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Event: 1931

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Intestinal barrier, disruption

Short name
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Disruption of the intestinal barrier
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Biological Context

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Level of Biological Organization
Organ

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Organ term
intestine

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
barrier epithelial cell disrupted

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
SARS-CoV-2 leads to intestinal barrier disruption KeyEvent Cataia Ives (send email) Under development: Not open for comment. Do not cite Under Development

Taxonomic Applicability

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Life Stages

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Sex Applicability

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Term Evidence
Male
Female

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

A proper definition (and related ontology) of the intestinal barrier and permeability would benefit the understanding of this biological event central in many diseases. However, it is generally accepted that the intestinal barrier is a multilayer system encompassing :

- a chemical barrier able to detoxify bacterial endotoxins,

- a mucus layer providing a physical barrier against bacteria,

- an one-cell-thick epithelial layer which physical barrier function is ensured by epithelial cell integrity and by tight junction proteins (occludins, claudins and zonulins), adherence junctions and desmosomes 2,4,5

- the cellular immune system present in the lamina propria underlying the epithelial cell layer

- the antibacterial proteins secreted by the specialized intestinal epithelial cells or the Paneth cells.

Together with the chemical barrier of the mucosal layer and the cellular immune system, the intestinal epithelial cell layer has actually two barrier functions:1–3

  1. It acts as a physical barrier against external factors (pathogens, toxins),
  2. It acts as a selective barrier by regulating the absorption of essential dietary nutrients and  ions, meaning their transport from the lumen into the blood.

Intestinal permeability6 describes the movement of molecules across the intestinal barrier from the lumen to the blood (Figure 1), and as such, is the measurable feature of the intestinal barrier.

Figure 1. Created with Biorender.com

Molecules can cross the epithelium via paracellular or transcellular route. Transcellular permeability encompass passive diffusion from the apical to the basal side (from the lumen to the blood), vesicle-mediated transcytosis and uptake mediated by a membrane receptor. Paracellular permeability is regulated by the tight junctions between adjacent cells and by the integrity of the epithelium.

Alteration or disruption of one or more layers of the intestinal barrier leads to increased intestinal permeability, also called intestinal hyperpermeability or “leaky gut”, enhancing the transport of pathogens, toxins (such as lipopolysaccharides), undigested nutrients and the translocation of bacteria of the gut microbiota from the intestinal lumen into the systemic circulation3.

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

The definition of intestinal permeability being relatively broad includes altered paracellular route, regulated by TJ proteins, transcellular routes involving membrane transporters and channels, and endocytic mechanisms. Paracellular intestinal permeability can be assessed in vivo via different molecules and via putatiive blood biomarkers and ex vivo in Ussing chambers combining electrophysiology and probes of different molecular sizes. The latter is still the gold standard technique for assessing the epithelial barrier function, whereas in vivo techniques are also broadly used despite limitations (doi: 10.3389/fnut.2021.717925).

In humans.

Virtually all in vivo methods to assess paracellular intestinal permeability rely on the urinary excretion of orally ingested probes. Several markers, including different sizes of PEG, 51CrEDTA, and especially sugars have been used, each with advantages and disadvantages (doi: 10.3389/fnut.2021.717925). Intestinal Permeability Assessment (IPA) directly measures the ability of two non-metabolized sugar molecules (lactulose and mannitol) to permeate the small intestinal barrier by paracellular passage (sign of perturbed TJ-lactulose) or by transcellular passage (giving information of the whole epithelial absorptive area-mannitol), respectively. The patient drinks a premeasured amount of those sugars and 6h after, the ratio of Lactulose/Mannitol levels is measured in the urine 11.

Levels in plasma/serum or in feces of:

  • Markers of epithelial cell damage, such as intestinal fatty acid binding protein (FABP)
  • Markers of tight junction alterations, such as zonulin levels (doi: 10.1080/21688370.2016.1251384)
  • Microbial translocation, such as peptidoglycans and lipopolysaccharides (LPS) and gut microbiota alteration.

