Citrobacter rodentium is an extracellular enteric mouse-specific pathogen used to model infections with human pathogenic Escherichia coli and inflammatory bowel disease. C. rodentium injects type III secretion system effectors into intestinal epithelial cells (IECs) to target inflammatory, metabolic and cell survival pathways and establish infection. While the host responds to infection by activating innate and adaptive immune signalling, required for clearance, the IECs respond by rapidly shifting bioenergetics to aerobic glycolysis, which leads to oxygenation of the epithelium, an instant expansion of mucosal-associated commensal Enterobacteriaceae and a decline of obligate anaerobes. Moreover, infected IECs reprogramme intracellular metabolic pathways, characterized by simultaneous activation of cholesterol biogenesis, import and efflux, leading to increased serum and faecal cholesterol levels. In this Review we summarize recent advances highlighting the intimate relationship between C. rodentium pathogenesis, metabolism and the gut microbiota.
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This work was supported by grants from the Wellcome Trust, the Medical Research Council and the Royal Society. The authors apologize to authors whose work could not be cited due to space constraints.
Nature Reviews Microbiology thanks G. Nunez and the other anonymous reviewer(s) for their contribution to the peer review of this work.
The authors declare no conflict of interest.
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- Attaching and effacing (A/E) lesions
Lesions formed on intestinal epithelial cells characterized by intimate bacterial attachment to the apical plasma membrane and effacement of the brush border microvilli.
Secreted growth factor which activates the canonical WNT/β-catenin pathway.
- Fluid shear force
Shear stress produced by fluid flow over a surface.
- Warburg effect
The production of ATP via glycolysis under aerobic conditions.
Major component of the outer membrane of Gram-negative bacteria which acts as a potent stimulator of the innate immune response.
- Lipid rafts
Membrane microdomains enriched in cholesterol and sphingolipids that facilitate the interaction between activated receptors and adaptors to promote downstream signalling.
Glycoprotein, secreted by goblet cells in the colon, which forms a protective mucus barrier on the apical side of the gut epithelium.
- Colonization resistance
Protection against pathogen colonization conferred to the host by its microbiota.
Enzymes which hydrolyse mucins.
Intracellular endogenous molecule that can act as a danger signal when recognized by the immune system on its release into the extracellular environment.
Cytosolic surveillance systems defined by sensor proteins that oligomerize and form signalling platforms for the activation of caspase 1.
Post-translational modification in which a glycosyltransferase catalyses the attachment of an N-acetylglucosamine (GlcNAc) moiety to the side chain amide of an asparagine or an arginine residue.
A form of cell death characterized by osmotic swelling and lysis triggered by the pore-forming amino terminus of GSDMD, which is liberated on proteolysis by caspases 1, 4 and 5.
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Mullineaux-Sanders, C., Sanchez-Garrido, J., Hopkins, E.G.D. et al. Citrobacter rodentium–host–microbiota interactions: immunity, bioenergetics and metabolism. Nat Rev Microbiol 17, 701–715 (2019). https://doi.org/10.1038/s41579-019-0252-z
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