Lactoferrin promotes intestinal stem cell-mediated epithelial regeneration by activating Wnt signaling

Nutritional intervention can greatly benefit people who suffer from side effects of medical treatments by improving intestinal post-damage recovery. The recovery process is dependent on the regeneration of intestinal epithelial cells, which is driven by Lgr5⁺ intestinal stem cells (ISCs). Lactoferrin (LF) is a natural milk-abundant protein with several gut health-related functions such as antibacterial and immunoregulation activities, thus protecting intestine from damage. However, it is unclear whether LF also plays a role in the repair of the injured intestine, despite limited clues on its ability to modulate intestinal epithelial cell growth in vitro. Here, we show that LF accelerates intestinal epithelial recovery after both dextran sulfate sodium challenge on mice and TNF-α treatment on intestinal organoids. Furthermore, we find LF gives rise to ISC-mediated epithelial regeneration by directly activating the Lgr5⁺ stem cells. Finally, we identify Lrp5/Wnt signaling as the key pathway for LF-enhancing ISC stemness and function. Overall, our study reveals the potential of LF as a nutrient that can be applied to promote intestinal healing.