Dataset Information

Citrobacter rodentium triggers exaggerated mucosal responses in mice developing severe intestinal disease

ABSTRACT: Citrobacter rodentium is commonly used to elucidate mucosal responses to infection in mice developing mild disease (e.g. C57BL/6), while little is known about host responses to infection in mice developing severe disease (e.g. C3H/HeN). We report that the phyla Bacteroidetes is a minor component of the tissue-associated microbiome in uninfected C3H/HeN mice. Following infection, C. rodentium rapidly and uniformly colonises the C3H/HeN colonic mucosa, which coincides with downregulation of proteins involved in the TCA cycle and oxidative phosphorylation in intestinal epithelial cells (IECs). In contrast, we observed upregulation of DNA replication and DNA damage repair processes, as well as cholesterol biogenesis, import and export, nutritional immunity, IL-22 and INFg responses, and expression of NLRP3, in IECs. Moreover, C. rodentium triggers a staggered cell proliferation response from 3 days post infection, which correlated with a higher abundance of SLC5A9 and reduced abundance of the IEC differentiation markers SLC26A3 and CA4. Uniquely, C. rodentium triggers differential secretion of gel-forming mucins, with the number of goblet cells filled with acidic and neutral mucins dramatically increasing and decreasing, respectively. Together, these results show that despite vigorous responses, C3H/HeN mice succumb to C. rodentium infection, possibly as a result of excessive and disordered mucosal responses.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Citrobacter Rodentium Mus Musculus (mouse)

TISSUE(S): Intestinal Epithelial Cell, Colon

SUBMITTER: James Wright

LAB HEAD: Jyoti Choudhary

PROVIDER: PXD012846 | Pride | 2020-01-21

REPOSITORIES: Pride

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			Action	DRS
	20180216_EH_Frankel_lab_FSN_set02_01.raw	Raw
	20180216_EH_Frankel_lab_FSN_set02_02.raw	Raw
	20180216_EH_Frankel_lab_FSN_set02_03.raw	Raw
	20180216_EH_Frankel_lab_FSN_set02_04.raw	Raw
	20180216_EH_Frankel_lab_FSN_set02_05.raw	Raw

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Publications

Intestinal Epithelial Cells and the Microbiome Undergo Swift Reprogramming at the Inception of Colonic Citrobacter rodentium Infection.

Hopkins Eve G D EGD Roumeliotis Theodoros I TI Mullineaux-Sanders Caroline C Choudhary Jyoti S JS Frankel Gad G

mBio 20190402 2

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, t ...[more]

PMID: 30940698

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Project description:Opioids analgesics are frequently prescribed in the United States and worldwide. However, serious side effects such as addiction, immunosuppression and gastrointestinal symptoms limit their use. It has been recently demonstrated that morphine treatment results in significant disruption in gut barrier function leading to increased translocation of gut commensal bacteria. Further study indicated distinct alterations in the gut microbiome and metabolome following morphine treatment, contributing to the negative consequences associated with opioid use. However, it is unclear how opioids modulate gut homeostasis in the context of a hospital acquired bacterial infection. In the current study, a mouse model of C. rodentium infection was used to investigate the role of morphine in the modulation of gut homeostasis in the context of a hospital acquired bacterial infection. Citrobacter rodentium is a natural mouse pathogen that models intestinal infection by enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC) and causes attaching and effacing lesions and colonic hyperplasia. Morphine treatment resulted in 1) the promotion of C. rodentium systemic dissemination, 2) increase in virulence factors expression with C. rodentium colonization in intestinal contents, 3) altered gut microbiome, 4) damaged integrity of gut epithelial barrier function, 5) inhibition of C. rodentium-induced increase in goblet cells, and 6) dysregulated IL-17A immune response. This is the first study to demonstrate that morphine promotes pathogen dissemination in the context of intestinal C. rodentium infection, indicating morphine modulates virulence factor-mediated adhesion of pathogenic bacteria and induces disruption of mucosal host defense during C. rodentium intestinal infection in mice. This study demonstrates and further validates a positive correlation between opioid drug use/abuse and increased risk of infections, suggesting over-prescription of opioids may increase the risk in the emergence of pathogenic strains and should be used cautiously. Therapeutics directed at maintaining gut homeostasis during opioid use may reduce the comorbidities associated with opioid use for pain management.