<i>Campylobacter fetus</i> impairs barrier function in HT‐29/B6 cells through focal tight junction alterations and leaks

Bücker, Roland; Krug, Susanne M.; Fromm, Anja; Nielsen, Hans Linde; Fromm, Michael; Nielsen, Henrik; Schulzke, Jörg–Dieter

doi:10.1111/nyas.13406

Cited by 11 publications

(6 citation statements)

References 48 publications

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“…Apoptosis and tight junction alterations are important mechanisms through which intestinal microbes invade the hosts [39]. In our study, we observed higher activity of apoptosis after CLP.…”

Section: Discussionsupporting

confidence: 60%

Cathelicidin preserves intestinal barrier function in polymicrobial sepsis

Chan

Liang

et al. 2020

Crit Care

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Objectives: The intestinal epithelium compartmentalizes the sterile bloodstream and the commensal bacteria in the gut. Accumulating evidence suggests that this barrier is impaired in sepsis, aggravating systemic inflammation. Previous studies reported that cathelicidin is differentially expressed in various tissues in sepsis. However, its role in sepsis-induced intestinal barrier dysfunction has not been investigated.Design: To examine the role of cathelicidin in polymicrobial sepsis, cathelicidin wild-(Cnlp +/+ ) and knockout (Cnlp −/− ) mice underwent cecal-ligation and puncture (CLP) followed by the assessment of septic mortality and morbidity as well as histological, biochemical, immunological, and transcriptomic analyses in the ileal tissues. We also evaluated the prophylactic and therapeutic efficacies of vitamin D3 (an inducer of endogenous cathelicidin) in the CLP-induced murine polymicrobial sepsis model. Results: The ileal expression of cathelicidin was increased by three-fold after CLP, peaking at 4 h. Knockout of Cnlp significantly increased 7-day mortality and was associated with a higher murine sepsis score. Alcian-blue staining revealed a reduced number of mucin-positive goblet cells, accompanied by reduced mucin expression. Increased number of apoptotic cells and cleavage of caspase-3 were observed. Cnlp deletion increased intestinal permeability to 4kD fluorescein-labeled dextran and reduced the expression of tight junction proteins claudin-1 and occludin. Notably, circulating bacterial DNA load increased more than two-fold. Transcriptome analysis revealed upregulation of cytokine/inflammatory pathway. Depletion of Cnlp induced more M1 macrophages and neutrophils compared with the wild-type mice after CLP. Mice pre-treated with cholecalciferol (an inactive form of vitamin D3) or treated with 1alpha, 25-dihydroxyvitamin D3 (an active form of VD3) had decreased 7-day mortality and significantly less severe symptoms. Intriguingly, the administration of cholecalciferol after CLP led to worsened 7-day mortality and the associated symptoms.Conclusions: Endogenous cathelicidin promotes intestinal barrier integrity accompanied by modulating the infiltration of neutrophils and macrophages in polymicrobial sepsis. Our data suggested that 1alpha, 25-dihydroxyvitamin D3 but not cholecalciferol is a potential therapeutic agent for treating sepsis.

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Section: Discussionsupporting

confidence: 60%

Cathelicidin preserves intestinal barrier function in polymicrobial sepsis

Chan

Liang

et al. 2020

Crit Care

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“…In our co-culture, C. jejuni provoked paradoxical upregulation of claudin-1 (Claudin-1 paradox); that is, upregulation of the barrier-forming TJ protein claudin-1 while epithelial resistance was reduced, which we explained by the re-distribution of claudin-1 off the tight junction domain [6]. Claudin-1 induction has also been observed before in human colon biopsies after C. jejuni infection [6], C. fetus or C. coli infection in HT-29/B6 cells [31], and pro-inflammatory cytokine stimulation in HT-29/B6 cells [32,33]. A correlation between increased claudin-1 protein expression and apoptosis induction also occurs in HT-29/B6 cells [34].…”

Section: Discussionmentioning

confidence: 85%

Curcumin Mitigates Immune-Induced Epithelial Barrier Dysfunction by Campylobacter jejuni

