Host-dependent zonulin secretion causes the impairment of the small intestine barrier function after bacterial exposure

Asmar, Rahzi El; Panigrahi, Pinaki; Bamford, Penelope; Berti, Irene; Not, Tarcisio; Coppa, Giovanni V.; Catassi, Carlo; Fasano, Alessio

doi:10.1053/gast.2002.36578

Cited by 311 publications

(262 citation statements)

References 25 publications

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“…Two independent studies tracking large cohorts of newborns at high risk for T1D showed that the odds ratio for developing the disease was 4-to 5-fold higher in subjects prematurely exposed (Ͻ3 months of age) to gluten (31,32). One possible explanation for these observations is that gluten, a protein introduced in large quantities in the human diet only after the advent of agriculture, activates the mechanism of zonulin innate immunity (3,27,33). In genetically susceptible individuals, this activation would lead to sustained zonulin up-regulation, resulting in the loss of the intestinal barrier function.…”

Section: Discussionmentioning

confidence: 99%

“…Epithelial tight junctions (tj) serve as the principle gate through which intact macromolecules with preserved immunogenicity may cross the intestinal barrier (1). When the integrity of the intestinal epithelial barrier function is compromised (i.e., during prematurity, exposure to radiation, chemotherapy, microorganisms, and their products), intestinal permeability to macromolecules increases (2)(3)(4). Consequently, an immune response to environmental antigens may ensue, giving rise to either an autoimmune response in genetically susceptible individuals or tolerance.…”

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confidence: 99%

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Role of the intestinal tight junction modulator zonulin in the pathogenesis of type I diabetes in BB diabetic-prone rats

Watts

Berti

Sapone

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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281

222

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Increased intestinal permeability has been observed in numerous human autoimmune diseases, including type-1 diabetes (T1D) and its' animal model, the BB-wor diabetic prone rat. We have recently described zonulin, a protein that regulates intercellular tight junctions. The objective of this study was to establish whether zonulindependent increased intestinal permeability plays a role in the pathogenesis of T1D. In the BB diabetic-prone rat model of T1D, intestinal intraluminal zonulin levels were elevated 35-fold compared to control BB diabetic-resistant rats. Zonulin up-regulation was coincident with decreased small intestinal transepithelial electrical resistance, and was followed by the production of autoantibodies against pancreatic beta cells, which preceded the onset of clinically evident T1D by Ϸ25 days. In those diabetic prone rats that did not progress to diabetes, both intraluminal zonulin and transepithelial electrical resistance were similar to those detected in diabetic-resistant animal controls. Blockade of the zonulin receptor reduced the cumulative incidence of T1D by 70%, despite the persistence of intraluminal zonulin up-regulation. Moreover, treatment responders did not seroconvert to islet cell antibodies. Combined together, these findings suggest that the zonulininduced loss in small intestinal barrier function is involved in the pathogenesis of T1D in the BB diabetic-prone animal model.intestinal permeability ͉ autoimmunity ͉ non-self antigens ͉ ussing chambers

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Role of the intestinal tight junction modulator zonulin in the pathogenesis of type I diabetes in BB diabetic-prone rats

Watts

Berti

Sapone

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

281

222

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“…TEER of small intestine segments mounted in microsnapwells apical side up was measured in triplicate using an EVOM Voltohmmeter (World Precision Instruments) as described (27). TEER of Caco-2 monolayers was measured using "chopstick: probes.…”

Section: Methodsmentioning

confidence: 99%

“…Caco-2 cells (ATCC, passage 35-45), cultured under standard cell culture conditions (27), were grown on Transwell filters (Costar) for up to 21 days for formation of polarized epithelial monolayers. For calcium switch experiments, 5-day filter-grown Caco-2 monolayers were exposed to low calcium medium (DMEM + 5 μM CaCl 2 ) for 15 h, after which medium was replaced with complete DMEM (1.6 mM CaCl 2 ) for up to 24 h. When used, the chemical inhibitors AEBSF (Calbiochem), CVS-3983 (10) or PKCζ myristolated-psi (Calbiochem), were added to culture media and replaced daily.…”

Section: Methodsmentioning

confidence: 99%

Membrane-anchored serine protease matriptase regulates epithelial barrier formation and permeability in the intestine

Buzza

Netzel‐Arnett

Shea‐Donohue³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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154

192

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The intestinal epithelium serves as a major protective barrier between the mammalian host and the external environment. Here we show that the transmembrane serine protease matriptase plays a pivotol role in the formation and integrity of the intestinal epithelial barrier. St14 hypomorphic mice, which have a 100-fold reduction in intestinal matriptase mRNA levels, display a 35% reduction in intestinal transepithelial electrical resistance (TEER). Matriptase is expressed during intestinal epithelial differentiation and colocalizes with E-cadherin to apical junctional complexes (AJC) in differentiated polarized Caco-2 monolayers. Inhibition of matriptase activity using a specific peptide inhibitor or by knockdown of matriptase by siRNA disrupts the development of TEER in barrierforming Caco-2 monolayers and increases paracellular permeability to macromolecular FITC-dextran. Loss of matriptase was associated with enhanced expression and incorporation of the permeabilityassociated, "leaky" tight junction protein claudin-2 at intercellular junctions. Knockdown of claudin-2 enhanced the development of TEER in matriptase-silenced Caco-2 monolayers, suggesting that the reduced barrier integrity was caused, at least in part, by an inability to regulate claudin-2 expression and incorporation into junctions. We find that matriptase enhances the rate of claudin-2 protein turnover, and that this is mediated indirectly through an atypical PKCζ-dependent signaling pathway. These results support a key role for matriptase in regulating intestinal epithelial barrier competence, and suggest an intriguing link between pericellular serine protease activity and tight junction assembly in polarized epithelia.claudin-2 | intestinal barrier | St14 | type II transmembrane serine protease | tight junction

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“…The colonic epithelial barrier function seems to be reduced by cytokines (e.g., IFNγ, IL-4, and IL-10) and there are convincing data that the proinflammatory cytokines TNFα and IFNγ can act synergistically to reduce epithelial cell barrier function (Walsh et al, 2000). Host dependent zonulin secretion, a modulator of small intestinal tight junctions, caused an impairment of the barrier function after exposure of rabbit jejunum to infection with S. typhimurium and E. coli (El Asmar et al, 2002). Vibrio cholerae toxin and other bacterial toxins have been found to increase the permeability of the small intestinal mucosa by affecting the structure of the intercellular tight junctions (Fasano et al, 1991).…”

Section: Gastrointestinal Absorption Of Nutrients and Chemical Substamentioning

confidence: 99%

Interactions between Infections, Nutrients and Xenobiotics

2005

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Host-dependent zonulin secretion causes the impairment of the small intestine barrier function after bacterial exposure

Cited by 311 publications

References 25 publications

Role of the intestinal tight junction modulator zonulin in the pathogenesis of type I diabetes in BB diabetic-prone rats

Role of the intestinal tight junction modulator zonulin in the pathogenesis of type I diabetes in BB diabetic-prone rats

Membrane-anchored serine protease matriptase regulates epithelial barrier formation and permeability in the intestine

Interactions between Infections, Nutrients and Xenobiotics

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