Oxalyl-CoA decarboxylase is a major and specific virulence factor for Adherent Invasive Escherichia coli

Adherent-invasive Escherichia coli (AIEC) are enriched in the gut microbiota of patients with Crohn’s disease (CD), but bacterial genes underlying their role in intestinal inflammation remain poorly defined. By integrating in vivo whole-genome transposon sequencing (TnSeq) with and without colitis conditions, RNA sequencing and mechanistic experiments, we identified oxc, which encodes oxalyl-CoA decarboxylase, as a major and specific determinant of AIEC virulence under inflammatory conditions. Disruption of oxc in AIEC, but not in laboratory or commensal E. coli strains, eliminated survival under acid and oxidative stress, reduced motility and biofilm formation, and suppressed adhesion, invasion, and intramacrophage persistence. In vivo, oxc was (i) required for AIEC survival in all gastrointestinal segments in colitis settings and (ii) exacerbated colitis severity. Transcriptomics analysis revealed repression of flagella and acid resistance systems encoding genes, linking metabolism to motility and stress defenses. Metabolically, loss of oxc suppressed prpBCDE operon induction at low pH and altered threonine/propionate and oxalate pathways, with concordant changes in energy and respiratory activities. Diet enriched in oxalate or propionate potentiated AIEC colonization and pathology in an oxc-dependent manner. Overall, oxc is linking metabolic to virulence pathways under inflammatory conditions and may represent a treatable target for microbiome-preserving interventions