-beta or IL-10, can modulate the effects of IL-4. METHODS: Confluent monolayers of human T84 epithelial cells were cultured with IL-4 alone or in combination with IL-10 or TGF-beta or with inhibitors of protein synthesis and blockers of IL-4 receptor signalling pathways. Permeability was evaluated by measuring transepithelial resistance (TER), flux of (3)H-fMLP (a small bacterial tripeptide) and horseradish peroxidase (HRP) (a macromolecule). RESULTS: T84 cells cultured with IL-4 showed a significant drop in TER as well as an increased flux of (3)H-fMLP and HRP. Co-treatment with IL-10 did not improve TER, whereas TGF-beta attenuated the resistance drop. However, neither TGF-beta nor IL-10 were able to correct the increased (3)H-fMLP flux. In contrast, the increased HRP flux caused by IL-4 was inhibited by both IL-10 and TGF-beta. TGF-beta and IL-10 significantly reduced IL-4-enhanced values for endosomal area and paracellular spaces containing HRP. Inhibitor studies indicated the requirement for protein synthesis and the involvement of phosphatidylinositol 3-kinase. CONCLUSIONS: These results provide new insights into the regulation of intestinal barrier function and may suggest a novel approach in the treatment of intestinal inflammation.

Biological Transport↗
PubMed2005

The HIV protease inhibitors saquinavir, ritonavir, and nelfinavir induce apoptosis and decrease barrier function in human intestinal epithelial cells.

BACKGROUND AND AIMS: Diarrhoea is a frequent adverse effect of HIV protease inhibitors (PIs) which may be due to intestinal barrier disruption. We investigated whether tight junction dysregulation, apoptosis or necrosis are responsible for this epithelial damage. METHODS: Saquinavir, nelfinavir, and ritonavir were added to the mucosal or serosal side of HT-29/B6 colon cell monolayers. Transepithelial resistance was monitored for 72 h to assess epithelial barrier function. Apoptosis and necrosis were investigated by light and electron microscopy and quantified by nucleosome ELISA and LDH measurement, respectively. Tight junction components were analysed by Western blots of occludin and zonula occludens. Apoptosis induction in normal human intestinal epithelium was examined by measurement of poly(ADP-ribose) polymerase (PARP) cleavage in Western blots of mucosal tissue explants cultured with PIs for 24 h. RESULTS: HIV PIs decreased transepithelial resistance by more than 44% in HT-29/B6 monolayers. Histology revealed massive apoptotic body formation but no evidence for necrosis after PI treatment. Correspondingly, LDH release was lower than 0.2%/h of total LDH, independent of PI treatment, and nucleosomes were increased up to 22-fold after drug treatment versus control. Occludin and zonula occludens-1 expression in the membrane were not diminished. PARP cleavage increased in normal human intestinal tissue treated with PIs. CONCLUSIONS: PI-induced barrier disruption in intestinal epithelial cells is not due to necrosis or tight junction alterations, but to induction of massive apoptosis which may lead to leak-flux diarrhoea in vivo. Our findings suggest that induction of apoptosis by PIs could have potential for antitumour therapy.

Adult↗
PubMed1995

[The roles of platelet activating factor in intestinal mucosal barrier injury after burn].

In order to investigate the roles of platelet activating factor (PAF) in postburn intestinal barrier injury, the changes in intestinal mucosal potential difference (PD), intestinal PAF, Phospholipase A2 (PLA2), myeloperoxidase (MPO) and malondialdehyde (MDA) were measured in a model of rats with 30% TBSA III degrees burns. The results showed that the intestinal PAF level was significantly elevated after severe burn and was negatively correlated with the decrease of intestinal mucosal PD (r = -0.94, P < 0.01). PAF antagonist WEB 2170 treatment could significantly inhibite the increase of PAF in intestinal tissue, enhance intestinal mucosal PD, attenuate the levels of PLA2, MPO and MDA in intestinal tissue, and alleviate the pathological changes in ileal mucosa, compared with the burn group. The results suggest that PAF is an important factor causing postburn intestinal mucosal barrier injury, and activation of leukocyte and PLA2 as well as the release of superoxide are important intermediate mechanisms for PAF leading to intestinal mucosal injury.

Animals↗
PubMed2002

Gut barrier permeability, reticuloendothelial system function and protease inhibitor levels following intestinal ischaemia and reperfusion--effects of pretreatment with N-acetyl-L-cysteine and indomethacin.

