Intestinal Epithelial Barrier Maturation by Enteric Glial Cells Is GDNF-Dependent

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Abstract

Enteric glial cells (EGCs) of the enteric nervous system are critically involved in the maintenance of intestinal epithelial barrier function (IEB). The underlying mechanisms remain undefined. Glial cell line-derived neurotrophic factor (GDNF) contributes to IEB maturation and may therefore be the predominant mediator of this process by EGCs. Using GFAP ^cre x Ai14 ^floxed mice to isolate EGCs by Fluorescence-activated cell sorting (FACS), we confirmed that they synthesize GDNF in vivo as well as in primary cultures demonstrating that EGCs are a rich source of GDNF in vivo and in vitro. Co-culture of EGCs with Caco2 cells resulted in IEB maturation which was abrogated when GDNF was either depleted from EGC supernatants, or knocked down in EGCs or when the GDNF receptor RET was blocked. Further, TNFα-induced loss of IEB function in Caco2 cells and in organoids was attenuated by EGC supernatants or by recombinant GDNF. These barrier-protective effects were blunted when using supernatants from GDNF-deficient EGCs or by RET receptor blockade. Together, our data show that EGCs produce GDNF to maintain IEB function in vitro through the RET receptor.

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Intestinal permeability – a new target for disease prevention and therapy

Stephan C Bischoff, Giovanni Barbara, Wim A Buurman … (2014)

Data are accumulating that emphasize the important role of the intestinal barrier and intestinal permeability for health and disease. However, these terms are poorly defined, their assessment is a matter of debate, and their clinical significance is not clearly established. In the present review, current knowledge on mucosal barrier and its role in disease prevention and therapy is summarized. First, the relevant terms ‘intestinal barrier’ and ‘intestinal permeability’ are defined. Secondly, the key element of the intestinal barrier affecting permeability are described. This barrier represents a huge mucosal surface, where billions of bacteria face the largest immune system of our body. On the one hand, an intact intestinal barrier protects the human organism against invasion of microorganisms and toxins, on the other hand, this barrier must be open to absorb essential fluids and nutrients. Such opposing goals are achieved by a complex anatomical and functional structure the intestinal barrier consists of, the functional status of which is described by ‘intestinal permeability’. Third, the regulation of intestinal permeability by diet and bacteria is depicted. In particular, potential barrier disruptors such as hypoperfusion of the gut, infections and toxins, but also selected over-dosed nutrients, drugs, and other lifestyle factors have to be considered. In the fourth part, the means to assess intestinal permeability are presented and critically discussed. The means vary enormously and probably assess different functional components of the barrier. The barrier assessments are further hindered by the natural variability of this functional entity depending on species and genes as well as on diet and other environmental factors. In the final part, we discuss selected diseases associated with increased intestinal permeability such as critically illness, inflammatory bowel diseases, celiac disease, food allergy, irritable bowel syndrome, and – more recently recognized – obesity and metabolic diseases. All these diseases are characterized by inflammation that might be triggered by the translocation of luminal components into the host. In summary, intestinal permeability, which is a feature of intestinal barrier function, is increasingly recognized as being of relevance for health and disease, and therefore, this topic warrants more attention.

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CHOPCHOP v2: a web tool for the next generation of CRISPR genome engineering

Kornel Labun, Tessa G. Montague, James A. Gagnon … (2016)

In just 3 years CRISPR genome editing has transformed biology, and its popularity and potency continue to grow. New CRISPR effectors and rules for locating optimum targets continue to be reported, highlighting the need for computational CRISPR targeting tools to compile these rules and facilitate target selection and design. CHOPCHOP is one of the most widely used web tools for CRISPR- and TALEN-based genome editing. Its overarching principle is to provide an intuitive and powerful tool that can serve both novice and experienced users. In this major update we introduce tools for the next generation of CRISPR advances, including Cpf1 and Cas9 nickases. We support a number of new features that improve the targeting power, usability and efficiency of CHOPCHOP. To increase targeting range and specificity we provide support for custom length sgRNAs, and we evaluate the sequence composition of the whole sgRNA and its surrounding region using models compiled from multiple large-scale studies. These and other new features, coupled with an updated interface for increased usability and support for a continually growing list of organisms, maintain CHOPCHOP as one of the leading tools for CRISPR genome editing. CHOPCHOP v2 can be found at http://chopchop.cbu.uib.no

