Physiologic hypoxia and oxygen homeostasis in the healthy intestine. A Review in the Theme: Cellular Responses to Hypoxia

Abstract

In recent years, the intestinal mucosa has proven to be an intriguing organ to study tissue oxygenation. The highly vascularized lamina propria juxtaposed to an anaerobic lumen containing trillions of metabolically active microbes results in one of the most austere tissue microenvironments in the body. Studies to date have determined that a healthy mucosa contains a steep oxygen gradient along the length of the intestine and from the lumen to the serosa. Advances in technology have allowed multiple independent measures and indicate that, in the healthy mucosa of the small and large intestine, the lumen-apposed epithelia experience Po2 conditions of <10 mmHg, so-called physiologic hypoxia. This unique physiology results from a combination of factors, including countercurrent exchange blood flow, fluctuating oxygen demands, epithelial metabolism, and oxygen diffusion into the lumen. Such conditions result in the activation of a number of hypoxia-related signaling processes, including stabilization of the transcription factor hypoxia-inducible factor. Here, we review the principles of mucosal oxygen delivery, metabolism, and end-point functional responses that result from this unique oxygenation profile.

Keywords: barrier function; colon; hypoxia; intestine; metabolism.

Fig. 1.

Comparison of basal hypoxia in intestinal tissue and other organs (A) and countercurrent blood flow in the healthy intestinal mucosa (B). A: organs from healthy hypoxia-inducible factor-luciferase reporter mice enable visualization of basal tissue hypoxia compared with other organs (113). B: a model of blood flow dynamics in the healthy intestinal mucosa. Countercurrent blood flow reduces local Po₂ along the crypt-villus axis and results in low Po₂ at the villus tip.

Fig. 2.

Physiologic hypoxia in the colonic epithelium mirrors localization of human β-defensin-1 (hBD1) in human colonic biopsies. A: “physiologic hypoxia.” Colonic mucosa of healthy mice shows small amounts of pimonidazole and nitroimidazole adduct along the luminal aspect of the colon (red), suggestive of physiologic hypoxia in the normal colon. B: immunofluorescence staining of hBD1 (green) in human colonic biopsies reveals localization within epithelium. The staining pattern is similar to that of pimonidazole, with the greatest intensity along the luminal aspect. DAPI (blue) was used to visualize nuclei.

Fig. 3.

Oxygen homeostasis and physiologic regulation of intestinal epithelial function. In addition to the influence of countercurrent blood flow (see Fig. 1), microbial-derived short-chain fatty acids (e.g., butyrate) stimulate epithelial metabolism and deplete intracellular oxygen to the extent that hypoxia-inducible factor (HIF) 1 is stabilized. Transcriptional HIF responses in the normal colon include the physiologic regulation of genes important for butyrate transport [monocarboxylate transporter 1 (MCT1)], xenobiotic clearance (P-glycoprotein), adenosine metabolism (CD39 and CD73), epithelial barrier function [MUC3, intestinal trefoil factor (ITF), and claudin (CLDN1)], energy metabolism [creatine kinase enzymes (CKM/CKB) and SLC6A8], antimicrobial defense (hBD1), and iron absorption [divalent metal transporter 1 (DMT1), ferroportin, and hepcidin]. TJ, tight junction; AJ, adherens junction.