The impact of hypoxia on intestinal epithelial cell functions: consequences for invasion by bacterial pathogens

Abstract

The maintenance of oxygen homeostasis in human tissues is mediated by several cellular adaptations in response to low-oxygen stress, called hypoxia. A decrease in tissue oxygen levels is initially counteracted by increasing local blood flow to overcome diminished oxygenation and avoid hypoxic stress. However, studies have shown that the physiological oxygen concentrations in several tissues are much lower than atmospheric (normoxic) conditions, and the oxygen supply is finely regulated in individual cell types. The gastrointestinal tract has been described to subsist in a state of physiologically low oxygen level and is thus depicted as a tissue in the state of constant low-grade inflammation. The intestinal epithelial cell layer plays a vital role in the immune response to inflammation and infections that occur within the intestinal tissue and is involved in many of the adaptation responses to hypoxic stress. This is especially relevant in the context of inflammatory disorders, such as inflammatory bowel disease (IBD). Therefore, this review aims to describe the intestinal epithelial cellular response to hypoxia and the consequences for host interactions with invading gastrointestinal bacterial pathogens.

Stress‐induced host membrane remodeling protects from infection by non‐motile bacterial pathogens

“…For example, IECs secrete pro‐inflammatory cytokines and chemokines in response to infection by certain enteroinvasive bacterial pathogens such as Shigella flexneri and Salmonella Typhimurium. This, in turn, leads to a massive infiltration of professional immune cells into the sites of inflammation, from which ensues a local increase in reactive oxygen species and a profound hypoxia (Colgan & Taylor, 2010; Zeitouni et al , 2016; Arena et al , 2017). Such change in environment not only constrains the pathogen but also dramatically affects the intestinal epithelium.…”

Good, Bad, or Risky? : intestinal permeability to protein: human and in vitro studies

“…Gardner [40,41] already discussed upon this topic, but there is still limited evidence that larger peptides and protein are taken up intactly by the intestine [42,43]. From the existence of food allergies, however, it can be deduced that indeed a small amount of immunologically active food protein can be taken up and enter the circulation [44].…”

“…Circulating citrulline is often used as a clinical measure of total intestinal metabolic mass [43]. The absence of an increase in circulating citrulline after ingestion of casein following the dual exercise protocol could reflect a reduced intestinal metabolic capacity.…”

“…A lower supply of oxygen affects especially the intestine, as this organ is particularly sensitive to changes in oxygen supply. This is because the intestinal epithelium exists in a state of relative 'physiological hypoxia', already under normal physiological conditions [42][43][44]. Therefore small changes in oxygen supply can already lead to oxygen deprivation, which in turn can result in mitochondrial ATP depletion.…”

“…One aspect is oxygen availability, which is much higher in routine culture than it actually is in vivo. The partial oxygen pressure in vivo at the serosal (basolateral) side of the intestinal epithelial cells lies around 60 mmHg [43,50], while this is only half at the luminal (apical) side [43]. Studies with Caco-2 monolayers have shown that with routine culture, the partial oxygen pressure of the basolateral medium was around 110 mmHg, which is almost double as seen in the in vivo situation [51].…”