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Intestinal Permeability in Inflammatory Bowel Disease: Pathogenesis, Clinical Evaluation, and Therapy of Leaky Gut

Andrea Michielan, Renata D’Incà

Mediators of Inflammation · 2015 · Review · CC BY

doi:10.1155/2015/628157

Abstract

The pathogenesis of inflammatory bowel disease (IBD) is multifactorial with data suggesting the role of a disturbed interaction between the gut and the intestinal microbiota. A defective mucosal barrier may result in increased intestinal permeability which promotes the exposition to luminal content and triggers an immunological response that promotes intestinal inflammation. IBD patients display several defects in the many specialized components of mucosal barrier, from the mucus layer composition to the adhesion molecules that regulate paracellular permeability. These alterations may represent a primary dysfunction in Crohn’s disease, but they may also perpetuate chronic mucosal inflammation in ulcerative colitis. In clinical practice, several studies have documented that changes in intestinal permeability can predict IBD course. Functional tests, such as the sugar absorption tests or the novel imaging technique using confocal laser endomicroscopy, allow an in vivo assessment of gut barrier integrity. Antitumor necrosis factor‐ α (TNF‐ α ) therapy reduces mucosal inflammation and restores intestinal permeability in IBD patients. Butyrate, zinc, and some probiotics also ameliorate mucosal barrier dysfunction but their use is still limited and further studies are needed before considering permeability manipulation as a therapeutic target in IBD.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 16, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

The gut has a major role in food digestion and absorption as well as in maintaining the general homeostasis. It is estimated that the total bacterial cell count in our body exceeds ten times the total number of human cells, with more than one thousand species hosted in the gastrointestinal tract. The gastrointestinal microbiota, whose genome contains one hundredfold more genes than the entire human genome, has important roles in nutrition, energy metabolism, host defense, and immune system development. Indeed the altered microbiota has been linked not only to gastrointestinal diseases but also to the pathogenesis of systemic conditions such as obesity and metabolic syndrome. Therefore, the term “mucosal barrier” seems to properly highlight the pivotal role of the gut in the interaction with microbiota: it is not a static shield but an active apparatus with specialized components. As stated by Bischoff et al. “permeability” is defined as a functional feature of this barrier that on one hand allows the coexistence with bacterial symbionts necessary for our organism and on the other hand prevents luminal penetration of macromolecules and pathogens. Altered intestinal permeability has been documented during several conditions, namely, acute pancreatitis, multiple organ failure, major surgery, and severe trauma, and could explain the high prevalence of Gram-negative sepsis and related mortality in critically ill patients. Furthermore, perturbation of the complex mechanism of permeability has been associated with the development of irritable bowel syndrome and steatohepatitis (NASH).

The pathogenesis of inflammatory bowel disease (IBD) is still unclear but in all probability is multifactorial and driven by an exaggerated immune response towards gut microbiome in a genetically susceptible host. Increasing evidence suggests that intestinal permeability may be crucial and some authors even considered IBD as an impaired barrier disease.

2. Components of the Intestinal Barrier and Related Dysfunction in Inflammatory Bowel Disease

The main component of the mucosal barrier is represented by the intestinal epithelium, which consists of a single layer of different specialized subtypes of cells: enterocytes, goblet cells, Paneth cells, and enteroendocrine cells but also immunity cells such as intraepithelial lymphocytes and dendritic cells (Figure 1). The mechanical cohesion of these cells and the regulation of paracellular permeability of ions and small molecules are ensured by three types of junctional complexes, namely, tight junctions (TJs), adherence junctions, and desmosomes.

IBD patients display increased paracellular permeability with TJs abnormalities documented in several studies. These are complex multiproteins structures with an extracellular portion, a transmembrane domain and an intracellular connection with cytoskeleton (Figure 1). A decreased expression and redistribution of their constituents, including occludins, claudins, and junctional adhesion molecules (JAM), have all been documented in IBD and a recent experimental mouse model found that deletion of claudin-7 initiates colonic inflammation. Furthermore, tumour necrosis factor-α (TNF-α), one of the main effectors of IBD inflammation, may modulate the transcription of TJs proteins while its antagonists (anti-TNF-α) can ameliorate intestinal permeability. However, TNF-α leads to altered permeability also, inducing apoptosis of enterocytes, increasing their rate of shedding, and hindering the redistribution of TJs that should seal the gaps left.

Goblet cells are specialized in the secretion of mucus which covers the surface of intestinal epithelium. Mucus is composed of proteins, carbohydrates, lipids, and a high degree of water but displays also antimicrobial properties thanks to antimicrobial peptides, mainly defensins produced by Paneth cells, and secretory IgA. Ulcerative Colitis (UC) patients show a reduced number of goblet cells, a reduced thickness of the mucus layer, and an altered mucus composition in terms of mucins, phosphatidylcholine, and glycosylation. Moreover, altered Paneth cell distribution and function have been documented in IBD: these cells are normally restricted to the small intestines, within the crypts of Lieberkühn, but in IBD metaplastic Paneth cells may be detected in colonic mucosa, with subsequent secretion of defensins also in the large intestine. However, the role of Paneth cells may be different in the two disease phenotypes since the expression of defensins is inducible by colonic inflammation in UC but is reduced in patients with colonic Crohn's disease (CD). Indeed, the diminished Paneth cell antimicrobial function might be a primary pathogenic factor in CD, particularly ileal CD, while the increased secretion of defensins in UC may be a physiological response to mucosal damage.

