Arachidonic Acid Promotes Intestinal Regeneration by Activating WNT Signaling

Intestinal regeneration is crucial for functional restoration after injury, and nutritional molecules can play an important role in this process. Here, we found that arachidonic acid (AA) serves as a direct proliferation promoter of intestinal epithelial cells that facilitates small intestinal regeneration in both three-dimensional cultured organoids and mouse models. As shown in the study, during post-irradiation regeneration, AA positively regulates intestinal epithelial cell proliferation by upregulating the expression of Ascl2 and activating WNT signaling, but negatively regulates intestinal epithelial cell differentiation. AA acts as a delicate regulator that efficiently facilitates epithelial tissue repair by activating radiation-resistant Msi1+ cells rather than Lgr5+ cells, which are extensively considered WNT-activated crypt base stem cells. Additionally, short-term AA treatment maintains optimal intestinal epithelial homeostasis under physiological conditions. As a result, AA treatment can be considered a potential therapy for irradiation injury repair and tissue regeneration. •AA promotes regeneration of intestinal epithelium after irradiation injury•AA triggers Ascl2 expression and activates WNT signaling in intestinal epithelium•AA facilitates intestinal repair by activating Msi1+ populations In this article, Wang et al. demonstrate that a long-chain polyunsaturated fatty acid, arachidonic acid (AA), promotes intestinal epithelium regeneration after injury. In this process, AA triggers the expression of Ascl2 and activates WNT signaling, possibly through activating the radiation-resistant Msi1+ cells but independent of Lgr5+ populations. The study yields promising nutritional therapeutic strategies for gut repair.