Enterococcus faecalis hijacks FABP2 to activate quorum-sensing signals and aggravate Crohn's disease by inducing gut dysbiosis

Abstract

Background: Crohn's disease (CD) is a chronic inflammatory disorder characterised by intestinal dysbiosis. While inflammation-induced leakage of host proteins is a known phenomenon in CD, how these proteins affect the gut microbiota and contribute to dysbiosis remains unclear. One hypothesis is that commensal bacteria hijack these proteins, exacerbating inflammation in CD.

Design: To investigate host-microbiota interactions in CD, we measured fatty acid-binding protein 2 (FABP2) levels in patients with CD and in mouse models of dextran sulfate sodium induced enteritis and interleukin 10 knockout spontaneous enteritis. Proteomic approaches, including bacterial pull-down and mass spectrometry, were employed to identify commensal targets of FABP2. Functional studies were conducted using wild type and EF3041-deficient Enterococcus faecalis strains, along with α-FABP2 antibody treatment, to assess their effects on intestinal inflammation and microbiota composition.

Results: FABP2 levels were elevated in plasma and faeces of patients with CD, as well as in the mouse models. This was accompanied by dysbiosis of gut commensal bacteria. E. faecalis hijacked luminal FABP2 to promote its proliferation via pheromone-binding protein EF3041, which activated quorum-sensing pathways. Deletion of EF3041 abolished this response, while complementation with EF3041 restored it. Injection of α-FABP2 antibody or transplantation of ΔEF3041 mutant strain significantly reduced epithelial damage, mitigated dysbiosis and alleviated inflammation and symptoms of enteritis in mice.

Conclusion: This study reveals a novel mechanism by which commensal bacteria use host-derived FABP2 to drive dysbiosis and worsen CD pathology. Targeting the FABP2-EF3041 axis may offer new diagnostic and therapeutic avenues for managing CD.

Keywords: CROHN'S DISEASE; IBD BASIC RESEARCH; INFLAMMATORY BOWEL DISEASE; INTESTINAL BACTERIA; SMALL INTESTINE.