Mitochondrial perturbation in the intestine causes microbiota-dependent injury and gene signatures discriminative of inflammatory disease
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Mitochondrial dysfunction is associated with inflammatory bowel diseases (IBD). To understand how microbial-metabolic circuits contribute to intestinal tissue injury, we disrupt mitochondrial function in the epithelium by deleting heat shock protein 60 (Hsp60 Δ/ΔIEC ). While metabolic perturbation causes self-resolving tissue injury, regeneration is disrupted in the absence of aryl hydrocarbon receptor (Hsp60 Δ/ΔIEC ;AhR -/- ) or IL-10 (Hsp60 Δ/ΔIEC ;Il10 -/- ) leading to IBD-like pathology. Injury is absent in the distal colon of germ-free (GF) Hsp60 Δ/ΔIEC mice, highlighting bacterial control of metabolic injury. Selective colonization of GF Hsp60 Δ/ΔIEC mice with the synthetic community OMM 12 confirms consistent expansion of metabolically-flexible Bacteroides spp. across all models and mono-colonization with B. caecimuris recapitulates injury. Transcriptional profiling of metabolically-impaired epithelium identifies gene signatures, including Ido1 , Nos2 , and Duox2 , distinguishing active from inactive tissue inflammation in 343 resected samples from Crohn’s disease patients. In conclusion, mitochondrial perturbation of the epithelium causes microbiota-dependent tissue injury and discriminative inflammatory gene profiles relevant for IBD.
Abstract Figure
Graphical Abstract:Control of metabolic injury by microbial signals.
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 vs. non-inflamed IBD samples
