Adiponectin regulated by IAA in Paneth cells controls renewal and differentiation of gut stem cells to maintain homeostasis of epithelial cells

We here demonstrate that adiponectin in Paneth cells can suppress renewal and differentiation of gut stem cells through adiponectin receptor 1 (AdipR1). Crypt cells (mainly stem and transit amplifying (TA) cells) in Adipfl/flpVilli-CreT (gut epithelial cell adiponectin conditioned knockout) mice exhibited stronger ability of renewal and differentiation. ScRNA-seq found that there had much more enrichment intestinal stem and TA cells in Adipfl/flpVilli-CreT mice. The renewal and development of gut epithelial cells in irradiated or DSS (dextran sulfate sodium) treated Adipfl/flpVilli-CreT mice was faster than control Adipfl/flp mice. In vitro culture gut organoid of Adipfl/flpVilli-CreT mice exhibited faster growth than those from Adipfl/flp mice. The gut epithelial cells in AdipR1 knockout (KO) mice had much longer crypts than control mice. Interestingly, indole-3-acetic acid (IAA) from gut microbiota could control the expression of adiponectin to promote the renewal and proliferation of gut stem cells. In vitro culture organoid also showed faster development after exposing to IAA. Thus, adiponectin, which is regulated by gut microbiota derived IAA controls the renewal and differentiation of gut stem cells to maintain the homeostasis of epithelial cells. Overall design: To further illustrate the function of adiponectin from gut Paneth cells, we again generated in vitro gut organoids from the intestines of Adipfl/flpVilli-CreT mice (Adip KO) and from control Adipfl/fl mice(WT).