Abstract
Inflammatory bowel disease (IBD) is a progressively advancing immune-mediated disorder characterized by intricate pathophysiological features. Despite extensive research, the mechanisms linking various risk factors to the development of IBD remain incompletely understood. We conducted analyses within a prospective cohort of unrelated European individuals, utilizing data from the UK Biobank. This cohort had over a decade of follow-up and included more than 500,000 participants aged between 37 and 73 years at recruitment, which took place between 2006 and 2010. A multivariate Cox proportional model was employed to investigate the impact of different risk factors on the incidence of IBD. Additionally, we examined the relationship between 220 peripheral biomarkers and the occurrence of IBD. Finally, we constructed a structural equation model to elucidate the complex pathogenic mechanisms and interactions among genetic risks, lifestyle factors, dietary habits, comorbidities, and immune metabolism in the progression of IBD. A total of 461,454 participants were included in the analysis, of whom 3,494 were newly diagnosed with IBD during the follow-up period. The multivariate Cox proportional model revealed the hazardous roles of polygenic risks, lifestyle factors, diet, immune metabolism, and pre-existing diseases. Specifically, insomnia, major illness-related dietary changes, and unhealthy dietary habits were associated with a 23%, 87%, and 15% increased risk of IBD, respectively. Smoking was found to increase the risk of IBD by 46% compared with never smoking. Comorbidities such as stomach pain, back pain, knee pain, and hip pain increased the risk of IBD by 128% , 27% , 22% and 17% respectively. Moreover, exposure to tobacco, lower educational degree, higher neuroticism score and seen a psychiatrist for nerves, anxiety, tension or depression before also identified as hazard risks. Among the 220 peripheral biomarkers analyzed, we found that cholesterol has the potential to become a new biomarker for predicting IBD. In terms of the pathways leading to IBD, a poor lifestyle contributed to a 5.2% increase in IBD risk, genetic risks accounted for a 2.7% increase, and immune metabolism was associated with a 1.1% increase. We developed an etiological model of IBD that elucidates the complex underlying mechanisms and highlights immune metabolism as the primary mediator in the emergence of IBD.