Childhood exposure to a sibling with Crohn's disease alters gut microbiome and Crohn's disease susceptibility.

Abstract

Siblings of individuals with Crohn's disease (CD) are at increased risk for developing CD but the underlying mechanisms remain unclear. We hypothesised that childhood (vs adult) exposure to a sibling with CD drives microbial perturbations, increasing CD susceptibility. We used the prospective Genetic Environmental Microbial (GEM) Project and the nationwide South Korean database to assess the association between childhood exposure to affected siblings and CD onset. The association between childhood exposure and gut microbiome was evaluated in the GEM cohort. A T-cell transfer model of colitis in germ-free mice was conducted to investigate the effects of stool from childhood-exposed versus adult-exposed siblings. Finally, an integrative risk model combining faecal calprotectin (FCP) and microbial enterotypes was trained and internally validated within the GEM cohort. In the GEM cohort, childhood exposure to an affected sibling was associated with a fourfold higher risk of developing CD compared with adult exposure (adjusted HR (aHR) (95% CI) 4.00 (1.83 to 8.75); p=5.3×10^-4), which was validated in the South Korean dataset (aHR (95%CI) 2.54 (1.70 to 3.81; p=6.0×10^-6)). Childhood exposure was associated with reduced abundances of <i>Lachnospira</i>, <i>Roseburia</i> and <i>Colidextribacter</i>, reductions that mediation analysis identified as partially mediating CD risk. In vivo, transplantation of childhood exposure-associated microbiota into germ-free recipient mice exacerbated colitis and elevated mucosal interleukin-22 expression, supporting a potential mechanistic role. Our model identified siblings with elevated FCP and <i>Blautia</i>-enriched or <i>Prevotella</i>-enriched enterotypes as highest risk, with a 10-year cumulative incidence of 22.5%. Childhood exposure to siblings with CD is an independent risk factor of CD onset, potentially mediated by early-life microbial perturbation.