Glutamine Restores Tight Junction Protein Claudin‐1 Expression in Colonic Mucosa of Patients With Diarrhea‐Predominant Irritable Bowel Syndrome

Bertrand, Julien; Ghouzali, Ibtissem; Guérin, Charlène; Bôle‐Feysot, Christine; Gouteux, M.; Déchelotte, Pierre; Ducrotté, Philippe; Coëffier, Moı̈se

doi:10.1177/0148607115587330

Cited by 38 publications

(30 citation statements)

References 38 publications

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“…These data indicate that strategies to block MiR29 might be a good way to restore intestinal permeability in IBS-D. Recent data related to the treatment of IBS also indicated that glutamine increased CLDN1 expression in the colonic mucosa in IBS-D [96]. Glutamine supplementation may be beneficial in IBS-D [83] NC (w) [83] NC (w) [83] NC (w) [79] Down (p-occl w) [79] Down (h) [79] mRNA NC [82] Down [84] Down [84] Down [84] NC [81] ZO-1 Protein Down (w) [83] NC (w) [83] NC (w) [83] NC (w) [83] Down (h) [93] Down (h) [92] …”

Section: Irritable Bowel Syndrome (Ibs)mentioning

confidence: 75%

Gastrointestinal mucosal barrier function and diseases

2016

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The gastrointestinal mucosal barrier plays an essential role in the separation of the inside of the body from the outside environment. Tight junctions (TJs) are the most important component for construction of a constitutive barrier of epithelial cells, and they regulate the permeability of the barrier by tightly sealing the cell-cell junctions. TJ proteins are represented by claudins, occludin, junctional adhesion molecules, and scaffold protein zonula occludens. Among these TJ proteins, claudins are the major components of TJs and are responsible for the barrier and the polarity of the epithelial cells. Gastrointestinal diseases including reflux esophagitis, inflammatory bowel disease, functional gastrointestinal disorders, and cancers may be regulated by these molecules, and disruption of their functions leads to chronic inflammatory conditions and chronic or progressive disease. Therefore, regulation of the barrier function of epithelial cells by regulating the expression and localization of TJ proteins is a potential new target for the treatment of these diseases. Treatment strategies for these diseases might thus be largely altered if symptom generation and/or immune dysfunction could be regulated through improvement of mucosal barrier function. Since TJ proteins may also modify tumor infiltration and metastasis, other important goals include finding a good TJ biomarker of cancer progression and patient prognosis, and developing TJ protein-targeted therapies that can modify patient prognosis. This review summarizes current understanding of gastrointestinal barrier function, TJ protein expression, and the mechanisms underlying epithelial barrier dysregulation in gastrointestinal diseases.

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Section: Irritable Bowel Syndrome (Ibs)mentioning

confidence: 75%

Gastrointestinal mucosal barrier function and diseases

2016

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“…Additional evidence suggests that glutamine directly modulates intestinal permeability in patients with IBS-D. In a study that evaluated the effects of glutamine on claudin-1 tight junction proteins,30 colonic biopsies from patients with IBS-D were incubated in cell culture with glutamine, which increased claudin-1 expression. Thus, glutamine may improve permeability in patients with IBS-D through restoration of tight junction proteins.…”

Section: Discussionmentioning

confidence: 99%

Randomised placebo-controlled trial of dietary glutamine supplements for postinfectious irritable bowel syndrome

Zhou¹,

Verne

Fields

et al. 2018

Gut

136

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BackgroundMore effective treatments are needed for patients with postinfectious, diarrhoea-predominant, irritable bowel syndrome (IBS-D). Accordingly, we conducted a randomised, double-blind, placebo-controlled, 8-week-long trial to assess the efficacy and safety of oral glutamine therapy in patients who developed IBS-D with increased intestinal permeability following an enteric infection.MethodsEligible adults were randomised to glutamine (5 g/t.i.d.) or placebo for 8 weeks. The primary end point was a reduction of ≥50 points on the Irritable Bowel Syndrome Severity Scoring System (IBS-SS). Secondary endpoints included: raw IBS-SS scores, changes in daily bowel movement frequency, stool form (Bristol Stool Scale) and intestinal permeability.ResultsFifty-four glutamine and 52 placebo subjects completed the 8-week study. The primary endpoint occurred in 43 (79.6%) in the glutamine group and 3 (5.8%) in the placebo group (a 14-fold difference). Glutamine also reduced all secondary endpoint means: IBS-SS score at 8 weeks (301 vs 181, p<0.0001), daily bowel movement frequency (5.4 vs 2.9±1.0, p<0.0001), Bristol Stool Scale (6.5 vs 3.9, p<0.0001) and intestinal permeability (0.11 vs 0.05; p<0.0001). ‘Intestinal hyperpermeability’ (elevated urinary lactulose/mannitol ratios) was normalised in the glutamine but not the control group. Adverse events and rates of study-drug discontinuation were low and similar in the two groups. No serious adverse events were observed.ConclusionsIn patients with IBS-D with intestinal hyperpermeability following an enteric infection, oral dietary glutamine supplements dramatically and safely reduced all major IBS-related endpoints. Large randomised clinical trials (RCTs) should now be done to validate these findings, assess quality of life benefits and explore pharmacological mechanisms.Trial registration numberNCT1414244; Results.

