Alteration of commensal bacterial composition is associated with many inflammatory diseases. However, few studies pinpointed the specific bacterial genes that may suppress host immune responses against microbes. By screening 3,983 E. coli mutants, we discovered that 9 bacterial genes, when deleted, activate innate immunity in the host Caenorhabditis elegans. The gene encoding bacterial lipocalin (blc), among these 9 genes, shown a distinctive SNP in many clinic pathogenic bacteria. We found bacteria with this SNP, which converts the BlcG84 to BlcE84, are highly enriched in the fecal of inflammatory bowel disease (IBD) patients. Exposure to the BlcE84-encoding bacteria resulted in epithelial barrier disruption and immune activation both in worm and mouse. Detailed analysis indicated the infection of the BlcE84-encoding bacteria causes a significant decrease in lysophosphatidylethanolamine (LPE) levels in the intestine, and subsequently the disruption of gut epithelial integrity in mice. Consistently, the levels of LPE in IBD patients are significantly lower compared to that of health people. Finally, supplement of LPE, which activating the LPA1/PLCβ/PKC signaling, can reverse all the defects induced by the BlcE84-encoding bacteria. Our results identified a novel bacterial gene in E. coli that regulates gut integrity and immunity. Funding Statement: This work was supported by the Ministry of Science and Technology of China (grant 2018YFA0801100), the National Natural Science Foundation of China (grant 31772550, grant 31971056 and grant 81772052) and the Natural Science Foundation of Jiangsu Province (BK20181260). Declaration of Interests: The authors declare no potential conflicts of interest concerning the research, authorship, and/or publication of this article. Ethics Approval Statement: All experiments were approved by the Institute animal ethics committee of Model Animal Research Center, Nanjing University.