3. Etiology of Permeability Dysfunction in Inflammatory Bowel Disease

Whether mucosal barrier impairment is a consequence of the inflammatory response or a primary defect that prompts mucosal inflammation is still under debate. However, several studies suggest that altered intestinal permeability may be an early event in CD pathogenesis. First of all an augmented paracellular permeability has been found also in patients with quiescent IBD and correlated with intestinal symptoms even when endoscopic activity was absent. Furthermore, an ex vivo study using Ussing chambers on colonic biopsies from CD patients demonstrated a spatially uniform increase in transepithelial conductivity despite the presence of minimal mucosal erosions. This finding was attributed to the downregulation of TJs proteins. Finally, animal models of CD, namely, IL-10 knockout mice and SAMP1/YitFc mice, confirmed that increased permeability can be detected before the onset of mucosal inflammation.

On the other hand, genes involved in intestinal barrier homeostasis have been associated with IBD susceptibility suggesting a genetic predisposition that is further supported by the observation that up to 40% of first-degree relatives of CD patients display an altered small intestinal permeability, with significant association with familial CD and NOD2/CARD15 variants. This gene, which is involved in bacterial recognition, modulates both innate and adaptive immune responses and is the main susceptibility locus for CD development. Other studies have not found a correlation between permeability and genetic polymorphisms but it is noteworthy that they have mostly involved sporadic CD cases. However, environmental factors too are main contributors in determining mucosal permeability since permeability is increased even in a proportion of CD spouses. Moreover, a recent study highlighted the importance of age and smoking status rather than genotype in relatives. Finally, to date there is only one reported case of CD development predicted by an abnormal permeability test in a healthy relative.

Independently from being genetically determined or caused by environmental factors, permeability impairment leads to the disruption of the physiological balance between mucosal barrier and luminal challenge which cannot be adequately counteracted by innate immunity of IBD patients, which on the contrary responds with an aberrant immune activation. As a matter of fact several defects in bacterial recognition and processing have been documented in CD patients carrying particular genetic polymorphisms, chiefly of pattern-recognition receptors such as NOD2/CARD15 and genes involved in autophagy like ATG16L1 and IRGM. In intestinal mucosa, the lack of feedback between mutated NOD2/CARD15 expression and gut luminal microbiota can lead to the breakdown of tolerance. Interestingly, a recent study by Nighot et al. demonstrated that autophagy is also involved in the regulation of TJs by degradation of a pore-forming claudin, linking autophagy to permeability.

Finally, intestinal microbiota per se is altered in IBD, particularly in its relative composition and diversity. This may represent a consequence of chronic mucosal inflammation but the influence of host genotype in shaping microbial community cannot be overlooked in CD and NOD2/CARD15 genotype has been shown to influence the composition of gut microbiota in humans. This dysbiosis may further aggravate permeability dysfunction by the loss of the symbiotic relationship between the microbiota and the mucosal barrier integrity.

4. Clinical Evaluation of Permeability in Inflammatory Bowel Disease

Permeability impairment may be early involved during the development of CD inflammation. Indeed, some of the known risk factors for disease relapse may induce inflammation through the increased mucosal permeability: this is a well-known mechanism for nonsteroids anti-inflammatory drugs (NSAIDs) and recent evidence demonstrated that even stress acts in a similar manner through the release of corticotropin-releasing factors. Furthermore, an impaired small intestinal permeability can predict the risk of CD relapse and patients with altered lactulose/mannitol test (L/M test) have 8-fold risk of relapse even if asymptomatic and with normal biochemical indices.

L/M test evaluates small intestinal permeability by measuring the urinary excretion after oral administration of these sugars. Lactulose is a large size oligosaccharide that usually does not have paracellular transport and can be adsorbed only in case of leakiness of intercellular junctions; mannitol is a smaller molecule that can freely cross the intestinal epithelium. Both the probes are equally affected by gastrointestinal dilution, motility, bacterial degradation, and renal function; thus, the ratio allows for correcting possible confounding factors. L/M test is used in clinical practice thanks to its noninvasiveness, its high sensitivity in detecting active IBD, and its ability to discriminate functional versus organic gastrointestinal disease. An altered L/M test has been reported in up to nearly 50% of CD patients. Other sugars are routinely used to evaluate the upper intestinal tract, such as sucrose which is degraded by duodenal sucrase, thus reflecting the permeability of the stomach and the proximal duodenum. Therefore, multisugar tests have been developed, with the recent addition of sucralose, which is scarcely absorbed throughout the human intestine and thus allows a functional assessment of the whole intestinal tract, widening the possible application to UC.

