Regulation of Oxygen Homeostasis at the Intestinal Epithelial Barrier Site

Abstract

The unique biology of the intestinal epithelial barrier is linked to a low baseline oxygen pressure (pO₂), characterised by a high rate of metabolites circulating through the intestinal blood and the presence of a steep oxygen gradient across the epithelial surface. These characteristics require tight regulation of oxygen homeostasis, achieved in part by hypoxia-inducible factor (HIF)-dependent signalling. Furthermore, intestinal epithelial cells (IEC) possess metabolic identities that are reflected in changes in mitochondrial function. In recent years, it has become widely accepted that oxygen metabolism is key to homeostasis at the mucosae. In addition, the gut has a vast and diverse microbial population, the microbiota. Microbiome-gut communication represents a dynamic exchange of mediators produced by bacterial and intestinal metabolism. The microbiome contributes to the maintenance of the hypoxic environment, which is critical for nutrient absorption, intestinal barrier function, and innate and/or adaptive immune responses in the gastrointestinal tract. In this review, we focus on oxygen homeostasis at the epithelial barrier site, how it is regulated by hypoxia and the microbiome, and how oxygen homeostasis at the epithelium is regulated in health and disease.

Keywords: IBD; hypoxia; microbiota; mitochondria; oxygen.

Figure 1

O₂ and its regulation at the intestinal epithelial barrier site. (A) Counter current blood flow reduces local pO₂ along the crypt–villus axis and results in low pO₂ at the villus tip. (B) Histological section of small intestine; villus–crypt axis, BALB/cOlaHsd mouse. (C) Hypoxic/normoxic environment along crypt–villus axis. (C.1) Hypoxic condition or intermittent hypoxia at the upper part of the villa; inactive HIF hydroxylases. HIF-1 is composed of two subunits—oxygen-sensitive HIF-1α and HIF-1β. Due to low O₂, PHD activity is decreased. HIF-1α is stabilised and binds to ARNT in the presence of co-activator p300; altogether, it activates transcription factor of HIF target genes. (C.2) Normoxic conditions at the bottom of the crypt. In the presence of O₂, PHD enzyme hydroxylates the two proline residues on HIF, enabling the binding of VHL to the HIF subunit, which degrades HIF-1α subunits under normoxic conditions. Fatty acid oxidation (FAO) is predominately present in normoxic cells.

Figure 2

Longitudinal gradient of O₂, bacterial load and pH along the intestine. Spatial heterogeneity of the gut microbiota in the gastrointestinal tract. The bacterial families of the small intestine and colon reflect physiological differences along the length of the gut. A gradient of oxygen and pH limits the bacterial density in the small intestine, whereas the colon carries high bacterial loads (darker brown = more bacteria).

Figure 3

Intestinal epithelial barrier in health and disease. This figure shows immunohistochemistry picture of small intestine crypts–villus axis in healthy and impaired intestine in BALB/cOlaHsd mice and highlight the main characteristics where the differences at the healthy or impaired (in disease) intestinal barrier were detected. Up and down arrows indicate an increase and decrease, respectively. Abbreviations: IEC, intestinal epithelial cells; LPS, lipopolysaccharide; SCFA, short-chain fatty acids; TJ, tight junctions.