Mucus as we know it

Mucus

Mucus is a sticky, and to be fair a quite tricky, matter. It is hopeless to work with; it´s mostly water and ridiculously large proteins. But it is nevertheless important. These large molecules attracts the water so that our ingested material, bile and bacteria can be transported along the gut without causing constant pain. And talking of bacteria, mucus facilitates a niche needed for beneficial bacteria to thrive in the gut, to help us digest food, produce essential vitamins and prevent harmful bacteria from taking command.

Maybe more importantly, mucus also provide an essential barrier keeping gut residing bacteria at a distance from the intestinal wall. Disturbances of the barrier properties are tightly linked to inflammation, especially the relapsing inflammatory bowel disease Ulcerative colitis.

However, we still don’t know much about mucus. Maybe because it is hard to study. We see it as a challenge- it drives us to develop methods to fit the needs (and very large proteins). In the past we have used these methods to identify that mucus actually is more complex , heterogenous and yet structured than what we could imagine. That the mucus defects seen in Ulcerative colitis persists in the remissive phases of the disease. And that these annoyingly large proteins are post-translationally modified with tunable modifications, dictating the properties of mucus.

Goblet cells

Most of the very large proteins making up the mucus are produced by one cell type, goblet cells. These sit in the intestinal epithelium, produce and secrete mucus proteins and that is the end of the story. Or? Not quite. The last decade or so has proven that goblet cells can have much more specialized functions and play a more active role in epithelial defense. For example, I helped in out in the identification of sentinel goblet cells which can sense and react to increased concentration of bacterial components, for example upon breaches of the mucus barrier defense.

We later identified a number of transcriptionally diverse goblet cell types in the distal colon, and were able to (partly) functionally characterize one of these; the intercrypt goblet cells (based on their spatial position along the crypt axis). These produce and secrete mucus with different properties compare to other colonic goblet cells, and are indispensable for a functional mucus barrier. In murine models we found that intestinal inflammation can be driven by a loss of intercrypt goblet cells and we also found reduced numbers if intercrypt goblet cells in biopsies from Ulcerative colitis patients.

In the same study we also identified non-canonical goblet cells, with a gene expression profile similar to absorptive epithelial cells. Frankly, we don’t know what they do. But we will soon find out!

Post-translational modifications

The major mucus proteins aren’t just large—they’re tunable. By diverse post-translational modifications, the host (or pathogens) can alter mucus properties. For example, our studies of the protein CLCA1 opened the door to proteolytic processing of mucus processing and how it may regulate mucus properties in health and disease. However, proteolysis is only one of many post-translational modifications so there is a lot of work to be done.

The really cool thing is that, if we manage to identify key post-translational modifications that regulates mucus function, we could target those as a way to modify faulty mucus properties in disease.

Do you want to join us in our mission? Get in touch with Elisabeth to find out more!