Citrobacter rodentium Subverts ATP Flux and Cholesterol Homeostasis in Intestinal Epithelial Cells In Vivo

Publication date: Available online 5 October 2017
Source:Cell Metabolism
Author(s): Cedric N. Berger, Valerie F. Crepin, Theodoros I. Roumeliotis, James C. Wright, Danielle Carson, Meirav Pevsner-Fischer, R. Christopher D. Furniss, Gordon Dougan, Mally Dori-Bachash, Lu Yu, Abigail Clements, James W. Collins, Eran Elinav, Gerald J. Larrouy-Maumus, Jyoti S. Choudhary, Gad Frankel
The intestinal epithelial cells (IECs) that line the gut form a robust line of defense against ingested pathogens. We investigated the impact of infection with the enteric pathogen Citrobacter rodentium on mouse IEC metabolism using global proteomic and targeted metabolomics and lipidomics. The major signatures of the infection were upregulation of the sugar transporter Sglt4, aerobic glycolysis, and production of phosphocreatine, which mobilizes cytosolic energy. In contrast, biogenesis of mitochondrial cardiolipins, essential for ATP production, was inhibited, which coincided with increased levels of mucosal O2 and a reduction in colon-associated anaerobic commensals. In addition, IECs responded to infection by activating Srebp2 and the cholesterol biosynthetic pathway. Unexpectedly, infected IECs also upregulated the cholesterol efflux proteins AbcA1, AbcG8, and ApoA1, resulting in higher levels of fecal cholesterol and a bloom of Proteobacteria. These results suggest that C. rodentium manipulates host metabolism to evade innate immune responses and establish a favorable gut ecosystem.

Graphical abstract

Teaser

Berger et al. reveal how C. rodentium infection manipulates host metabolism to evade innate immune responses and establish a favorable gut ecosystem. Binding of C. rodentium to the gut epithelium rewires cellular bioenergetics and cholesterol metabolism, altering the composition of the gut microbiota and processes involved in fighting infection.


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