Other functional tests, such as 51Cr-EDTA or the Ussing chambers, have demonstrated good accuracy but their invasiveness and the complex detection methods preclude their use in humans. Whereas promising results are shown by novel imaging techniques, particularly confocal laser endomicroscopy. this endoscopic technique allows an in vivo evaluation of the epithelial lining and vasculature with the use of intravenous fluorescein as a molecular contrast agent, which usually does not have paracellular transport. Confocal laser endomicroscopy is now widely used in diagnosis and classification of gastrointestinal tumours but it has also been applied in nonneoplastic conditions such as celiac disease, collagenous colitis, and irritable bowel syndrome. The up to one thousandfold magnification permits detection of cellular and subcellular changes such as cell shedding, making it a powerful technique for the imaging of any defects in mucosal barrier in IBD. Confocal laser endomicroscopy demonstrated increased density of mucosal gaps after cell shedding in small bowel of CD patients but also in macroscopically normal duodenum in both CD and UC. Far from being just speculative findings these alterations may represent a subclinical impairment of intestinal permeability possibly predicting subsequent clinical relapse. Recently confocal laser endomicroscopy has been applied in UC patients demonstrating that the occurrence of crypt architectural abnormalities can predict disease relapse in patients with apparent endoscopic remission (Figure 2).

5. Permeability-Oriented Therapies

Agents routinely used in the therapeutic armamentarium of IBD may induce and maintain mucosal remission not only for their immunomodulating effect, but also through the restoration of epithelial integrity and permeability, as has been demonstrated for anti-TNF-α drugs in CD. Since similar effects have been obtained using elemental diets in CD, increasing interest relies on dietary approaches with the use of immunomodulatory nutrients and probiotics.

Western diet with its high content of fat and refined sugars is a risk factor for the development of CD probably inducing a low-grade inflammation via gut dysbiosis and increased intestinal permeability. Furthermore, there is increasing concern about the role of industrial food additives as promoters of immune-related diseases. A recent review showed the ability of additives to increase intestinal permeability by interfering with the TJs, promoting the passage of immunogenic antigens. On the contrary, certain fatty acids (propionate, acetate, butyrate, omega-3, and conjugated linoleic acid), amino acids (glutamine, arginine, tryptophan, and citrulline), and oligoelements, essential for intestinal surface integrity, when supplemented to experimental models of gut diseases, can reduce inflammation and restore mucosal permeability. However, their therapeutic efficacy, particularly in IBD, remains debatable: butyrate, zinc, and probiotics have the strongest evidence in this regard.

Butyrate is a short chain fatty acid produced by intestinal microbial fermentation of dietary fibres which in experimental models stimulates mucus production and expression of TJs in vitro but a wider range of action is expected. It is so crucial for general homeostasis of enterocytes that its deficiency, measured as faecal concentrations, has been taken as an indirect indicator of altered barrier function. In clinical practice topical butyrate had proved efficacy in refractory distal UC.

Other fatty acids with similar properties have also been proposed as an adjuvant therapy in IBD, namely, omega-3 and phosphatidylcholine, but their use in clinical practice is still limited.

Zinc is a trace element essential for cell turnover and repair systems. Inflammatory conditions and malnutrition are known risk factors for zinc deficiency and several works proved the efficacy of its supplementation during acute diarrhoea and experimental colitis. We have shown that oral zinc therapy can restore intestinal permeability in CD patients probably through its ability to modulate TJs both in the small and the large bowels.

The rationale for the use of probiotics in IBD is the aforementioned dysbiosis that characterizes these diseases. Several trials have tested the efficacy of different species of probiotics in IBD, with conflicting results. To date the ones with proven efficacy are Escherichia coli Nissle 1917, Bifidobacterium, Lactobacillus rhamnosus GG, or the multispecies VSL#3 which contains eight different probiotics. Yet their use is still limited to UC and often aimed at maintaining remission rather than treating active disease, as highlighted by the meta analysis by Jonkers et al.. The mechanisms of their effect in UC have not been fully understood but probably, along with direct anti-inflammatory effects, they may strengthen mucosal barrier and reduce intestinal permeability once again upregulating TJs proteins. Even the beneficial effect of probiotics in pouchitis seems to be related to the enhancement of mucosal barrier function. Another potential mechanism of action is the restoration of butyrate-producing bacteria: UC patients have reduced bacterial species like Faecalibacterium prausnitzii and supplementation with butyrate-producing species or probiotics along with preformed butyrate showed efficacy in experimental models.

Finally, vitamin D is worth a mention because it is involved in maintaining intestinal barrier function and polymorphisms of its receptor have been associated with the development of IBD. While the expression of vitamin D receptor on intestinal epithelium inhibits inflammation-induced apoptosis, its deletion leads to defective autophagy that promotes experimental colitis. However, further data and clinical trials are needed to rationalize vitamin D use in IBD management.

6. Conclusions

The impairment of intestinal barrier function is one of the key events in the pathogenesis of IBD. Whether it precedes and predisposes disease development is still under investigation, especially in CD, but surely it perpetuates and enhances chronic mucosal inflammation by increasing paracellular transport of luminal pathogens.

Novel functional and imaging techniques allow us to assess mucosal permeability in vivo and help identifying patients at risk of relapse guiding therapeutic management.

