Microenvironmental modulation of the intestinal epithelial barrier

A healthy gut is essential for human health and healthy aging. Indeed, many diseases are characterized by a disturbed function of the gut, which is often reflected by an abnormal composition of the gut microbiota, e.g., the gut bacteria that help in food digestion and immune regulation. Most of these gut bacteria are anaerobes, which means that they grow and are active under oxygen-free conditions. Instead, all human cells require oxygen to stay alive. Only one monolayer of cells, the intestinal epithelium, separates these anaerobic gut bacteria from all the internal organs of our body. The oxygen-sensitive hypoxia-inducible factor-1α (HIF1α) is a very important factor to maintain a strong intestinal epithelium, a barrier that is often compromised in patients with gastrointestinal disorders, such as inflammatory bowel disease (IBD). The aim of this thesis was to identify factors in the gut microenvironment that control the human intestinal epithelial barrier, with particular focus on the role of HIF1α. For this, we combined detailed IBD patient data with laboratory experiments using an in-house developed system in which oxygen-requiring human epithelium cells can be cocultured with anaerobic gut bacteria, e.g., the Human-oxygen Bacteria-anaerobe (HoxBan) system. We found that specific gut bacteria, dietary fibers, iron levels and inflammatory factors directly control the intestinal epithelial barrier function, in most cases involving HIF1α. As drugs that activate HIF1α are currently under investigation for various diseases, they may also be promising to improve gut health, for example in patients with IBD.