Tobacco Smoke Exposure From Prenatal To Adolescent Periods Drives IBD Pathogenesis: Dynamic DNA Methylation Signatures Across Lifespan Stages

ABSTRACT The association between early life exposure to smoking and the risk of inflammatory bowel disease (IBD) needs to be further verified, and the potential role of DNA methylation in the association is unclear. Through an integrated study design, this study demonstrates that maternal smoking during pregnancy (MSDP) is potentially associated with increased risk of IBD, Crohn's disease (CD), and ulcerative colitis (UC) in offspring. In addition, individuals who started smoking in adolescence have a higher risk of developing CD and IBD. Mechanistically, MSDP‐associated DNA methylation alterations in ADCY7 (newborn), AKAP8L (newborn), TIGD7 (newborn), and TNF/LTA (across life stages) are significantly correlated with increased risk of CD in offspring; MSDP‐induced DNA methylation changes in PRRT1 (newborn), AHRR (across life stages), and MYO1G (across life stages) show significant associations with UC risk in offspring. Notably, the alterations of DNA methylation status within AHRR , MYO1G , and TNF/LTA loci associated with smoking exposure are present throughout the life course. Collectively, MSDP may serve as an independent risk factor for IBD in offspring, and active smoking during adolescence may cause increased risk of developing CD and IBD. MSDP may contribute to IBD susceptibility by inducing persistent DNA methylation alterations at multiple developmental stages.