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Abstract
Abstract Background The association between night shift work and the risk of inflammatory bowel disease (IBD) remains unclear. We aim to investigate the association between night shift work and the risk of IBD, ulcerative colitis (UC), and Crohn’s disease (CD), while further investigating the roles of genetic susceptibility and circulating proteins. Methods This cohort study included 149,014 UK Biobank participants without IBD at baseline, with 28,772 undergoing proteomic detection. Cox regression assessed associations between night shift work, circulating proteins, and IBD risk, while multinomial logistic regression identified proteins linked to night shift work. Bulk RNA-seq (1,030 blood, 453 intestinal tissue, and 176 Ustekinumab-treated intestinal samples) and single-cell transcriptomics (51 samples, 163,336 cells) were integrated to explore the roles of night shift-related proteins in IBD development and progression. Results During a mean follow-up of 13.66 years, 818 incident IBD (556 UC and 262 CD) cases were documented. Compared to day workers, there was a significant increasing trend in the frequency of current shift work and the risk of incident IBD (Ptrend=0.018). Among individuals with usual or permanent night shifts work, the risk of IBD incidence increased by 56% compared to those with no shift work, with a hazard ratio (HR) of 1.56 (95% CI: 1.15-2.13), especially for in those with intermediate genetic susceptibility to IBD. Additionally, there was a significant increasing trend in the frequency of current shift work and the risk of incident UC (Ptrend=0.037). High genetic risk individuals with usual or permanent night shifts work were respectively associated with a 3.60-fold increase in the risk of IBD, a 3.13-fold increase in the risk of CD, and a 2.77-fold increase in the risk of UC. Compared with shift workers never working nights, participants with an average frequency of more than 8 nights per month of night shift work exposure possessed higher IBD risk (HR 1.54, 95%Cl: 1.07-2.23). Six circulating proteins (IL18R1, GDNF, SOD1, TNFRSF6B, MMP12, and CCL7) related to night shift work were associated with the risk of incident IBD. Multi-omics evidence indicated that MMP12 increased UC risk through macrophage function and reduces the efficacy of Ustekinumab, while CCL7+ monocytes, possibly in conjunction with ACKR1, may facilitate the initiation of inflammation in CD. Conclusion Night shift work has been associated with an increased risk of IBD, CD, and UC, with MMP12 and CCL7 identified as potential drivers of this association. Further research is needed to assess whether reducing night shift frequency and duration, combined with targeted protein interventions, could mitigate IBD risk and improve prognosis.
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