Intestinal epithelial cell metabolism at the interface of microbial dysbiosis and tissue injury

Abstract

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.

Fig. 1. The novel concept of metabolic injury as underlying mechanism of recurrent inflammation in patients with inflammatory bowel diseases (IBD).

Mitochondrial perturbation of the colonic epithelium e.g., caused by a combination of genetic predisposition and environmental triggers results in tissue injury (referred to as metabolic injury). Unresolved metabolic injury and incomplete tissue regeneration take place at the intersection of mitochondrial stress signaling (UPRmt) and changes of epithelial metabolism driving microbial dysbiosis and chronic inflammation in patients with IBD. UPRmt mitochondrial unfolded protein responses, IARSC injury-associated regenerative stem cells.

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.

Fig. 3. Intestinal epithelial cell mitochondria serve as metabolic signaling platform translating microbiome-derived signals into mucosal responses.

Intestinal epithelial cells (IECs) sense the microbial environment via pattern recognition receptors including toll-like receptors (TLR) and take up diet and microbiota-derived metabolites. Activation of TLR signaling can impact the electron transport chain (ETC) and oxidative phosphorylation (OXPHOS) via TNF receptor associated factor (TRAF) 6 and ECSIT (Evolutionarily conserved signaling intermediate in Toll pathway), altering production of reactive oxygen species (ROS). Viral sensing involves mitochondrial antiviral-signaling protein (MAVS) and initiates inflammatory responses i.e., activating NFκB pathway. Microbiota-derived metabolites feed the tricarboxylic acid (TCA) cycle and mitochondrial beta oxidation or can enhance cellular energetics through salvage pathways (purines). Hydrogen sulfide (H2S) produced by bacteria can as electron donor for the ETC, but at high concentrations, inhibit Complex IV activity and other mitochondrial proteins. Mitochondria are embedded in an organelle network, in particular, an exchange of calcium, FAD, and ATP with the endoplasmic reticulum (ER) occurs at mitochondria-associated membranes (MAM) and is important for ER oxidative protein folding. Proteostasis, depending on protein import, chaperone activity, and proteases, is crucial to sustain mitochondrial functions, and disturbances of mitochondrial proteostasis are signaled by the mitochondrial unfolded protein response (UPRmt). Release of mitochondrial DNA and double-stranded (ds) mitochondrial RNA under stress conditions promotes inflammatory signaling and regulates cell cycle progression. Fission and fusion events as well as mitophagy are critical regulators of mitochondrial homeostasis and prevent accumulation of dysfunctional mitochondria and excess ROS production. Thus, mitochondria integrate environmental signals into metabolism, downstream employing various signaling pathways to contribute to cell fate decisions and determine cellular phenotypes. Gene names of known IBD risk variants involved in mitochondrial functions are given in dark red. AMPK AMP-activated protein kinase, NLRP3 NLR family pyrin domain containing 3, PGC1α Peroxisome proliferator-activated receptor gamma coactivator 1-alpha, PKR double-stranded RNA-activated protein kinase, SCFAs short chain fatty acids.