Dataset Information

Intestinal crypt cells and the microbiome undergo abrupt reprogramming at the onset of colonic infection

ABSTRACT: We used the mouse pathogen Citrobacter rodentium to model gut infections. Following oral inoculation C. rodentium resides in the caecum for the first 3 days, before it infects the colon on the 4th day. Here we show that while the host is unresponsive to the infection on day 3, there is an abrupt reprogramming of the cellular composition of the crypt, involving depletion of goblet and deep crypt secretory cells, as well as metabolism (e.g. simultaneous up-regulation of cholesterol biogenesis, import and efflux), DNA damage repair and proliferation, which correlated with Ki67 staining, on day 4. Reduction in the abundance of proteins involved in the TCA cycle and oxidative phosphorylation, leading to oxygenation of the gut, coincided with instant expansion of mucosal-associated Enterobacteriaceae. These results show that sensing a small number of pathogenic bacteria triggers immediate intrinsic changes to the epithelium physiology and the microbiota, which parallel innate gut immune responses.

INSTRUMENT(S): Orbitrap Fusion

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

TISSUE(S): Colon

SUBMITTER: James Wright

LAB HEAD: Jyoti Choudhary

PROVIDER: PXD012031 | Pride | 2019-03-05

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20180212_EH_Frankel_lab_FSN_set01_01.raw	Raw
	20180212_EH_Frankel_lab_FSN_set01_02.raw	Raw
	20180212_EH_Frankel_lab_FSN_set01_03.raw	Raw
	20180212_EH_Frankel_lab_FSN_set01_04.raw	Raw
	20180212_EH_Frankel_lab_FSN_set01_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.