Background Metabolic disorders exhibit strong inflammatory underpinnings and vice versa. This study aimed to investigate the association between metabolic health status, genetic predisposition, and the risk of inflammatory bowel disease (IBD), and to explore the potential benefits of maintaining ideal metabolic status for individuals with a predetermined genetic risk of IBD. Method This population-based prospective study included 385,820 unrelated European descent participants from the UK Biobank. Using multivariable Cox regression, we assessed the relationship of metabolic phenotypes with risk of IBD and its subtypes. We also developed a polygenic risk score to examine how metabolic health status interacted with genetic risk in relation to IBD risk. Results During the follow-up period of 4,328,895 person-years, 2,044 newly-diagnosed IBD cases were identified. Higher genetic risk and an increasing number of abnormal metabolic phenotypes were associated with elevated IBD risk (p-trend <0.001). Individuals with high genetic risk and poor metabolic health had a significantly higher risk of IBD (HR=4.56, 95 % CI=3.27–6.36) compared to those with low genetic risk and ideal metabolic health. These results remained consistent for IBD subtypes. Maintaining ideal metabolic status reduced IBD risk within each genetic risk category and jointly decreased subsequent risk by 40 % in high genetic risk individuals. Conclusion Our study reveals a combined impact of poor metabolic health and genetic risk on IBD incidence. Those with low genetic risk and optimal metabolic health exhibit the lowest IBD risk, offering insights into potential management strategies for individuals at predefined genetic risk.

Background: Metabolic syndrome has been linked to an increased risk of colorectal cancer (CRC) incidence and mortality, but whether adopting a healthy lifestyle could attenuate the risk of CRC conferred by metabolic syndrome remains unclear. The aim of the study is to investigate the individual and joint effects of modifiable healthy lifestyle and metabolic health status on CRC incidence and mortality in the UK population. Methods: This prospective study included 328,236 individuals from the UK Biobank. An overall metabolic health status was assessed at baseline and categorized based on the presence or absence of metabolic syndrome. We estimated the association of the healthy lifestyle score (derived from 4 modifiable behaviors: smoking, alcohol consumption, diet, physical activity and categorized into "favorable," "intermediate", and "unfavorable") with CRC incidence and mortality, stratified by metabolic health status. Results: During a median follow-up of 12.5 years, 3,852 CRC incidences and 1,076 deaths from CRC were newly identified. The risk of incident CRC and its mortality increased with the number of abnormal metabolic factors and decreased with healthy lifestyle score (P trend = 0.000). MetS was associated with greater CRC incidence (HR = 1.24, 95% CI: 1.16 - 1.33) and mortality (HR = 1.24, 95% CI: 1.08 - 1.41) when compared with those without MetS. An unfavorable lifestyle was associated with an increased risk (HR = 1.25, 95% CI: 1.15 - 1.36) and mortality (HR = 1.36, 95% CI: 1.16 - 1.59) of CRC across all metabolic health status. Participants adopting an unfavorable lifestyle with MetS had a higher risk (HR = 1.56, 95% CI: 1.38 - 1.76) and mortality (HR = 1.75, 95% CI: 1.40 - 2.20) than those adopting a favorable healthy lifestyle without MetS. Conclusion: This study indicated that adherence to a healthy lifestyle could substantially reduce the burden of CRC regardless of the metabolic status. Behavioral lifestyle changes should be encouraged for CRC prevention even in participants with MetS.