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Key Event Title
Intestinal permeability, increased
Key Event Components
Key Event Overview
AOPs Including This Key Event
Key Event Description
Together with the chemical barrier of the mucosal layer and the cellular immune system, the intestinal epithelial cell layer has two barrier functions:1–3
i. It acts as a physical barrier against external factors (pathogens, toxins),
ii. 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.
The physical barrier function of the one-cell-thick intestinal epithelium is ensured by tight junction proteins (occludins, claudins and zonulins), adherence junctions and desmosomes 2,4,5 and by epithelial cell integrity.
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.
Molecules can cross the epithelium via paracellular or transcellular route. Transcellular permeability encompass passive diffusion from the apical to the basal side, vesicle-mediated transcytosis and uptake mediated by a membrane receptor. Paracellular permeability is regulated by the tight junctions between adjacent cells.
Disruption of the intestinal barrier leads to increased intestinal permeability (Figure 2), also called intestinal hyperpermeability or “leaky gut”, enhancing the transport of pathogens, toxins (such as lipopolysaccharides), undigested nutrients, bacteria of the microbiota from the intestinal lumen into the systemic circulation3.
How It Is Measured or Detected
- In humans6
Intestinal Permeability Assessment (IPA) directly measures the ability of two non-metabolized sugar molecules (lactulose and mannitol) to permeate the intestinal barrier by paracellular passage (sign of perturbed tight junction-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 4
- 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 assay15.[MOU1]
- 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 14.
Domain of Applicability
Evidence for Perturbation by Stressor
Evidence: High levels of plasma markers of intestinal hyperpermeability and microbial translocation in moderate and severe COVID-19 patients 9,10 .
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).