Manipulation of intestinal permeability is an intriguing therapeutic approach but more studies on efficacy and safety are warranted before nutritional immune-modulators can be used in clinical practice.

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    May G. R., Sutherland L. R., Meddings J. B. Is small intestinal permeability really increased in relatives of patients with Crohn's disease? Gastroenterology. 1993;104(6):1627-1632.

    Not in our library10.1016/0016-5085(93)90638-s

  59. 59.

    Munkholm P., Langholz E., Hollander D., et al. Intestinal permeability in patients with Crohn's disease and ulcerative colitis and their first degree relatives. Gut. 1994;35(1):68-72.

    Not in our library10.1136/gut.35.1.68

  60. 60.

    Peeters M., Geypens B., Claus D., et al. Clustering of increased small intestinal permeability in families with Crohn's disease. Gastroenterology. 1997;113(3):802-807.

    Not in our library10.1016/s0016-5085(97)70174-4

  61. 61.

    Russell R. K., Satsangi J. IBD: a family affair. Best Practice and Research: Clinical Gastroenterology. 2004;18(3):525-539.

    Not in our library10.1016/j.bpg.2003.12.006

  62. 62.

    Fries W., Renda M. C., Lo Presti M. A., et al. Intestinal permeability and genetic determinants in patients, first-degree relatives, and controls in a high-incidence area of Crohn's disease in Southern Italy. The American Journal of Gastroenterology. 2005;100(12):2730-2736.

    Not in our library10.1111/j.1572-0241.2005.00325.x

  63. 63.

    D'Incà R., Annese V., Di Leo V., et al. Increased intestinal permeability and NOD2 variants in familial and sporadic Crohn's disease. Alimentary Pharmacology and Therapeutics. 2006;23(10):1455-1461.

    Not in our library10.1111/j.1365-2036.2006.02916.x

  64. 64.

    Buhner S., Buning C., Genschel J., et al. Genetic basis for increased intestinal permeability in families with Crohn's disease: role of CARD15 3020insC mutation? Gut. 2006;55(3):342-347.

    Not in our library10.1136/gut.2005.065557

  65. 65.

    Kevans D., Turpin W., Madsen K., et al. Determinants of intestinal permeability in healthy first-degree relatives of individuals with Crohn's disease. Inflammatory Bowel Diseases. 2015;21(4):879-887.

    Not in our library10.1097/mib.0000000000000323

  66. 66.

    Irvine E. J., Marshall J. K. Increased intestinal permeability precedes the onset of Crohn's disease in a subject with familial risk. Gastroenterology. 2000;119(6):1740-1744.

    Not in our library10.1053/gast.2000.20231

  67. 67.

    Chichlowski M., Hale L. P. Bacterial-mucosal interactions in inflammatory bowel disease—an alliance gone bad. The American Journal of Physiology—Gastrointestinal and Liver Physiology. 2008;295(6):G1139-G1149.

    Not in our library10.1152/ajpgi.90516.2008

  68. 68.

    Hugot J.-P., Chamaillard M., Zouali H., et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature. 2001;411(6837):599-603.

    Not in our library10.1038/35079107

  69. 69.

    Ogura Y., Bonen D. K., Inohara N., et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature. 2001;411(6837):603-606.

    Not in our library10.1038/35079114

  70. 70.

    Hampe J., Franke A., Rosenstiel P., et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nature Genetics. 2007;39(2):207-211.

    Not in our library10.1038/ng1954

  71. 71.

    Parkes M., Barrett J. C., Prescott N. J., et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nature Genetics. 2007;39(7):830-832.

    Not in our library10.1038/ng2061

  72. 72.

    McCarroll S. A., Huett A., Kuballa P., et al. Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease. Nature Genetics. 2008;40(9):1107-1112.

    Not in our library10.1038/ng.215

  73. 73.

    Petnicki-Ocwieja T., Hrncir T., Liu Y.-J., et al. Nod2 is required for the regulation of commensal microbiota in the intestine. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(37):15813-15818.

    Not in our library10.1073/pnas.0907722106

  74. 74.

    Nighot P. K., Hu C. A., Ma T. Y. Autophagy enhances intestinal epithelial tight junction barrier function by targeting claudin-2 protein degradation. The Journal of Biological Chemistry. 2015;290(11):7234-7246.

    Not in our library10.1074/jbc.m114.597492

  75. 75.

    Willing B., Halfvarson J., Dicksved J., et al. Twin studies reveal specific imbalances in the mucosa-associated microbiota of patients with ileal Crohn's disease. Inflammatory Bowel Diseases. 2009;15(5):653-660.

    Not in our library10.1002/ibd.20783

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    Rehman A., Sina C., Gavrilova O., et al. Nod2 is essential for temporal development of intestinal microbial communities. Gut. 2011;60(10):1354-1362.

    Not in our library10.1136/gut.2010.216259

  77. 77.

    Fava F., Danese S. Intestinal microbiota in inflammatory bowel disease: friend of foe? World Journal of Gastroenterology. 2011;17(5):557-566.

    Not in our library10.3748/wjg.v17.i5.557

  78. 78.

