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Mice Deficient in Epithelial or Myeloid Cell I??? Have Distinct Colonic Microbiomes and Increased Resistance to Citrobacter rodentium Infection.

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-?B pathway. Research has focused on leukocyte-mediated signaling as the main driver for C. rodentium-induced colitis, however we hypothesize that epithelial cell NF-?B also contributes to the exacerbation of infectious colitis. To test this hypothesis, compartmentalized classical NF-?B defective mice, via the deletion of IKK? in either intestinal epithelial cells (IKK??IEC) or myeloid-derived cells (IKK??MY), and wild type (WT) mice were challenged with C. rodentium. Both pathogen colonization and colonic histopathology were significantly reduced in IKK?-deficient mice compared to WT mice. Interestingly, colonic IL-10, RegIII?, TNF-?, and iNOS gene expression were increased in IKK?-deficient mice in the absence of bacterial challenge. This was associated with increased p52, which is involved with activation of NF-?? through the alternative pathway. IKK?-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-?B signaling can lead to enhanced enteric pathogen colonization and resulting colonic histopathology.

SUBMITTER: Mackos AR

PROVIDER: S-EPMC6746829 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Mice Deficient in Epithelial or Myeloid Cell Iκκβ Have Distinct Colonic Microbiomes and Increased Resistance to Citrobacter rodentium Infection.

Mackos Amy R AR Allen Jacob M JM Kim Eunsoo E Ladaika Chris A CA Gharaibeh Raad Z RZ Moore Cathy C Parry Nicola M A NMA Boyaka Prosper N PN Bailey Michael T MT

Frontiers in immunology 20190910

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 coliti ...[more]

PMID: 31552024

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Project description:We used the mouse attaching and effacing (A/E) pathogen Citrobacter rodentium, which models the human A/E pathogens enteropathogenic Escherichia coli and enterohemorrhagic E. coli (EPEC and EHEC), to temporally resolve intestinal epithelial cell (IEC) responses and changes to the microbiome during in vivo infection. We found the host to be unresponsive during the first 3 days postinfection (DPI), when C. rodentium resides in the caecum. In contrast, at 4 DPI, the day of colonic colonization, despite only sporadic adhesion to the apex of the crypt, we observed robust upregulation of cell cycle and DNA repair processes, which were associated with expansion of the crypt Ki67-positive replicative zone, and downregulation of multiple metabolic processes (including the tricarboxylic acid [TCA] cycle and oxidative phosphorylation). Moreover, we observed dramatic depletion of goblet and deep crypt secretory cells and an atypical regulation of cholesterol homeostasis in IECs during early infection, with simultaneous upregulation of cholesterol biogenesis (e.g., 3-hydroxy-3-methylglutaryl-coenzyme A reductase [Hmgcr]), import (e.g., low-density lipoprotein receptor [Ldlr]), and efflux (e.g., AbcA1). We also detected interleukin 22 (IL-22) responses in IECs (e.g., Reg3γ) on the day of colonic colonization, which occurred concomitantly with a bloom of commensal Enterobacteriaceae on the mucosal surface. These results unravel a new paradigm in host-pathogen-microbiome interactions, showing for the first time that sensing a small number of pathogenic bacteria triggers swift intrinsic changes to the IEC composition and function, in tandem with significant changes to the mucosa-associated microbiome, which parallel innate immune responses.IMPORTANCE The mouse pathogen C. rodentium is a widely used model for colonic infection and has been a major tool in fundamental discoveries in the fields of bacterial pathogenesis and mucosal immunology. Despite extensive studies probing acute C. rodentium infection, our understanding of the early stages preceding the infection climax remains relatively undetailed. To this end, we apply a multiomics approach to resolve temporal changes to the host and microbiome during early infection. Unexpectedly, we found immediate and dramatic responses occurring on the day of colonic infection, both in the host intestinal epithelial cells and in the microbiome. Our study suggests changes in cholesterol and carbon metabolism in epithelial cells are instantly induced upon pathogen detection in the colon, corresponding with a shift to primarily facultative anaerobes constituting the microbiome. This study contributes to our knowledge of disease pathogenesis and mechanisms of barrier regulation, which is required for development of novel therapeutics targeting the intestinal epithelium.

Dataset Information

Mice Deficient in Epithelial or Myeloid Cell I??? Have Distinct Colonic Microbiomes and Increased Resistance to Citrobacter rodentium Infection.

Publications

Mice Deficient in Epithelial or Myeloid Cell Iκκβ Have Distinct Colonic Microbiomes and Increased Resistance to <i>Citrobacter rodentium</i> Infection.

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