Oxygen in the regulation of intestinal epithelial transport

Abstract

The transport of fluid, nutrients and electrolytes to and from the intestinal lumen is a primary function of epithelial cells. Normally, the intestine absorbs approximately 9 l of fluid and 1 kg of nutrients daily, driven by epithelial transport processes that consume large amounts of cellular energy and O2. The epithelium exists at the interface of the richly vascularised mucosa, and the anoxic luminal environment and this steep O2 gradient play a key role in determining the expression pattern of proteins involved in fluid, nutrient and electrolyte transport. However, the dynamic nature of the splanchnic circulation necessitates that the epithelium can evoke co-ordinated responses to fluctuations in O2 availability, which occur either as a part of the normal digestive process or as a consequence of several pathophysiological conditions. While it is known that hypoxia-responsive signals, such as reactive oxygen species, AMP-activated kinase, hypoxia-inducible factors, and prolyl hydroxylases are all important in regulating epithelial responses to altered O2 supply, our understanding of the molecular mechanisms involved is still limited. Here, we aim to review the current literature regarding the role that O2 plays in regulating intestinal transport processes and to highlight areas of research that still need to be addressed.

Figure 1. Schematic representation of intestinal absorptive and secretory mechanisms

A, transport processes occur in a spatially distinct manner along the crypt–villus axis. While transporters responsible for nutrient and fluid absorption are primarily expressed in villus cells and upper crypt cells, Cl⁻ and fluid secretion occur primarily from the base of the crypt. B: upper panel, intestinal epithelial cell with a complement of transporters involved in nutrient absorption; middle panel, cell expressing transporters responsible for fluid absorption; lower panel, a crypt cell expressing the transport proteins involved in Cl⁻ and fluid secretion. aa, amino acid; VIP, vasoactive intestinal polypeptide. It should be noted that these figures are purely schematic representations, designed to summarise various transport mechanisms that can be expressed in intestinal epithelial cells. They do not take into account that transport proteins are differentially expressed along the crypt villus axis and in different intestinal sections.

Figure 2. ATP generation in normoxic and hypoxic conditions

When oxygen supply is sufficient to meet cellular demands, pyruvate formed by glycolysis enters the tricarboxylic acid (TCA) cycle which yields 2 molecules of ATP and NADH. NADH is then used in the process of oxidative phosphorylation, yielding 32 molecules of ATP. In normoxia there is sufficient ATP available to drive Na⁺/K⁺-ATPase activity. However, in hypoxic conditions lower levels of ATP production result in reduced Na⁺/K⁺-ATPase activity. Arrows in green only occur in normoxic conditions.

Figure 3. Effects of hypoxia on epithelial signalling pathways

In conditions where oxygen supply meets demand, PHDs can hydroxylate target proteins, such as HIF-α, which is subsequently targeted for proteasomal degradation. However, in hypoxic conditions, insufficient oxygen availability prevents PHDs from hydroxylating HIFα, leading to its stabilisation, nuclear translocation, dimerisation with HIFβ and ultimately, the transcription of HIF-responsive genes. Hypoxia also induces mitochondrial ROS production which can regulate transport protein expression and activity in several ways, including elevation of intracellular Ca²⁺ and AMPK activation. TJ, tight junction.