In vitro systems12

Transepithelial electrical resistance (TEER) or the Lucifer Yellow (LY) leakage assay are techniques to measure barrier integrity and permeability of a cell layer13. Caco-2 cells are human epithelial colorectal adenocarcinoma cells with a structure and function similar to the differentiated small intestinal epithelial cells (e.g. exhibit microvilli). Caco-2 cells can be plated in wells as monolayers14,11. Other cell lines can be used, such as intestinal epithelial cells (IEC) or primary epithelial cells from human intestinal biopsies12. Co-culturing of enterocyte-like cells with immune cells in three-dimensional structure and within a microfluidic gut-on-chip has been shown to reflect better the physiology of the gut epithelium. Epi-IntestinalTM is an example of 3D human primary cell-based organotypic small intestinal model which allows evaluation of TEER and LY leakage assay (doi: 10.1007/s11095-018-2362-0).

In vivo system

In mice, one way to study intestinal paracellular permeability is by measuring the ability of fluorescein isothiocyanate (FITC)-dextran to cross from the lumen into the blood. After gavaging mice with FITC-dextran, the concentrations are measured in collected serum samples (doi: 10.3791/57032).

Domain of Applicability

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References

List of the literature that was cited for this KE description. More help

1.            Chelakkot, C., Ghim, J. & Ryu, S. H. Mechanisms regulating intestinal barrier integrity and its pathological implications. Exp. Mol. Med. 50, (2018).

2.            Groschwitz, K. R. & Hogan, S. P. Intestinal barrier function: Molecular regulation and disease pathogenesis. J. Allergy Clin. Immunol. 124, 3–20 (2009).

3.            Ghosh, S. S., Wang, J., Yannie, P. J. & Ghosh, S. Intestinal barrier dysfunction, LPS translocation, and disease development. J. Endocr. Soc. 4, 1–15 (2020).

4.            Sturgeon, C. & Fasano, A. Zonulin, a regulator of epithelial and endothelial barrier functions, and its involvement in chronic inflammatory diseases. Tissue Barriers 4, 1–19 (2016).

5.            Sturgeon, C., Lan, J. & Fasano, A. Zonulin transgenic mice show altered gut permeability and increased morbidity/mortality in the DSS colitis model. Ann N Y Acad Sci 1397, 130–142 (2017).

6.            Bischoff, S. C. et al. Intestinal permeability - a new target for disease prevention and therapy. BMC Gastroenterol. 14, 1–25 (2014).

7.            Qiu, W. et al. PUMA-mediated intestinal epithelial apoptosis contributes to ulcerative colitis in humans and mice. J. Clin. Invest. 121, 1722–1732 (2011).

8.            Hering, N. A., Fromm, M. & Schulzke, J. D. Determinants of colonic barrier function in inflammatory bowel disease and potential therapeutics. J. Physiol. 590, 1035–1044 (2012).

9.            Giron, L. B. et al. Plasma Markers of Disrupted Gut Permeability in Severe COVID-19 Patients. medRxiv 2020.11.13.20231209 (2021).

10.          Prasad, R. et al. Plasma microbiome in COVID-19 subjects: an indicator of gut barrier defects and dysbiosis Ram. BioRxiv (2021).

11.          Aguirre Valadez, J. M. et al. Intestinal permeability in a patient with liver cirrhosis. Ther. Clin. Risk Manag. 12, 1729–1748 (2016).

12.          Fedi, A. et al. In vitro models replicating the human intestinal epithelium for absorption and metabolism studies: A systematic review. J. Control. Release 335, 247–268 (2021).

13.          Lea, T. Epithelial Cell Models; General Introduction. in The Impact of Food Bioactives on Health: in vitro and ex vivo models (eds. Verhoeckx, K. et al.) 95–102 (Springer International Publishing, 2015). doi:10.1007/978-3-319-16104-4_9

14.          Li, B. R. et al. In Vitro and In Vivo Approaches to Determine Intestinal Epithelial Cell Permeability. J. Vis. Exp. 1–6 (2018). doi:10.3791/57032

15.          Ayehunie, S. et al. Human Primary Cell-Based Organotypic Microtissues for Modeling Small Intestinal Drug Absorption Seyoum. Pharm. Res. 35, 72 (2019).