Erythroid differentiation regulator-1 is induced by microbiota in early life and drives intestinal stem cell proliferation and regeneration

Gut microbiota and their metabolites are instrumental in regulating homeostasis in the intestine. However, the complex effects of early-life microbiota on intestinal development leading to durable changes in gene expression and function remains incompletely understood. Here we show that mice born germ-free (GF) and subsequently co-housed with specific-pathogen free (SPF) mice at the time of weaning (exGF), harbored altered intestinal gene expression well into adulthood when compared to SPF controls. One of the top-most differentially expressed genes between SPF and exGF mouse colons as identified by RNAseq was erythroid differentiation regulatory-1 (Erdr1). Erdr1 was induced early during development in SPF but not GF or exGF mice in association with histone acetylation of the Erdr1 promoter region. RNAscope analysis in SPF mice revealed that Erdr1 localized to the proliferative zone of the small and large intestine, particularly Lgr5+ stem cells and transit amplifying (TA) cells. Erdr1 induced Wnt signaling in epithelial cells, increased Lgr5+ stem cells, and promoted the growth of intestinal organoids, and was capable of reversing impaired growth and stem cell signature gene expression in GF or exGF organoids. Consistent with these pro-proliferative effects, Erdr1 accelerated wound closure in intestinal scratch-wound assays in vitro and dramatically increased Lgr5+ intestinal stem cell regeneration following radiation-induced injury in vivo. Additionally, administration of Erdr1 enhanced recovery from dextran sodium sulfate (DSS)-induced colonic damage, while anti-Erdr1 antibody had the opposite effect. Collectively, our findings indicate that early-life microbiota controls Erdr1-mediated intestinal epithelial proliferation and regeneration in response to mucosal damage.