Highlights
• Mitochondrial perturbation of the intestinal epithelium induces tissue injury
• Loss of IL-10 and AhR-related host mechanisms accelerate injury and inflammation
• Mitochondrial dysfunction induces dysbiosis and expansion of Bacteroides spp.
• Metabolic injury gene signature discriminates inflamed versus non-inflamed IBD samples
Mitochondrial dysfunction is associated with inflammatory bowel diseases (IBDs). To understand how microbial-metabolic circuits contribute to intestinal injury, we disrupt mitochondrial function in the epithelium by deleting the mitochondrial chaperone, heat shock protein 60 (Hsp60Δ/ΔIEC). This metabolic perturbation causes self-resolving tissue injury.
These signatures are observed in samples from Crohn’s disease patients, distinguishing active from inactive inflammation. Thus, mitochondrial perturbation of the epithelium causes microbiota-dependent injury with discriminative inflammatory gene profiles relevant for IBD.
In summary, we provide evidence that bacterial communities adjust to changes in epithelial metabolism, creating a dysbiotic adaptation of the microbiota in the intestine.
What remains elusive and requires further analysis is how metabolic changes in the epithelium select the growth of distinct members of the bacterial community.
Here, we demonstrate that metabolic flexibility of B. caecimuris coincides with metabolic injury, but the explicit contribution of bacterial pathways in these adverse microbial-metabolic circuits remains to be identified.
MT perturbation and bacterial signals cooperate in the development of metabolic injury, and host-derived metabolic gene signatures discriminate active and inactive inflammatory processes in IBD patients.
Thus, targeting specific MT pathways or microbe-host circuits may yield therapeutic options in recurrent inflammatory pathologies in the intestine.