Better mental wellbeing substantially reduces the risk of developing irritable bowel syndrome (IBS), with effects that are independent of genetic predisposition and partly mediated through lower depression and anxiety. In this prospective UK Biobank cohort of 75,842 IBS-free participants followed for 12.4 years, 1,400 incident IBS cases occurred, and higher life satisfaction and positive affect were strongly protective (HRs 0.41 and 0.50), while neuroticism and depressive/anxiety symptoms markedly increased risk (HRs 2.35 and 3.09). These associations were consistent across IBS subtypes, and mediation analyses attributed about 27% of the protective effect of mental wellbeing to reductions in depression and anxiety. Mendelian randomization supported a causal protective role of positive wellbeing, and proteomic profiling linked mental wellbeing–related proteins—particularly chromogranin A and gastrin—to IBS risk, with pathways enriched in cytokine–cytokine receptor signaling. Overall, the findings highlight mental wellbeing as a powerful determinant of IBS risk and underscore psychological health as a promising target for primary prevention. Source: https://journals.lww.com/ajg
