A SNP of bacterial blc disturbs gut lysophospholipid homeostasis and induces inflammation through epithelial barrier disruption

Abstract

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 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 Blc^E84-encoding bacteria resulted in epithelial barrier disruption and immune activation in both worms and mice. Detailed analysis indicated that infection with Blc^E84-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 Blc^E84-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.