Immune phenotype-guided identification of disease-associated pathobionts in Crohn’s disease

Aberrant immune activation within the gut mucosa and gut dysbiosis have been implicated in the pathogenesis of Crohn’s disease (CD). However, the specific immune responses triggered by dysbiotic microbiota, as well as the bacteria responsible for this activation, remain incompletely understood. Here, using the human microbiota-associated (HMA) mouse system, we demonstrated that colonization with dysbiotic gut microbiota from CD patients specifically induces the accumulation of mononuclear phagocytes, which may drive an interleukin-1 (IL-1)-driven inflammatory signature. Moreover, we identified pathobiont strains with a potent IL-1β-inducing capacity, termed ‘IL-1β-inducing pathobionts’ (IBIP). Isolated IBIP strains exhibit genetic and functional similarities to adherent-invasive Escherichia coli but harbor unique virulence-associated genes. Colonization with the IBIP E. coli strain exacerbated experimental colitis in an IL-1 signal-dependent manner. Notably, the colonization of IBIP E. coli can be detected by measuring the levels of specific immunoglobulin A (IgA) in their stool samples. Moreover, the level of IBIP-reactive IgA in stool may serve as a predictive biomarker for treatment response to anti-TNF therapies in treatment-naïve pediatric CD patients. Altogether, IBIP colonization could help identify CD patients with inflammatory dysbiosis who are likely to be refractory to anti-TNF therapies.