The mechanisms by which the mouse pathogen Citrobacter rodentium triggers effacement of the brush border microvilli, colitis, hyperplasia and dysbiosis remain poorly understood. We investigated the impact of C. rodentium infection on the proteomic and metabolic landscapes of intestinal epithelial cells (IECs) in vivo using isobaric labeling proteomics and targeted metabolomics. We found that infection depletes proteins involved in butyrate uptake, glycolysis, TCA cycle, lipid metabolism and oxidative phosphorylation with aparallel, increased production of creatine/phosphocreatine and cholesterol. The evolving ecological niche within the infected gut was concomitant with a reduction in butyrate-producing commensal bacteria and expansion of Proteobacteria that can metabolize cholesterol. These changes coincide with the modulation of IEC transcription factors by C. rodentium, specifically phosphorylation of Kdm5a, demethylation of histone H3 (Lys-4) and cleavage of Srebp2. Taken together our results show that whilst engaging with the host in a race to control innate immune responses, C. rodentium and the changing microbiota shape the metabolism flow in IECs.