Abstract

The colonic microenvironment, stemming from microbial, immunologic, stromal, and epithelial factors, serves as an important determinant of the host response to enteric pathogenic colonization. Infection with the enteric bacterial pathogen Citrobacter rodentium elicits a strong mucosal Th1-mediated colitis and monocyte-driven inflammation activated via the classical NF-κB pathway. Research has focused on leukocyte-mediated signaling as the main driver for C. rodentium-induced colitis, however we hypothesize that epithelial cell NF-κB also contributes to the exacerbation of infectious colitis. To test this hypothesis, compartmentalized classical NF-κB defective mice, via the deletion of IKKβ in either intestinal epithelial cells (IKKβΔIEC) or myeloid-derived cells (IKKβΔMY), and wild type (WT) mice were challenged with C. rodentium. Both pathogen colonization and colonic histopathology were significantly reduced in IKKβ-deficient mice compared to WT mice. Interestingly, colonic IL-10, RegIIIγ, TNF-α, and iNOS gene expression were increased in IKKβ-deficient mice in the absence of bacterial challenge. This was associated with increased p52, which is involved with activation of NF-κβ through the alternative pathway. IKKβ-deficient mice also had distinct differences in colonic tissue-associated and luminal microbiome that may confer protection against C. rodentium. Taken together, these data demonstrate that classical NF-κB signaling can lead to enhanced enteric pathogen colonization and resulting colonic histopathology.

Highlights

  • Gastrointestinal infections are a significant source of morbidity and mortality worldwide with enterohemorrhagic Escherichia coli (EHEC) and enteropathogenic E. coli (EPEC) contributing significantly to bacterial-induced gastrointestinal disease

  • This study addressed the corollary hypothesis that inflammatory monocytes contribute to infectious colitis via NF-κB activation

  • Citrobacter rodentium colonization was significantly reduced in both IKKβ-deficient mice strains compared to wild type (WT) mice [F [2, 61] = 4.475, P < 0.05; Figure 1A] with the most evident reduction occurring in IKKβ MY mice on Days 3, 6, and 12 post-challenge

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Summary

Introduction

Gastrointestinal infections are a significant source of morbidity and mortality worldwide with enterohemorrhagic Escherichia coli (EHEC) and enteropathogenic E. coli (EPEC) contributing significantly to bacterial-induced gastrointestinal disease. Pathogenic EPEC and EHEC do not readily colonize mice. Citrobacter rodentium, a naturally occurring murine pathogen and member of the A/E family, is used to study EPEC/EHEC host responses [3,4,5]. Mice challenged with C. rodentium develop Th1-mediated infectious colitis characterized by inflammatory monocyte/macrophage and neutrophil accumulation [3,4,5,6]. The response to C. rodentium infection is initiated by colonic epithelial cells (CECs) and is perpetuated by newly recruited immune cells including inflammatory monocytes, neutrophils, and Th1 and Th17 CD4+ T cells through the activation of transcription factors, such as NF-κB [3, 4, 6, 9]

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