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“…The relevance of the small changes in claudin-1 expression observed is also called into question by the lack of reports suggesting any effect of an ~30% reduction in claudin-1 expression, even though complete knockout or nearly complete knockdown of claudin-1 expression has been associated with defective epidermal barrier function in mice 53 and reduced intestinal epithelial barrier function in vitro, 54 respectively, Further, given the low level of claudin-1 expression within the intestine 44 and other studies that failed to detect altered claudin-1 expression in IBS-D patients, 55 it is unlikely that changes in claudin-1 expression can explain barrier loss associated with IBS-D. Rather, reduced claudin-1 expression may be a marker of overall epithelial health, as it can be restored by ex vivo culture with glutamine. 56 Similarly, modest reductions in occludin and ZO-1 expression are also unlikely to explain observed permeability changes given the normal intestinal barrier function of occludin knockout mice 8, 9 and the functional redundancy between ZO-1 and ZO-2. 57, 58 Finally, while many studies have confirmed the presence of intestinal barrier defects in IBS-D patients, 25, 51, 59 the mechanisms underlying such barrier loss remain undefined.…”

Section: Discussionmentioning

confidence: 99%

Gluten-induced symptoms in diarrhea-predominant irritable bowel syndrome are associated with increased myosin light chain kinase activity and claudin-15 expression

Vázquez-Roque

Carlson

et al. 2017

Laboratory Investigation

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The mechanisms underlying diarrhea-predominant irritable bowel syndrome (IBS-D) are poorly understood, but increased intestinal permeability is thought to contribute to symptoms. A recent clinical trial of gluten-free diet (GFD) demonstrated symptomatic improvement, relative to gluten-containing diet (GCD), that was associated with reduced intestinal permeability in non-celiac disease IBS-D patients. The aim of this study was to characterize intestinal epithelial tight junction composition in IBS-D before and after dietary gluten challenge. Biopsies from 27 IBS-D patients (13 GFD; 14 GCD) were examined by H&E staining and semi-quantitative immunohistochemistry for phosphorylated myosin II regulatory light chain (MLC), MLC kinase, claudin-2, claudin-8, and claudin-15. Diet-induced changes were assessed and correlated with urinary mannitol excretion (after oral administration). In the small intestine, epithelial MLC phosphorylation was increased or decreased by GCD or GFD, respectively, and this correlated with increased intestinal permeability (P < 0.03). Colonocyte expression of the paracellular Na+ channel claudin-15 was also markedly augmented following GCD challenge (P < 0.05). Conversely, colonic claudin-2 expression correlated with reduced intestinal permeability (P < 0.03). Claudin-8 expression was not affected by dietary challenge. These data show that alterations in MLC phosphorylation and claudin-15 and claudin-2 expression are associated with gluten-induced symptomatology and intestinal permeability changes in IBS-D. The results provide new insight into IBS-D mechanisms and can explain permeability responses to gluten challenge in these patients.

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Glutamine Restores Tight Junction Protein Claudin‐1 Expression in Colonic Mucosa of Patients With Diarrhea‐Predominant Irritable Bowel Syndrome

Abstract: Glutamine increased claudin-1 expression in the colonic mucosa of patients with IBS-D. In addition, glutamine effect seems to be dependent on basal expression of tight junction proteins.

Cited by 38 publications

References 38 publications

Gastrointestinal mucosal barrier function and diseases

Gastrointestinal mucosal barrier function and diseases

Randomised placebo-controlled trial of dietary glutamine supplements for postinfectious irritable bowel syndrome

Gluten-induced symptoms in diarrhea-predominant irritable bowel syndrome are associated with increased myosin light chain kinase activity and claudin-15 expression

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