A basic principle of all life is separation between an organism and its environment. Humans separate their inner tissues from the environment by engulfing them in an outer layer, the skin. The guiding principle of this separation is that the outer layer of the skin comprises dead epithelial cells, thus providing a physical barrier from intruders and harmful substances. It is tempting to think that our skin is the largest surface area of our body that interacts with the environment. Yet this is not true. The largest surface area that is exposed to the environment, is our intestine.
The surface area of the human intestine is roughly the size of a tennis court. Yet, unlike skin cells, intestinal epithelial cells do not have the privilege of being dead to form a barrier. This is because, unlike the skin, the intestine has a crucial role in absorbing nutrients from our diet. As these cells are alive, and face the outside world, they are equipped with microbial sensors that can identify virtually all microbial life (for example toll-like receptors). These sensors can then trigger a robust inflammatory response, as the intestinal tissue holds the largest number of immune cells in the body. To complicate things, these cells face one of the densest microbial ecosystems in the world, the gut microbiome, reaching densities of 10 to the power of 12 bacteria per gram of intestinal content. So, how does this work? Why do these microbes not constantly invoke an inflammatory response in the intestine?
The answer is mucus. Every live tissue that faces the outside world, such as the lungs, urogenital tract, and the oral cavity, is covered in mucus (hence their name, mucosal tissues). This mucus provides separation between our live cells and the microbes in the environment while still allowing nutrients, gasses, and water to be absorbed. Mucus might sound ordinary and mundane, perhaps even annoying under some circumstances (such as having a cold), but it is in fact incredibly complex and modular. We recognize how important this mucus is in the instances where it fails. When mucus malfunctions in the lungs, we get diseases such as cystic fibrosis or asthma. When this mucus malfunctions in the intestine, we get inflammatory bowel diseases.
Inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis, are chronic illnesses of the intestinal tract. We do not know exactly why these chronic inflammations begin, or how to cure them. We do know however, that failure of the intestinal mucus layer, and penetrance of microbes through it, are hallmarks of inflammatory bowel diseases. Given the crucial role of the mucus layer in maintaining separation, we can understand why its failure, leading to constant contact between the intestinal tissue and the trillions of microbes in our gut, can develop into a chronic inflammation in which our immune system overreacts to our gut microbiome.
The goal our ERC-funded project, GCMech, is to understand how mucus-secreting goblet cells function during health and disease, and attempt to prevent their dysfunction during inflammatory bowel diseases.
