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

Background Siblings of individuals with Crohn’s disease (CD) are at increased risk for developing CD but the underlying mechanisms remain unclear. Objective We hypothesised that childhood (vs adult) exposure to a sibling with CD drives microbial perturbations, increasing CD susceptibility. Design 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. Results 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 Lachnospira , Roseburia and Colidextribacter , 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 Blautia -enriched or Prevotella -enriched enterotypes as highest risk, with a 10-year cumulative incidence of 22.5%. Conclusion Childhood exposure to siblings with CD is an independent risk factor of CD onset, potentially mediated by early-life microbial perturbation.

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Journal
Gut
Published
2026-08-25
DOI
https://doi.org/10.1136/gutjnl-2026-339257
Primary Topic
Inflammatory Bowel Disease
Type
article
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article

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

Jeffrey S. Hyams, G Aumais, Remo Panaccione, Çharles N. Bernstein et al.
Gut
Inflammatory Bowel Disease
article

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

Jeffrey S. Hyams, G Aumais, Remo Panaccione, Çharles N. Bernstein, Anthony Otley, John K. Marshall, Irit Avni‐Biron, Iris Dotan, Osvaldo Espin‐Garcia, Kevan Jacobson, Scott B. Snapper, Baruch Yerushalmi, Colette Deslandres, Cong Phi Dang, Rirong Chen, Hyun Jung Kim, Sun-Ho Lee, Maria Abreu, Maham Bushra, Alain Bitton, Hien Q. Huynh, Qilong Li, Paul Moayyedi, Lee Denson, Anne M Griffiths, A Hillary Steinhart, Iwona Wrobel, Mark S Silverberg, Williams Turpin, David Mack, Kenneth Croitoru
article en

Abstract

Background Siblings of individuals with Crohn’s disease (CD) are at increased risk for developing CD but the underlying mechanisms remain unclear. Objective We hypothesised that childhood (vs adult) exposure to a sibling with CD drives microbial perturbations, increasing CD susceptibility. Design 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. Results 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 Lachnospira , Roseburia and Colidextribacter , 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 Blautia -enriched or Prevotella -enriched enterotypes as highest risk, with a 10-year cumulative incidence of 22.5%. Conclusion Childhood exposure to siblings with CD is an independent risk factor of CD onset, potentially mediated by early-life microbial perturbation.

Gut
Ben-Gurion University of the Negev (IL), Western University (CA), Cincinnati Children's Hospital Medical Center (US), Boston Children's Hospital (US), Mount Sinai Hospital (CA), Dalhousie University (CA), University Health Network (CA), University of Miami (US), University of Alberta (CA), University of Calgary (CA), University of Toronto (CA), Children's Hospital of Eastern Ontario (CA), Rabin Medical Center (IL), Hospital for Sick Children (CA), McGill University Health Centre (CA), Centre Hospitalier Universitaire Sainte-Justine (CA), Population Health Research Institute (CA), Hôpital Maisonneuve-Rosemont (CA), Connecticut Children's Medical Center (US), Public Health Ontario (CA), BC Children's Hospital (CA), Korea University (JP), University of Manitoba (CA), Université de Montréal (CA), McMaster University (CA)
Leona M. and Harry B. Helmsley Charitable Trust, Biocodex Microbiota Foundation, Weston Family Foundation, Crohn's and Colitis Canada, Canadian Institutes of Health Research
Openalex Percentile: Top 10%
Inflammatory Bowel Disease
DOISourceOpenAlex
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