    Martin T. D., Chan S. S. M., Hart A. R. Environmental factors in the relapse and recurrence of inflammatory bowel disease: a review of the literature. Digestive Diseases and Sciences. 2015;60(5):1396-1405.

    Not in our library10.1007/s10620-014-3437-3

  79. 79.

    Rodiño-Janeiro B. K., Alonso-Cotoner C., Pigrau M., Lobo B., Vicario M., Santos J. Role of corticotropin-releasing factor in gastrointestinal permeability. Journal of Neurogastroenterology and Motility. 2015;21(1):33-50.

    Not in our library10.5056/jnm14084

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    Wyatt J., Vogelsang H., Hübl W., Waldhöer T., Lochs H. Intestinal permeability and the prediction of relapse in Crohn's disease. The Lancet. 1993;341(8858):1437-1439.

    Not in our library10.1016/0140-6736(93)90882-h

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    D'Incà R., Di Leo V., Martines D., et al. Can permeability to sugars predict relapses in Crohn's disease? Gut. 1993;34(1, supplement):S50-S73.

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    D'Incà R., Di Leo V., Corrao G., et al. Intestinal permeability test as a predictor of clinical course in Crohn's disease. The American Journal of Gastroenterology. 1999;94(10):2956-2960.

    Not in our library10.1016/s0002-9270(99)00500-6

  83. 83.

    Di Leo V., D'Incà R., Diaz-Granado N., et al. Lactulose/mannitol test has high efficacy for excluding organic causes of chronic diarrhea. The American Journal of Gastroenterology. 2003;98(10):2245-2252.

    Not in our library10.1016/s0002-9270(03)00703-2

  84. 84.

    Caccaro R., D'Incà R., Martinato M., et al. Fecal lactoferrin and intestinal permeability are effective non-invasive markers in the diagnostic work-up of chronic diarrhea. BioMetals. 2014;27(5):1069-1076.

    Not in our library10.1007/s10534-014-9745-4

  85. 85.

    Ukabam S. O., Clamp J. R., Cooper B. T. Abnormal small intestinal permeability to sugars in patients with Crohn’s disease of the terminal ileum and colon. Digestion. 1983;27(2):70-74.

    Not in our library10.1159/000198932

  86. 86.

    Andre F., Andre C., Emery Y., Forichon J., Descos L., Minaire Y. Assessment of the lactulose—mannitol test in Crohn's disease. Gut. 1988;29(4):511-515.

    Not in our library10.1136/gut.29.4.511

  87. 87.

    Wyatt J., Oberhuber G., Pongratz S., et al. Increased gastric and intestinal permeability in patients with Crohn's disease. American Journal of Gastroenterology. 1997;92(10):1891-1896.

    Not in our library

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    Meddings J. B., Sutherland L. R., Byles N. I., Wallace J. L. Sucrose: a novel permeability marker for gastroduodenal disease. Gastroenterology. 1993;104(6):1619-1626.

    Not in our library10.1016/0016-5085(93)90637-r

  89. 89.

    van Wijck K., Verlinden T. J. M., van Eijk H. M. H., et al. Novel multi-sugar assay for site-specific gastrointestinal permeability analysis: a randomized controlled crossover trial. Clinical Nutrition. 2013;32(2):245-251.

    Not in our library10.1016/j.clnu.2012.06.014

  90. 90.

    Bjarnason I., O'Morain C., Levi A. J., Peters T. J. Absorption of 51-chromium-label ethylenediaminoacetate in inflammatory bowel disease. Gastroenterology. 1983;85(2):318-322.

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  91. 91.

    Jenkins R. T., Ramage J. K., Jones D. B., Collins S. M., Goodacre R. L., Hunt R. H. Small bowel and colonic permeability to 51Cr-EDTA in patients with active inflammatory bowel disease. Clinical and Investigative Medicine. 1988;11(2):151-155.

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    Pironi L., Miglioli M., Ruggeri E., et al. Relationship between intestinal permeability to [51Cr]EDTA and inflammatory activity in asymptomatic patients with Crohn's disease. Digestive Diseases and Sciences. 1990;35(5):582-588.

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    Becker V., von Delius S., Bajbouj M., Karagianni A., Schmid R. M., Meining A. Intravenous application of fluorescein for confocal laser scanning microscopy: evaluation of contrast dynamics and image quality with increasing injection-to-imaging time. Gastrointestinal Endoscopy. 2008;68(2):319-323.

    Not in our library10.1016/j.gie.2008.01.033

  94. 94.

    Canto M. I., Anandasabapathy S., Brugge W., et al. In vivo endomicroscopy improves detection of Barrett's esophagus-related neoplasia: a multicenter international randomized controlled trial (with video). Gastrointestinal Endoscopy. 2014;79(2):211-221.

    Not in our library10.1016/j.gie.2013.09.020

  95. 95.

    Bok G. H., Jeon S. R., Cho J. Y., et al. The accuracy of probe-based confocal endomicroscopy versus conventional endoscopic biopsies for the diagnosis of superficial gastric neoplasia (with videos). Gastrointestinal Endoscopy. 2013;77(6):899-908.