Sá

Butkevych

Nattramilarasu

et al. 2019

IJMS

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Campylobacter jejuni (C. jejuni) is the most common cause of foodborne gastroenteritis worldwide. The bacteria induce diarrhea and inflammation by invading the intestinal epithelium. Curcumin is a natural polyphenol from turmeric rhizome of Curcuma longa, a medical plant, and is commonly used in curry powder. The aim of this study was the investigation of the protective effects of curcumin against immune-induced epithelial barrier dysfunction in C. jejuni infection. The indirect C. jejuni-induced barrier defects and its protection by curcumin were analyzed in co-cultures with HT-29/B6-GR/MR epithelial cells together with differentiated THP-1 immune cells. Electrophysiological measurements revealed a reduction in transepithelial electrical resistance (TER) in infected co-cultures. An increase in fluorescein (332 Da) permeability in co-cultures as well as in the germ-free IL-10−/− mouse model after C. jejuni infection was shown. Curcumin treatment attenuated the C. jejuni-induced increase in fluorescein permeability in both models. Moreover, apoptosis induction, tight junction redistribution, and an increased inflammatory response—represented by TNF-α, IL-1β, and IL-6 secretion—was observed in co-cultures after infection and reversed by curcumin. In conclusion, curcumin protects against indirect C. jejuni-triggered immune-induced barrier defects and might be a therapeutic and protective agent in patients.

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“…We also observed a claudin-1 upregulation in C. jejuni infection, the claudin-1 paradox, claudin-1 increase while the TER is decreased, as also shown before for C. fetus and C. jejuni in vivo. (Bücker et al, 2017(Bücker et al, , 2018Lobo de Sá et al, 2019). The overall increase of claudin-1 was associated with retraction of the protein from tight junction strands and localization in the basolateral membrane and intracellular compartments during the infection (Bücker et al, 2018).…”

Section: No Downregulation Of Barrier-relevant Tight Junction Proteinsmentioning

confidence: 93%

Contribution of Epithelial Apoptosis and Subepithelial Immune Responses in Campylobacter jejuni-Induced Barrier Disruption

et al. 2020

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Campylobacter jejuni is a widespread zoonotic pathogen and the leading bacterial cause of foodborne gastroenteritis in humans. Previous infection studies showed disruption of intercellular contacts, induction of epithelial apoptosis, and immune activation, all three contributing to intestinal barrier dysfunction leading to diarrhea. The present study aims to determine the impact of subepithelial immune cells on intestinal barrier dysfunction during Campylobacter jejuni infection and the underlying pathological mechanisms. Infection was performed in a co-culture of confluent monolayers of the human colon cell line HT-29/B6-GR/MR and THP-1 immune cells. Twenty-two hours after infection, transepithelial electrical resistance (TER) was decreased by 58 ± 6% compared to controls. The infection resulted in an increase in permeability for fluorescein (332 Da; 4.5-fold) and for FITC-dextran (4 kDa; 3.5-fold), respectively. In contrast, incubation of the co-culture with the pan-caspase inhibitor Q-VD-OPh during the infection resulted in a complete recovery of the decrease in TER and a normalization of flux values. Fluorescence microscopy showed apoptotic fragmentation in infected cell monolayers resulting in a 5-fold increase of the apoptotic ratio, accompanied by an increased caspase-3 cleavage and caspase-3/7 activity, which both were not present after Q-VD-OPh treatment. Western blot analysis revealed increased claudin-1 and claudin-2 protein expression. Inhibition of apoptosis induction did not normalize these tight junction changes. TNFα concentration was increased during the infection in the co-culture. In conclusion, Campylobacter jejuni infection and the consequent subepithelial immune activation cause intestinal barrier dysfunction mainly through caspase-3-dependent epithelial apoptosis. Concomitant tight junction changes were caspase-independent. Anti-apoptotic and immune-modulatory substances appear to be promising agents for treatment of campylobacteriosis.

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Campylobacter fetus impairs barrier function in HT‐29/B6 cells through focal tight junction alterations and leaks

Cited by 11 publications

References 48 publications

Cathelicidin preserves intestinal barrier function in polymicrobial sepsis

Cathelicidin preserves intestinal barrier function in polymicrobial sepsis

Curcumin Mitigates Immune-Induced Epithelial Barrier Dysfunction by Campylobacter jejuni

Contribution of Epithelial Apoptosis and Subepithelial Immune Responses in Campylobacter jejuni-Induced Barrier Disruption

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