Contribution of Host Genetics and Maternal Inflammatory Bowel Disease to Fecal Calprotectin and Microbiota Composition During Early Life

ABSTRACT Background and Aims Parental diagnosis is one of the strongest predictors of developing inflammatory bowel disease (IBD) in offspring. However, the contribution of genetic heritability versus exposure to the perinatal environment remains poorly understood. We sought to determine the effects of host genetics and maternal IBD on intestinal inflammation and microbiota diversity during pregnancy and early life. Methods Polygenic risk scores (PRS) for IBD (PRS‐IBD), Crohn's disease (PRS‐CD) and ulcerative colitis were calculated in 281 pregnant women (74 with IBD) and 214 babies participating in the MECONIUM study. Fecal calprotectin (FC) and microbiota composition were measured at each trimester of pregnancy and repeatedly up to 3 years of age. Associations between PRS, maternal IBD, FC and microbiome composition were assessed using mixed‐effects regression models. Results Babies born to mothers with CD, but not UC, had significantly higher PRS‐IBD ( P = 0.04) and PRS‐CD ( P = 0.004) than control babies. Higher offspring PRS‐CD was associated with higher FC during 12–36 months of life ( P = 0.015), even though the association was attenuated after adjustment for maternal CD status, and altered microbiota composition, including higher abundance of Eubacterium and Pseudorimonococcus and depletion of Roseburia inulinivorans , Gordonibacter pamelaeae , and Lachnospira . Conclusions CD is more genetically transmissible to offspring than UC. Babies with higher genetic predisposition to CD were more likely to have a mother with IBD, elevated FC and altered gut microbiota during early life. Perinatal IBD exposure in genetically susceptible individuals may disrupt microbial colonization and heighten intestinal inflammation, potentially affecting immune development and increasing future disease risk.