    Not in our library10.1016/j.gie.2013.01.018

  96. 96.

    Shahid M. W., Buchner A. M., Heckman M. G., et al. Diagnostic accuracy of probe-based confocal laser endomicroscopy and narrow band imaging for small colorectal polyps: a feasibility study. The American Journal of Gastroenterology. 2012;107(2):231-239.

    Not in our library10.1038/ajg.2011.376

  97. 97.

    Shahid M. W., Buchner A. M., Coron E., et al. Diagnostic accuracy of probe-based confocal laser endomicroscopy in detecting residual colorectal neoplasia after EMR: a prospective study. Gastrointestinal Endoscopy. 2012;75(3):525.e1-533.e1.

    Not in our library10.1016/j.gie.2011.08.024

  98. 98.

    Leong R. W. L. Confocal endomicroscopy in the evaluation of celiac disease. Endoscopy. 2010;42(7, article 607).

    Not in our library10.1055/s-0030-1255541

  99. 99.

    Zambelli A., Villanacci V., Buscarini E., Bassotti G., Albarello L. Collagenous colitis: a case series with confocal laser microscopy and histology correlation. Endoscopy. 2008;40(7):606-608.

    Not in our library10.1055/s-2008-1077376

  100. 100.

    Fritscher-Ravens A., Schuppan D., Ellrichmann M., et al. Confocal endomicroscopy shows food-associated changes in the intestinal mucosa of patients with irritable bowel syndrome. Gastroenterology. 2014;147(5):1012-1020.e3.

    Not in our library10.1053/j.gastro.2014.07.046

  101. 101.

    Kiesslich R., Goetz M., Angus E. M., et al. Identification of epithelial gaps in human small and large intestine by confocal endomicroscopy. Gastroenterology. 2007;133(6):1769-1778.

    Not in our library10.1053/j.gastro.2007.09.011

  102. 102.

    Liu J. J., Madsen K. L., Boulanger P., Dieleman L. A., Meddings J., Fedorak R. N. Mind the gaps. Confocal endomicroscopy showed increased density of small bowel epithelial gaps in inflammatory bowel disease. Journal of Clinical Gastroenterology. 2011;45(3):240-245.

    Not in our library10.1097/mcg.0b013e3181fbdb8a

  103. 103.

    Lim L. G., Neumann J., Hansen T., et al. Confocal endomicroscopy identifies loss of local barrier function in the duodenum of patients with Crohn's disease and ulcerative colitis. Inflammatory Bowel Diseases. 2014;20(5):892-900.

    Not in our library10.1097/mib.0000000000000027

  104. 104.

    Kiesslich R., Duckworth C. A., Moussata D., et al. Local barrier dysfunction identified by confocal laser endomicroscopy predicts relapse in inflammatory bowel disease. Gut. 2012;61(8):1146-1153.

    Not in our library10.1136/gutjnl-2011-300695

  105. 105.

    Buda A., Hatem G., Neumann H., et al. Confocal laser endomicroscopy for prediction of disease relapse in ulcerative colitis: a pilot study. Journal of Crohn's and Colitis. 2014;8(4):304-311.

    Not in our library10.1016/j.crohns.2013.09.005

  106. 106.

    Suenaert P., Bulteel V., Vermeire S., Noman M., Van Assche G., Rutgeerts P. Hyperresponsiveness of the mucosal barrier in Crohn's disease is not tumor necrosis factor-dependent. Inflammatory Bowel Diseases. 2005;11(7):667-673.

    Not in our library10.1097/01.mib.0000168371.87283.4b

  107. 107.

    Sanderson I. R., Boulton P., Menzies I., Walker-Smith J. A. Improvement of abnormal lactulose/rhamnose permeability in active Crohn's disease of the small bowel by an elemental diet. Gut. 1987;28(9):1073-1076.

    Not in our library10.1136/gut.28.9.1073

  108. 108.

    Teahon K., Smethurst P., Pearson M., Levi A. J., Bjarnason I. The effect of elemental diet on intestinal permeability and inflammation in Crohn's disease. Gastroenterology. 1991;101(1):84-89.

    Not in our library10.1016/0016-5085(91)90463-u

  109. 109.

    Chapman-Kiddell C. A., Davies P. S. W., Gillen L., Radford-Smith G. L. Role of diet in the development of inflammatory bowel disease. Inflammatory Bowel Diseases. 2010;16(1):137-151.

    Not in our library10.1002/ibd.20968

  110. 110.

    Hildebrandt M. A., Hoffmann C., Sherrill-Mix S. A., et al. High-fat diet determines the composition of the murine gut microbiome independently of obesity. Gastroenterology. 2009;137(5):1716.e2-1724.e2.

    Not in our library10.1053/j.gastro.2009.08.042

  111. 111.

    Serino M., Luche E., Gres S., et al. Metabolic adaptation to a high-fat diet is associated with a change in the gut microbiota. Gut. 2012;61(4):543-553.

    Not in our library10.1136/gutjnl-2011-301012

  112. 112.

    Martinez-Medina M., Denizot J., Dreux N., et al. Western diet induces dysbiosis with increased E coli in CEABAC10 mice, alters host barrier function favouring AIEC colonisation. Gut. 2014;63(1):116-124.

