The intestinal epithelium represents the most regenerative tissue in the human body, located in proximity to the dense and functionally diverse microbial milieu of the microbiome. Episodes of tissue injury and incomplete healing of the intestinal epithelium are a prerequisite for immune reactivation and account for recurrent, chronically progressing phenotypes of inflammatory bowel diseases (IBD). Mitochondrial dysfunction and associated changes in intestinal epithelial functions are emerging concepts in the pathogenesis of IBD, suggesting impaired metabolic flexibility of epithelial cells affects the regenerative capacity of the intestinal tissue. Next to rendering the intestinal mucosa susceptible to inflammatory triggers, metabolic reprogramming of the epithelium is implicated in shaping adverse microbial environments. In this review, we introduce the concept of "metabolic injury" as a cell autonomous mechanism of tissue wounding in response to mitochondrial perturbation. Furthermore, we highlight epithelial metabolism as intersection of microbiome, immune cells and epithelial regeneration.
© 2022. The Author(s).