1. Citrobacter rodentium subverts ATP flux 1 and cholesterol homeostasis in 2 intestinal epithelial cell in vivo
- Author
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Berger, C, Crepin, V, Roumeliotis, TI, Wright, JC, Carson, D, Pevsner-Fischer, M, Furniss, RCD, Dougan, G, Bachash, M, Yu, L, Clements, A, Collins, JW, Elinav, E, Larrouy-maumus, G, Choudhary, JS, Frankel, GM, Medical Research Council (MRC), and Wellcome Trust
- Subjects
Male ,Proteomics ,INHIBITION ,type III secretion system effectors ,Srebp2 ,METABOLISM ,0601 Biochemistry and Cell Biology ,digestive system ,Cell Line ,ENERGY ,Endocrinology & Metabolism ,cholesterol biogenesis ,Feces ,Mice ,Adenosine Triphosphate ,INFLAMMATION ,INFECTION ,Animals ,Humans ,Metabolomics ,reprogram metabolism ,NITRIC-OXIDE SYNTHASE ,MODULATION ,Intestinal Mucosa ,ADAPTATION ,SPECIFICITY ,GENE-EXPRESSION ,Mice, Inbred C3H ,Science & Technology ,hypoxia ,Epithelial Cells ,Cell Biology ,creatine biogenesis ,Immunity, Innate ,Mitochondria ,Mice, Inbred C57BL ,Cholesterol ,1101 Medical Biochemistry and Metabolomics ,Citrobacter rodentium ,lipids (amino acids, peptides, and proteins) ,Abca1 ,Female ,Life Sciences & Biomedicine ,cholesterol efflux - Abstract
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.
- Published
- 2017