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Mend Your Fences

Eva Martini, Susanne Krug, Britta Siegmund … (2017)

The intestinal epithelium can be easily disrupted during gut inflammation as seen in inflammatory bowel disease (IBD), such as ulcerative colitis or Crohn’s disease. For a long time, research into the pathophysiology of IBD has been focused on immune cell–mediated mechanisms. Recent evidence, however, suggests that the intestinal epithelium might play a major role in the development and perpetuation of IBD. It is now clear that IBD can be triggered by disturbances in epithelial barrier integrity via dysfunctions in intestinal epithelial cell–intrinsic molecular circuits that control the homeostasis, renewal, and repair of intestinal epithelial cells. The intestinal epithelium in the healthy individual represents a semi-permeable physical barrier shielding the interior of the body from invasions of pathogens on the one hand and allowing selective passage of nutrients on the other hand. However, the intestinal epithelium must be considered much more than a simple physical barrier. Instead, the epithelium is a highly dynamic tissue that responds to a plenitude of signals including the intestinal microbiota and signals from the immune system. This epithelial response to these signals regulates barrier function, the composition of the microbiota, and mucosal immune homeostasis within the lamina propria. The epithelium can thus be regarded as a translator between the microbiota and the immune system and aberrant signal transduction between the epithelium and adjacent immune cells might promote immune dysregulation in IBD. This review summarizes the important cellular and molecular barrier components of the intestinal epithelium and emphasizes the mechanisms leading to barrier dysfunction during intestinal inflammation.

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Roberto De Giorgio: Role: Academic Editor

Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 14 February 2021

Publication date Collection: February 2021

Volume: 22

Issue: 4

Electronic Location Identifier: 1887

Affiliations

[1 ]Department of General, Visceral, Vascular and Pediatric Surgery University Hospital Würzburg, Oberduerrbacherstrasse 6, 97080 Wuerzburg, Germany; Meir_M@ 123456ukw.de (M.M.); felix.kannapin@ 123456yahoo.de (F.K.); Ghoreishi_Y@ 123456ukw.de (Y.G.); Kollmann_C@ 123456ukw.de (C.K.); flemming_s@ 123456ukw.de (S.F.); germer_c@ 123456ukw.de (C.-T.G.); burkard_n@ 123456ukw.de (N.B.)

[2 ]Department of Biochemistry and Molecular Biochemistry, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany; markus.diefenbacher@ 123456uni-wuerzburg.de

[3 ]Department of Anatomy and Cell Biology University of Munich, Pettenkoferstrasse 11, 80336 Munich, Germany; jens.waschke@ 123456med.uni-muenchen.de

[4 ]Department of Surgery, University Clinic Bonn, Venusberg-Campus 1, 53105 Bonn, Germany; patrick.leven@ 123456ukbonn.de (P.L.); reiner.schneider@ 123456ukbonn.de (R.S.); Sven.Wehner@ 123456ukbonn.de (S.W.)

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[* ]Correspondence: Schlegel_N@ 123456ukw.de ; Tel.: +49-931-201-38217

Author information

Markus Diefenbacher https://orcid.org/0000-0002-7402-7949

Yalda Ghoreishi https://orcid.org/0000-0003-0205-5577

Sven Flemming https://orcid.org/0000-0002-6304-3169

Reiner Schneider https://orcid.org/0000-0002-7194-2703

Sven Wehner https://orcid.org/0000-0002-8632-7631

Nicolas Schlegel https://orcid.org/0000-0001-5705-3945

Article

Publisher ID: ijms-22-01887

DOI: 10.3390/ijms22041887

PMC ID: 7917776

PubMed ID: 33672854

SO-VID: 18572c76-f9ad-4c0d-b48f-8e3434f8290c

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Intestinal Epithelial Barrier Maturation by Enteric Glial Cells Is GDNF-Dependent

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CHOPCHOP v2: a web tool for the next generation of CRISPR genome engineering

Mend Your Fences

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