Tissue metabolism and the inflammatory bowel diseases

Abstract

The intestinal mucosa provides a selective barrier between the anaerobic lumen and a highly metabolic lamina propria. A number of recent studies indicate that acute inflammation of the mucosa can result in tissue hypoxia and associated shifts in tissue metabolism. The activation of hypoxia-inducible factor (HIF) under these conditions has been demonstrated to function as an endogenous molecular cue to promote resolution of inflammation, particularly through the orchestration of barrier repair toward homeostasis. Given the central role of oxygen in tissue metabolism, ongoing studies have defined metabolic endpoints of HIF stabilization as important biomarkers of disease activity. Such findings make HIF and HIF-associated metabolic pathways particularly attractive therapeutic targets in inflammatory bowel disease (IBD). Here, we review the recent literature related to tissue metabolism in IBD.

Keywords: Hypoxia; Inflammation; Metabolite; Microbiota; Nucleotide.

Figure 1. Adenine nucleotide metabolism by intestinal epithelial cells

During acute inflammation, PMN transmigration, platelet co-migration and direct cellular injury result in the accumulation of extracellular ATP on the luminal aspect of the intestinal mucosa. ATP is metabolized to AMP by ecto-nucleotidases (CD39) and then to adenosine by ecto-5′-nucleotidase (CD73). Extracellular adenosine then signals in an autocrine and paracrine manner through adenosine receptors expressed on the apical membrane of intestinal epithelial cells, the most prominent of which is Adora2B.

Figure 2. Summary of the tryptophan (Trp) metabolism pathway including the enzymes involved in the primary metabolism of Trp

From left to right: The enzyme indoleamine 2,3-dioxygenase-1 (IDO1) converts Trp to kynurenine (Kyn), host microbes producing tryptophanases catabolize Trp into indole metabolites, and Trp hydroxylase produces serotonin from Trp.

Figure 3. Microbiota derived metabolites act as signaling molecules in colonic epithelial cells

Butyrate produced by anaerobic bacteria increases epithelial oxygen consumption, stabilizes HIF, and activates HIF dependent gene transcription. Indole metabolites are produced by a variety of enteric bacteria and can alter colonic epithelial cell signaling through activation of AHR.