Orchestrating the intestinal epithelial niche: Intestinal smooth muscle tissue and cytokines in epithelial regulation

Abstract

Gut disorders, like inflammatory bowel disease, are becoming increasingly common. To develop better treatments, we need to understand how the gut works and what happens at the cellular level when these disorders occur. This study reveals new findings about how specific factors within the gut contribute to maintain the health of the gut lining (intestinal epithelium), manage immune responses, and help the epithelium heal after injury. One of our key findings was that smooth muscle tissue, which is part of the gut wall, plays a significant and previously unknown role in supporting intestinal stem cells. These stem cells are vital for the maintenance and repair of the epithelium. Specifically, we found out that smooth muscle cells produce certain factors, called bone morphogenetic protein (BMP) antagonists, that are essential for keeping these stem cells healthy and functional. Our research then focused on a particular protein that is found in smooth muscle cells, called Matrix metalloproteinase 17 (MMP17), that belongs to a group of proteins involved in extracellular matrix modulation. Using a knock-out mouse model that lacks MMP17, we found that this protein is crucial for the repair of the epithelium after injury. Interestingly, mice lacking MMP17 were also better at clearing infections with Trichuris muris, a type of parasitic worm. We believe this may be due to higher levels of certain infection-related effectors, produced by goblet cells, secretory-type cells, in their guts. We also examined the effects of exposing lab-grown mini-guts, known as organoids, to different cytokines, which are signaling molecules that shape the immune response to infections. The cytokines IL-13 and IL-22 led to changes in goblet cells and tuft cells, a sensor-type cell that is important during immune responses to gut parasites. In this context we discovered a new role of BMP signaling, a pathway known to encourage the maturation of cells, in limiting the formation of tuft cells in response to IL-13. Additionally, we detected more activity of the BMP pathway in MMP17-deficient mice, suggesting that a higher number of mature goblet cells could explain the higher levels of effectors. In conclusion, this research helps us better understand how the intestinal epithelium is regulated, shedding light on the roles of smooth muscle tissue, MMP17, and cytokines. It highlights the importance of certain signaling processes, like BMP, in controlling how the intestine maintains homeostasis but also responds to injury and infections.