Terminal differentiation of villus tip enterocytes is governed by distinct Tgfβ superfamily members

The protective and absorptive functions of the intestinal epithelium rely on differentiated enterocytes in the villi. The differentiation of enterocytes is orchestrated by sub‐epithelial mesenchymal cells producing distinct ligands along the villus axis, in particular Bmps and Tgfβ. Here, we show that individual Bmp ligands and Tgfβ drive distinct enterocytic programs specific to villus zonation. Bmp4 is expressed from the centre to the upper part of the villus and activates preferentially genes connected to lipid uptake and metabolism. In contrast, Bmp2 is produced by villus tip mesenchymal cells and it influences the adhesive properties of villus tip epithelial cells and the expression of immunomodulators. Additionally, Tgfβ induces epithelial gene expression programs similar to those triggered by Bmp2. Bmp2‐driven villus tip program is activated by a canonical Bmp receptor type I/Smad‐dependent mechanism. Finally, we establish an organoid cultivation system that enriches villus tip enterocytes and thereby better mimics the cellular composition of the intestinal epithelium. Our data suggest that not only a Bmp gradient but also the activity of individual Bmp drives specific enterocytic programs. Synopsis While moving upwards the intestinal villi enterocytes acquire different cellular fates, which is promoted by a gradient of Bmp ligands. In addition to this gradient individual Bmps have distinct activities in the differentiation of enterocytes. Bmp4 induces the expression of genes involved in lipid metabolism and uptake. Bmp2 promotes the terminal differentiation of enterocytes by activating villus tip programs. Bmp2‐driven differentiation depends on Bmp receptor type I and Smad4. The addition of Bmp2 enriches terminally differentiated enterocytes in intestinal organoids. Graphical Abstract While moving upwards, the intestinal villi enterocytes acquire different cellular fates, which are promoted by a gradient of Bmp ligands. In addition to this gradient, individual Bmps have distinct activities in the differentiation of enterocytes.