Sex-specific analyses of early-life tobacco smoke exposure and later-life irritable bowel syndrome: Sensitive window, mediation pathway, and genetic predisposition

Tobacco smoke can relax colonic smooth muscles and increase intestinal permeability, but whether early-life exposure affects later-life irritable bowel syndrome (IBS) and its underlying pathway remain unknown. We obtained the data from a large-scale cohort study in UK biobank, including information on age of smoking initiation (in utero period, childhood, adolescence, and adulthood), levels of C-reactive protein (CRP), genetic risk score (GRS), and IBS onset. We employed Cox proportional hazards models to examine the association between tobacco smoke exposure at different stages of life and incident IBS, and recognize the sensitive window. We further analyzed the interaction and joint effects of tobacco smoke exposure and GRS on IBS, as well as the mediation of CRP. Participants with initiating exposure to tobacco smoke in utero showed a higher IBS risk with hazard ratio (HR) of 1.149 (95 % CI: 1.093, 1.207), compared to unexposed individuals. Those who started smoking in childhood showed a greater risk with HR of 1.274 (95 % CI: 1.161, 1.399) than never smokers. Dose-response relationship showed the incident IBS increased with the earlier initiation and the longer duration of tobacco smoke. Notably, joint effect of initiating tobacco smoke at different stages presented participants initiating in utero and childhood had the strongest impact on IBS onset, with HR of 1.516 (95 % CI: 1.313, 1.751). The relations of early-life tobacco smoke exposure and IBS differed with genetic susceptibilities, being stronger in individuals with higher GRS. Furthermore, CRP partially mediated the associations of early-life tobacco smoke exposure at different stages of life with the incident IBS, with mediating proportions ranging from 5.73 % to 9.10 %. What's more, these aforementioned relationships are more pronounced in females than males. Accordingly, early-life tobacco smoke exposure, particularly during utero period and childhood in females, elevated the IBS onset, differing with genetic predisposition and mediated by the inflammation pathway.