    Not in our library10.1136/gutjnl-2012-304119

  113. 113.

    Lerner A., Matthias T. Changes in intestinal tight junction permeability associated with industrial food additives explain the rising incidence of autoimmune disease. Autoimmunity Reviews. 2015;14(6):479-489.

    Not in our library10.1016/j.autrev.2015.01.009

  114. 114.

    Andrade M. E., Araújo R. S., de Barros P. A. V., et al. The role of immunomodulators on intestinal barrier homeostasis in experimental models. Clinical Nutrition. 2015.

    Not in our library10.1016/j.clnu.2015.01.012

  115. 115.
    Central Role of the Gut Epithelial Barrier in the Pathogenesis of Chronic Intestinal Inflammation: Lessons Learned from Animal Models and Human Genetics · 2013
    No notice
  116. 116.

    Finnie I. A., Dwarakanath A. D., Taylor B. A., Rhodes J. M. Colonic mucin synthesis is increased by sodium butyrate. Gut. 1995;36(1):93-99.

    Not in our library10.1136/gut.36.1.93

  117. 117.

    Barcelo A., Claustre J., Moro F., Chayvialle J.-A., Cuber J.-C., Plaisancié P. Mucin secretion is modulated by luminal factors in the isolated vascularly perfused rat colon. Gut. 2000;46(2):218-224.

    Not in our library10.1136/gut.46.2.218

  118. 118.

    Mariadason J. M., Barkla D. H., Gibson P. R. Effect of short-chain fatty acids on paracellular permeability in Caco-2 intestinal epithelium model. American Journal of Physiology—Gastrointestinal and Liver Physiology. 1997;272(4):G705-G712.

    Not in our library10.1152/ajpgi.1997.272.4.g705

  119. 119.

    Peng L., He Z., Chen W., Holzman I. R., Lin J. Effects of butyrate on intestinal barrier function in a Caco-2 cell monolayer model of intestinal barrier. Pediatric Research. 2007;61(1):37-41.

    Not in our library10.1203/01.pdr.0000250014.92242.f3

  120. 120.

    Hamer H. M., Jonkers D., Venema K., Vanhoutvin S., Troost F. J., Brummer R.-J. Review article: the role of butyrate on colonic function. Alimentary Pharmacology & Therapeutics. 2008;27(2):104-119.

    Not in our library10.1111/j.1365-2036.2007.03562.x

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    Plöger S., Stumpff F., Penner G. B., et al. Microbial butyrate and its role for barrier function in the gastrointestinal tract. Annals of the New York Academy of Sciences. 2012;1258(1):52-59.

    Not in our library10.1111/j.1749-6632.2012.06553.x

  122. 122.

    Venkatraman A., Ramakrishna B. S., Pulimood A. B., Patra S., Murthy S. Increased permeability in dextran sulphate colitis in rats: time course of development and effect of butyrate. Scandinavian Journal of Gastroenterology. 2000;35(10):1053-1059.

    Not in our library10.1080/003655200451171

  123. 123.

    Vernia P., Annese V., Bresci G., et al. Topical butyrate improves efficacy of 5-ASA in refractory distal ulcerative colitis: results of a multicentre trial. European Journal of Clinical Investigation. 2003;33(3):244-248.

    Not in our library10.1046/j.1365-2362.2003.01130.x

  124. 124.

    Lorenz-Meyer H., Bauer P., Nicolay C., et al. Omega-3 fatty acids and low carbohydrate diet for maintenance of remission in Crohn's disease. A randomized controlled multicenter trial. Scandinavian Journal of Gastroenterology. 1996;31(8):778-785.

    Not in our library10.3109/00365529609010352

  125. 125.

    Stremmel W., Merle U., Zahn A., Autschbach F., Hinz U., Ehehalt R. Retarded release phosphatidylcholine benefits patients with chronic active ulcerative colitis. Gut. 2005;54(7):966-971.

    Not in our library10.1136/gut.2004.052316

  126. 126.

    Stremmel W., Ehehalt R., Autschbach F., Karner M. Phosphatidylcholine for steroid-refractory chronic ulcerative colitis: a randomized trial. Annals of Internal Medicine. 2007;147(9):603-610.

    Not in our library10.7326/0003-4819-147-9-200711060-00004

  127. 127.

    Roy S. K., Behrens R. H., Haider R., et al. Impact of zinc supplementation on intestinal permeability in Bangladeshi children with acute diarrhoea and persistent diarrhoea syndrome. Journal of Pediatric Gastroenterology and Nutrition. 1992;15(3):289-296.

    Not in our library10.1097/00005176-199210000-00010

  128. 128.

    Alam A. N., Sarker S. A., Wahed M. A., Khatun M., Rahaman M. M. Enteric protein loss and intestinal permeability changes in children during acute shigellosis and after recovery: effect of zinc supplementation. Gut. 1994;35(12):1707-1711.

    Not in our library10.1136/gut.35.12.1707

  129. 129.