BACKGROUND: Pathophysiological mechanisms and ways to intervene on intestinal barrier dysfunction following small intestinal ischaemia and prolonged reperfusion are still not fully clarified. AIMS: To evaluate the effect of oxygen free radical and prostaglandin inhibition on intestinal barrier injury following intestinal ischaemia/reperfusion. METHODS: Endothelial and epithelial barrier permeability was evaluated by clearance of radiolabelled albumin. Parameters included 125I-Escherichia coli uptake rate index, host reticuloendothelial system function and organ distribution, as well as protease inhibitor and proenzyme activities in rats subjected to small intestinal ischaemia for 40 minutes followed by 12 hours reperfusion (ischaemia/reperfusion), pretreated with N-acetyl-L-cysteine or indomethacin. RESULTS: Following ischaemia/reperfusion, endothelial and epithelial permeability increased, reticuloendothelial system activation occurred and plasma protease inhibitors were consumed. N-acetyl-L-cysteine pretreatment resulted in improved endothelial and epithelial barrier integrity, a decrease in protease inhibitor consumption and less pronounced reticuloendothelial system activation. Pretreatment with indomethacin was not effective. CONCLUSION: Oxygen free radicals seem to play an important role in the development of intestinal barrier impairment following ischaemia/reperfusion. N-acetyl-L-cystine may be a potential agent for preventing ischaemia/reperfusion damage.

Acetylcysteine↗
PubMed1999

Rupture of the intestinal epithelial barrier and mucosal invasion by Shigella flexneri.

Invasion of the intestinal barrier by Shigella flexneri involves complex interactions with epithelial and phagocytic cells. Major perturbation of the signals that maintain epithelial integrity permits mucosal invasion, leading to tissue destruction. Expression of this invasive phenotype depends on the secretion of Ipa proteins (invasins), which can trigger entry of the pathogen into epithelial cells by causing massive rearrangement of the host cell cytoskeleton and cause macrophage apoptotic death by direct interaction of IpaB with interleukin-1beta (IL-1beta)-converting enzyme. This results in the killing of defense cells and in the release of IL-1beta. In vivo, bacteria translocate through the epithelial barrier, essentially via M cells of the follicle-associated epithelium in the colonic and rectal mucosa. Apoptotic death of macrophages in subepithelial tissues allows bacterial survival and triggers inflammation, which destabilizes epithelial structures and facilitates further bacterial entry. Once they are intracellular, bacteria multiply within the cytoplasm and move from cell to cell by an actin-dependent process.

Animals↗
PubMed1995

Elemental diet and IV-TPN-induced bacterial translocation is associated with loss of intestinal mucosal barrier function against bacteria.

OBJECTIVE: The goal of the current study was to directly assess the role of loss of mucosal barrier function in nutritionally induced bacterial translocation. BACKGROUND: Parenteral and certain elemental enteral diets have been shown to promote bacterial translocation. The mechanisms underlying this observation, especially the question of whether nutritionally induced bacterial translocation is primarily related to loss of intestinal barrier function, versus an impaired immune system, remain to be fully elucidated. METHODS: Bacterial translocation was measured in vivo, ileal mucosal membranes were harvested, and their electrophysiologic properties and barrier function were measured ex vivo in the Ussing chamber system 7 days after receiving total parenteral nutrition solution parenterally (IV-TPN) or enterally (elemental diet). Chow-fed rats served as control subjects. RESULTS: The incidence of bacterial translocation was significantly increased both to the mesenteric lymph nodes in vivo and across the in vitro Ussing chamber-mounted ileal mucosal membranes of the elemental diet-fed and IV-TPN-fed rats. The magnitude of Escherichia coli and phenol red transmucosal passage in the Ussing chamber was significantly higher in the IV-TPN-fed rats than in the elemental diet-fed or chow-fed animals. The potential differences across the ileal membrane were similar between the three groups at all time points. However, the specific resistances of the ileal membranes of the IV-TPN and elemental diet groups were significantly less than the chow-fed animals, indicating increased membrane permeability. CONCLUSIONS: Loss of intestinal barrier function plays a major role in nutritionally induced bacterial translocation, and the loss of mucosal barrier function to both E. coli and phenol red appeared greater in the IV-TPN than the elemental diet-fed rats.

Animals↗
PubMed1977

The intestinal mucosal barrier to intact antigenic protein. Difference between colon and small intestine.

The integrity of the normal mature intestinal mucosal barrier to unaltered proteins was evaluated with tritiated bovine albumin in rats. Intact H3-BSA placed into either colon or small intestinal lumen regularly reached the bloodstream in quantities sufficient to be antigenic or toxigenic, although the fraction of H3-BSA absorbed from the colon (0.13 per cent) was significantly smaller than that absorbed from the small intestine (1.7 per cent). These studies support the possibility that uptake of ingested or bacterial antigens from the normal gut may be involved in the pathogenesis of local intestinal and systemic disease in man.

Animals↗