Campylobacter jejuni Disrupts Protective Toll-Like Receptor 9 Signaling in Colonic Epithelial Cells and Increases the Severity of Dextran Sulfate Sodium-Induced Colitis in Mice

Abstract

Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation associated with a dysregulated immune response to commensal bacteria in susceptible individuals. The relapse of IBD may occur following an infection with Campylobacter jejuni. Apical epithelial Toll-like receptor 9 (TLR9) activation by bacterial DNA is reported to maintain colonic homeostasis. We investigated whether a prior C. jejuni infection disrupts epithelial TLR9 signaling and increases the severity of disease in a model of mild dextran sulfate sodium (DSS) colitis in mice. In a further attempt to identify mechanisms, T84 monolayers were treated with C. jejuni followed by a TLR9 agonist. Transepithelial resistance (TER) and dextran flux across confluent monolayers were monitored. Immunohistochemistry, Western blotting, and flow cytometry were used to examine TLR9 expression. Mice colonized by C. jejuni lacked any detectable pathology; however, in response to low levels of DSS, mice previously exposed to C. jejuni exhibited significantly reduced weight gain and increased occult blood and histological damage scores. Infected mice treated with DSS also demonstrated a significant reduction in levels of the anti-inflammatory cytokine interleukin-25. In vitro studies indicated that apical application of a TLR9 agonist enhances intestinal epithelial barrier function and that this response is lost in C. jejuni-infected monolayers. Furthermore, infected cells secreted significantly more CXCL8 following the basolateral application of a TLR9 agonist. Surface TLR9 expression was reduced in C. jejuni-infected monolayers subsequently exposed to a TLR9 agonist. In conclusion, infection by C. jejuni disrupts TLR9-induced reinforcement of the intestinal epithelial barrier, and colonization by C. jejuni increases the severity of mild DSS colitis.

Contentious host–microbiota relationship in inflammatory bowel disease – can foes become friends again?

“…However, some of the changes may be secondary to (chronic) inflammation and not leading to it. On the other hand, pathogens (including bacteria, viruses, and fungi) can induce changes in the TLR expression of epithelial cells in vitro [86][87][88]. It remains speculative whether enteric infections, leading to altered TLR expression and dysregulated recognition of microbiota, play a role in the pathogenesis of IBD, but antibiotic usage shows that subjects who will develop IBD have had more infections [52,53].…”

Gut Inflammation: Current Update on Pathophysiology, Molecular Mechanism and Pharmacological Treatment Modalities

“…Activation of TLR2 enhances the transepithelial resistance in vitro (through redistribution of the tight junction protein ZO-1) and increases tight junction-associated IEC barrier integrity in vivo [80,81], and recent evidence suggest that NOD2 potentiates the TLR2-induced improvement of mucosal barrier [82]. Beside TLR2 also TLR9 has been shown to enhance transepithelial resistance [83], while the action of TLR4 is still not clear, since both improvement and disruption of the mucosal barrier have been described upon stimulation with LPS [82,84].…”

Pathogenesis of Human Enterovirulent Bacteria: Lessons from Cultured, Fully Differentiated Human Colon Cancer Cell Lines

“…C. jejuni isolates expressing ganglioside-like LOS increase the secretion of the T-cell attractant CXCL10 in fully differentiated Caco-2 and T84 cells (348). C. jejuni infection in fully differentiated T84 cell monolayers disrupts epithelial TLR9 signaling, thus exerting a protective effect (727). Fully differentiated T84 cells when invaded by C. jejuni display oncosis that is independent of cytolethal distending toxin activity (728).…”