BackgroundFormyl peptide receptor 2 (Fpr2) plays a crucial role in colon homeostasis and microbiota balance. CommensalE. coliis known to promote the regeneration of damaged colon epithelial cells. The aim of the study was to investigate the connection betweenE. coliand Fpr2 in the recovery of colon epithelial cells.ResultsThe deficiency of Fpr2 was associated with impaired integrity of the colon mucosa and an imbalance of microbiota, characterized by the enrichment of Proteobacteria in the colon. Two serotypes ofE. coli, O22:H8 and O91:H21, were identified in the mouse colon through complete genome sequencing.E. coliO22:H8 was found to be prevalent in the gut of mice and exhibited lower virulence compared to O91:H21. Germ-free (GF) mice that were pre-orally inoculated withE. coliO22:H8 showed reduced susceptibility to chemically induced colitis, increased proliferation of epithelial cells, and improved mouse survival. Following infection withE. coliO22:H8, the expression of Fpr2 in colon epithelial cells was upregulated, and the products derived fromE. coliO22:H8 induced migration and proliferation of colon epithelial cells through Fpr2. Fpr2 deficiency increased susceptibility to chemically induced colitis, delayed the repair of damaged colon epithelial cells, and heightened inflammatory responses. Additionally, the population ofE. coliwas observed to increase in the colons ofFpr2−/−mice with colitis.ConclusionCommensalE. coliO22:H8 stimulated the upregulation of Fpr2 expression in colon epithelial cells, and the products fromE. coliinduced migration and proliferation of colon epithelial cells through Fpr2. Fpr2 deficiency led to an increasedE. colipopulation in the colon and delayed recovery of damaged colon epithelial cells in mice with colitis. Therefore, Fpr2 is essential for the effects of commensalE. colion colon epithelial cell recovery.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13099-023-00557-w.