IDDF2023-ABS-0105 Causal relationships between immunological proteins and common intestinal diseases: a bidirectional two-sample mendelian randomization study

Background

Disrupted intestinal homeostasis plays a vital role in the pathogenesis of irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and colorectal cancer (CRC). Dysregulated immunobiology contributes to intestinal homeostasis disorder. However, it is not clear whether there is a clear causal association between immunological proteins and the aforementioned intestinal diseases.

Methods

The bidirectional two-sample Mendelian randomization (MR) analysis was utilized to examine the bidirectional causality between 62 representative immunological proteins and interested intestinal diseases, including IBS, IBD, and CRC. Crohn’s disease (CD) and ulcerative colitis (UC), subtypes of IBD, were also examined.

Results

Genetically predisposed interleukin (IL)-1β level was associated with the decreased risk of IBS (odds ratio [OR] = 0.783, 95% CI: 0.676–0.908, P = 0.001), and genetic predisposition to IBS was related to the decreased levels of IL-11(β = −0.196, 95% CI: −0.335 to −0.057, P = 0.006) and IL-25 (β = −0.233, 95% CI: −0.372 to −0.094, P = 0.001). Genetic predisposition to IBD was correlated with elevated levels of IL-6 (β = 0.046, 95% CI: 0.022–0.069, P = 1.68E-04). In addition, IL-1 receptor antagonist (IL-1Ra) (OR = 0.871, 95% CI: 0.631–0.960, P = 0.005) and IL-37 (OR = 1.170, 95% CI: 1.051–1.303, P = 0.004) were associated with the decreased and increased risk of CD, respectively. UC was correlated with the increased IL-1α (β = 0.074, 95% CI: 0.022–0.125, P = 0.005). Moreover, our results indicated that genetically predisposed tumor necrosis factor (TNF)-α level was associated with an increased risk of CRC (OR = 1.252, 95% CI: 1.102–1.423, P = 0.001), and genetic predisposition to CRC was related to the increased levels of IL-37 (β = 0.128, 95% CI: 0.029–0.227, P = 0.012).

Conclusions

Our study provided markable evidence for the causality between immunological proteins and intestinal diseases (IBS, IBD, and CRC), which would pave the way for developing novel immunomodulation therapies for intestinal diseases. Further exploration of the underlying mechanisms remains a research priority for us in the future.