Role of Stress on Driving the Intestinal Paracellular Permeability.

The gut epithelium is a polarized monolayer that exhibits apical and basolateral membrane surfaces. Monolayer cell components are joined side by side via protein complexes known as tight junction proteins (TJPs), expressed at the most apical extreme of the basolateral membrane. The gut epithelium is a physical barrier that determinates intestinal permeability, referred to as the measurement of the transit of molecules from the intestinal lumen to the bloodstream or, conversely, from the blood to the gut lumen. TJPs play a role in the control of intestinal permeability that can be disrupted by stress through signal pathways triggered by the ligation of receptors with stress hormones like glucocorticoids. Preclinical studies conducted under in vitro and/or in vivo conditions have addressed underlying mechanisms that account for the impact of stress on gut permeability. These mechanisms may provide insights for novel therapeutic interventions in diseases in which stress is a risk factor, like irritable bowel syndrome. The focus of this study was to review, in an integrative context, the neuroendocrine effects of stress, with special emphasis on TJPs along with intestinal permeability.

E7 oncoprotein from human papillomavirus 16 alters claudins expression and the sealing of epithelial tight junctions.

Tight junctions (TJs) are cell­cell adhesion structures frequently altered by oncogenic transformation. In the present study the role of human papillomavirus (HPV) 16 E7 oncoprotein on the sealing of TJs was investigated and also the expression level of claudins in mouse cervix and in epithelial Madin­Darby Canine Kidney (MDCK) cells. It was found that there was reduced expression of claudins ­1 and ­10 in the cervix of 7­month­old transgenic K14E7 mice treated with 17ß­estradiol (E2), with invasive cancer. In addition, there was also a transient increase in claudin­1 expression in the cervix of 2­month­old K14E7 mice, and claudin­10 accumulated at the border of cells in the upper layer of the cervix in FvB mice treated with E2, and in K14E7 mice treated with or without E2. These changes were accompanied by an augmented paracellular permeability of the cervix in 2­ and 7­month­old FvB mice treated with E2, which became more pronounced in K14E7 mice treated with or without E2. In MDCK cells the stable expression of E7 increased the space between adjacent cells and altered the architecture of the monolayers, induced the development of an acute peak of transepithelial electrical resistance accompanied by a reduced expression of claudins ­1, ­2 and ­10, and an increase in claudin­4. Moreover, E7 enhances the ability of MDCK cells to migrate through a 3D matrix and induces cell stiffening and stress fiber formation. These observations revealed that cell transformation induced by HPV16 E7 oncoprotein was accompanied by changes in the pattern of expression of claudins and the degree of sealing of epithelial TJs.

Time-dependent alteration to the tight junction structure of distal intestinal epithelia in type 2 prediabetic mice.

AIM: High-fat diet (HFD) intake has been associated with changes in intestinal microbiota composition, increased intestinal permeability, and onset of type 2 diabetes mellitus (T2DM). The aim of this work was twofold: 1) to investigate the structural and functional alterations of the tight junction (TJ)-mediated intestinal epithelial barrier of ileum and colon, that concentrate most of the microbiota, after exposure to a HFD for 15, 30 and 60 days, and 2) to assess the effect of in vitro exposure to free fatty acids (FFAs), one of the components of HFD, on paracellular barrier of colon-derived Caco-2 cells. METHODS/KEY FINDINGS: HFD exposure induced progressive metabolic changes in male mice that culminated in prediabetes after 60d. Morphological analysis of ileum and colon mucosa showed no signs of epithelial rupture or local inflammation but changes in the junctional content/distribution and/or cellular content of TJ-associated proteins (claudins-1, -2, -3, and occludin) in intestinal epithelia were seen mainly after a prediabetes state has been established. This impairment in TJ structure was not associated with significant changes in intestinal permeability to FITC-dextran. Exposure of Caco-2 monolayers to palmitic or linoleic acids seems to induce a reinforcement of TJ structure while treatment with oleic acid had a more diverse effect on TJ protein distribution. SIGNIFICANCE: TJ structure in distal intestinal epithelia can be specifically impaired by HFD intake at early stage of T2DM, but not by FFAs in vitro. Since the TJ change in ileum/colon was marginal, probably it does not contribute to the disease onset.