    Di Leo V., D'Incà R., Barollo M., et al. Effect of zinc supplementation on trace elements and intestinal metallothionein concentrations in experimental colitis in the rat. Digestive and Liver Disease. 2001;33(2):135-139.

    Not in our library10.1016/s1590-8658(01)80068-2

  130. 130.

    Sturniolo G. C., Di Leo V., Ferronato A., D'Odorico A., D'Inc R. Zinc supplementation tightens ‘leaky gut’ in Crohn's disease. Inflammatory Bowel Diseases. 2001;7(2):94-98.

    Not in our library10.1097/00054725-200105000-00003

  131. 131.

    Sturniolo G. C., Fries W., Mazzon E., Di Leo V., Barollo M., D'Inca R. Effect of zinc supplementation on intestinal permeability in experimental colitis. Journal of Laboratory and Clinical Medicine. 2002;139(5):311-315.

    Not in our library10.1067/mlc.2002.123624

  132. 132.

    Wang W., Chen L., Zhou R., et al. Increased proportions of Bifidobacterium and the Lactobacillus group and loss of butyrate-producing bacteria in inflammatory bowel disease. Journal of Clinical Microbiology. 2014;52(2):398-406.

    Not in our library10.1128/jcm.01500-13

  133. 133.

    Jonkers D., Penders J., Masclee A., Pierik M. Probiotics in the management of inflammatory bowel disease. A systematic review of intervention studies in adult patients. Drugs. 2012;72(6):803-823.

    Not in our library10.2165/11632710-000000000-00000

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    Vilela E. G., Ferrari M. D. L. D. A., Torres H. O. D. G., et al. Influence of Saccharomyces boulardii on the intestinal permeability of patients with Crohn's disease in remission. Scandinavian Journal of Gastroenterology. 2008;43(7):842-848.

    Not in our library10.1080/00365520801943354

  135. 135.
    Lysate of Probiotic Lactobacillus casei DN-114 001 Ameliorates Colitis by Strengthening the Gut Barrier Function and Changing the Gut Microenvironment · 2011
    No notice
  136. 136.

    Patel R. M., Myers L. S., Kurundkar A. R., Maheshwari A., Nusrat A., Lin P. W. Probiotic bacteria induce maturation of intestinal claudin 3 expression and barrier function. American Journal of Pathology. 2012;180(2):626-635.

    Not in our library10.1016/j.ajpath.2011.10.025

  137. 137.
    Probiotic Escherichia coli Nissle 1917 Inhibits Leaky Gut by Enhancing Mucosal Integrity · 2007
    No notice
  138. 138.

    Persborn M., Gerritsen J., Wallon C., Carlsson A., Akkermans L. M. A., Söderholm J. D. The effects of probiotics on barrier function and mucosal pouch microbiota during maintenance treatment for severe pouchitis in patients with ulcerative colitis. Alimentary Pharmacology and Therapeutics. 2013;38(7):772-783.

    Not in our library10.1111/apt.12451

  139. 139.

    Machiels K., Joossens M., Sabino J., et al. A decrease of the butyrate-producing species roseburia hominis and faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut. 2014;63(8):1275-1283.

    Not in our library10.1136/gutjnl-2013-304833

  140. 140.

    Marteau P. Butyrate-producing bacteria as pharmabiotics for inflammatory bowel disease. Gut. 2013;62(12, article 1673).

    Not in our library10.1136/gutjnl-2012-304240

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    Moeinian M., Ghasemi-Niri S. F., Mozaffari S., et al. Beneficial effect of butyrate, Lactobacillus casei and L-carnitine combination in preference to each in experimental colitis. World Journal of Gastroenterology. 2014;20(31):10876-10885.

    Not in our library10.3748/wjg.v20.i31.10876

  142. 142.

    Simmons J. D., Mullighan C., Welsh K. I., Jewell D. P. Vitamin D receptor gene polymorphism: association with Crohn's disease susceptibility. Gut. 2000;47(2):211-214.

    Not in our library10.1136/gut.47.2.211

  143. 143.

    Dresner-Pollak R., Ackerman Z., Eliakim R., Karban A., Chowers Y., Fidder H. H. The BsmI vitamin D receptor gene polymorphism is associated with ulcerative colitis in Jewish Ashkenazi patients. Genetic Testing. 2004;8(4):417-420.

    Not in our library10.1089/gte.2004.8.417

  144. 144.

    Li Y. C., Chen Y., Du J. Critical roles of intestinal epithelial vitamin D receptor signaling in controlling gut mucosal inflammation. The Journal of Steroid Biochemistry and Molecular Biology. 2015;148:179-183.

    Not in our library10.1016/j.jsbmb.2015.01.011

  145. 145.

    Wu S., Zhang Y.-G., Lu R., et al. Intestinal epithelial vitamin D receptor deletion leads to defective autophagy in colitis. Gut. 2015;64(7):1082-1094.

    Not in our library10.1136/gutjnl-2014-307436

  146. 146.

    O'Sullivan M. Vitamin D as a novel therapy in inflammatory bowel disease: new hope or false dawn? Proceedings of the Nutrition Society. 2015;74(1):5-12.

    Not in our library10.1017/s0029665114001621

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