Abstract Mitochondrial dysfunction in intestinal epithelial cells (IECs) is associated with chronic inflammation. To understand how microbial-metabolic circuits contribute to tissue injury, we disrupt mitochondrial function in IECs by deleting heat shock protein 60 (Hsp60 Δ/ΔIEC ). While metabolic perturbation causes self-resolving tissue injury, regeneration is disrupted in the susceptible host (Hsp60 Δ/ΔIEC ; Il10 -/- ). Interestingly, metabolic injury induces microbial dysbiosis, including Bacteroides spp. expansion. Tissue pathology is absent in the distal colon of germfree (GF) Hsp60 Δ/ΔIEC mice, highlighting bacterial control of metabolic injury. In line, host tryptophan metabolism is rewired, and the absence of bacterial-mediated AhR signaling (Hsp60 Δ/ΔIEC ; AhR -/- ) causes severe acceleration of injury independent of IL-22. Furthermore, selective colonization of GF Hsp60 Δ/ΔIEC mice with OMM 12 induces metabolic injury and Bacteroides caecimuris expansion, which generates metabolic injury in mono-colonized mice. In conclusion, mitochondrial perturbation of the epithelium causes dysbiotic expansion of Bacteroides spp., supporting the concept that microbe-host cross-talk contributes to metabolic injury in intestinal inflammation. Graphical Abstract: Control of metabolic injury by microbial signals Hsp60 deletion is induced in intestinal epithelial cells leading to mitochondrial perturbation, causing a shift in colonocyte metabolism (1, 2) Intestinal crypts display loss of stemness and weakening of the mucus barrier accompanied by dysbiotic changes, notably expansion of Bacteroides spp. (3 – 6) The injury phenotype is accompanied by immune cell recruitment and loss of regulatory mechanisms in a colitis-susceptible model (7) AhR-dependent signals are critical to maintain balanced bacterial-metabolic circuits for tissue healing and homeostasis (8) Created with BioRender.com. D: day; Hsp60+: heat shock protein 60-positive; Lgr5+: leucine-rich repeat-containing G-protein coupled receptor 5-positive; AhR: aryl hydrocarbon receptor; OXPHOS: oxidative phosphorylation; MT-UPR: mitochondrial unfolded protein response; Trb3: tribbles pseudokinase 3; Ido1: indoleamine 2, 3-dioxygenase 1.