Fig. 2. Intestinal epithelial mitochondrial function as intersection of microbiome, immune cells and epithelial regeneration.

The intestinal epithelium senses the microbial environment via pattern recognition receptors and receptors sensing metabolites. Left: Under homeostatic conditions, intestinal epithelial cell (IEC) mitochondrial function contributes to the selection of a beneficial microbiome by maintaining low luminal oxygen concentration through oxidative phosphorylation (OXPHOS) and supporting production of antimicrobial peptides (AMPs). The microbiome provides metabolic support of epithelial cells by fermentation products such as short chain fatty acids (SCFAs), lactate, purines, and carnitines, thereby promoting cellular energetics and metabolic flexibility of IECs. As the ability to adapt mitochondrial functionality to the cellular demand determines the epithelial regenerative capacity, perturbations of mitochondrial metabolism result in metabolic injury of the epithelium (right). Shifting cellular metabolism away from OXPHOS to glycolysis (leading to elevated O2 levels) and impaired AMP production might result in dysbiosis, in turn aggravating the pro-inflammatory environment by reducing beneficial metabolites/ increasing disadvantageous microbial functions. IECs suffering from mitochondrial perturbation are exposed to high levels of reactive oxygen species (ROS) and activate mitochondrial stress signaling pathways such as mitochondrial unfolded protein response (UPRmt). Host genetics impact the selection of microbiota (left) and mitochondrial functions (right). IEC metabolism in conjunction with microbiota-derived metabolites likely controls mucosal immune cell recruitment and differentiation, thus orchestrating healing responses. Vice versa, immune cell-derived factors such as cytokines steer epithelial responses by targeting mitochondrial functions and metabolism. IL interleukin, TNF tumor necrosis factor.