A SNP of bacterial blc disturbs gut lysophospholipid homeostasis and induces inflammation through epithelial barrier disruption
Dayuan Zou,
Jingwen Pei,
Jianfeng Lan,
Hong Sang,
Hongjuan Chen,
Haoliang Yuan,
Di Wu,
Yuanyuan Zhang,
Yufang Wang,
Dingyu Wang,
Yujie Zou,
Di Chen,
Jianan Ren,
Xiang Gao,
Zhaoyu Lin
Affiliations
Dayuan Zou
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Drum Tower Hospital, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, China
Jingwen Pei
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Drum Tower Hospital, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, China
Jianfeng Lan
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Drum Tower Hospital, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, China
Hong Sang
Department of Dermatology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China
Hongjuan Chen
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Drum Tower Hospital, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, China
Haoliang Yuan
State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China
Di Wu
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Drum Tower Hospital, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, China
Yuanyuan Zhang
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Drum Tower Hospital, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, China
Yufang Wang
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Drum Tower Hospital, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, China
Dingyu Wang
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Drum Tower Hospital, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, China
Yujie Zou
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Drum Tower Hospital, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, China
Di Chen
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Drum Tower Hospital, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, China
Jianan Ren
Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China; Corresponding authors.
Xiang Gao
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Drum Tower Hospital, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, China; Corresponding authors.
Zhaoyu Lin
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Drum Tower Hospital, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, China; Corresponding authors.
Background: Alteration of commensal bacterial composition is associated with many inflammatory diseases. However, few studies have pinpointed the specific bacterial genes that may suppress host immune responses against microbes and maintain homeostasis in the host intestine. Methods: High-throughput screening was performed in Caenorhabditis elegans with a single gene knockout ut screening was performed in Caenorhabditis elegans with a single gene knockout Escherichia coli (E. coli) library and identified the immune suppression gene blc. The coding sequences of blc among different kinds of E. coli strains were aligned to identify the single nucleotide polymorphisms (SNPs). Physiological and biochemical experiments were performed in C. elegans and mice to explore the function of the blc variant. Findings: By screening 3983 E. coli mutants, we discovered that 9 bacterial genes, when deleted, activate innate immunity in the host C. elegans. Among these 9 genes, the gene encoding blc showed a distinctive SNP in many clinically pathogenic bacteria. We found that bacteria with this SNP, which converts Blc G84 to Blc E84, are highly enriched in the faeces of patients with inflammatory bowel disease (IBD). Exposure to BlcE84-encoding bacteria resulted in epithelial barrier disruption and immune activation in both worms and mice. Detailed analysis indicated that infection with BlcE84-encoding bacteria causes a significant decrease in LPE levels in the intestine and subsequently disrupts gut epithelial integrity in mice. Consistently, the levels of LPE in patients with IBD are significantly lower than those in healthy people. Finally, supplementation with LPE, which activates LPA1/PLCβ/PKC signaling, reversed the defects induced by BlcE84-encoding bacteria. Interpretation: Our results identified a novel bacterial gene, blc, in E. coli that regulates host gut integrity and immunity. Fund: The Ministry of Science and Technology of China; the National Natural Science Foundation of China; and the Natural Science Foundation of Jiangsu Province. Keywords: Bacterial lipocalin, Gut homeostasis, Epithelial barrier, lysophosphatidylethanolamine (LPE), Keio collection
