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.

Inside the Gut: Understanding the immune system’s dance with the microbiome.

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 10¹² bacteria per gram of intestinal content. So, how does this work? Why do these microbes not constantly invoke an inflammatory response in the intestine?