To our knowledge, this is the first MR study to investigate the causality between CRS and IBD, and we found CRS was significantly associated with an increased risk of UC, while IBD was associated with a decreased risk of CRS. Several studies have explored the link between CRS and IBD previously. A small single-center retrospective study from UChicago Medicine suggested that the diagnosis and duration of UC may be more associated with development of CRS, while CRS may be considered as an extraintestinal manifestation of IBD due to CRS precedes IBD in some patients[14]. Besides, Lin et al. found that patients with IBD history, especially UC, had an increased risk of subsequent development of CRS[16]. A 10-year-long retrospective cohort study by Lee et al. including 15,175 CRS patients and 30,350 controls to assess the subsequent incidence of IBD, shown that CRS was significantly related to the risk of UC(adjusted HR = 1.72, 95% CI = 1.26–2.36) after adjusting for sex, age, residence, income level, and comorbidities, but not CD, and more precisely, the subgroup analysis shown that CRS without nasal polyps was related to an increased incidence of UC(adjusted HR = 1.71, 95% CI = 1.24–2.35)[15]. However, not all observational studies have found a correlation between CRS and IBD[17, 28]. Regrettably, causality could not be addressed through the above studies. Rather, our MR study overcame these limitations.
The epithelial barrier integrity plays a critical role in maintaining homeostasis in the nose and paranasal sinuses[11]. There are multiple factors such as geographical, ethnic, environmental exposure, changed sinonasal microbiota, decreased mucociliary clearance, abnormal epithelial barrier and immune response are involved in the development of CRS[29], which leads to chronic inflammation in several pathways, like activating inflammatory cytokines, releasing exosome, dysregulating Vitamin D3 and so on[30–32]. Additionally, some reports suggested that S. aureus, a bacterium can secrete a variety of virulence factors such as superantigens, hemolysins, enterotoxins and so on, colonizes in the nasal cavity, may also have played a key role in the development of CRS[33]. Surprisingly, S. aureus superantigens deriving from sinuses may reach the gut via swallowing and impair the intestinal mucosal barrier to induce ulcerative colitis[13, 34]. On the other hand, there are not only in the nasal cavity[35], but in the gut existing microbiota dysbiosis in CRS patients, which may be caused by the treatment of CRS, especially antibiotic use[36], or by the lung-gut crosstalk, a certain pathophysiological correlation between the respiratory and gastrointestinal system[37]. These suggest a possible association between CRS and IBD.
In conclusion, our MR study revealed that CRS was associated with an increased risk of UC, and we suggested that clinicians should pay attention to the intestinal symptoms in CRS patients and a timely screening colonoscopy to detect early lesions. Additionally, our reverse MR analysis revealed that IBD was associated with a decreased risk of CRS, although the effect is mild as the OR is very close to 1, and the specific mechanism is not completely clear, which may be associated with microbiota dysbiosis. It had the following strengths in our study. Firstly, our study drawn a convincing causality between CRS and IBD by implementing MR analysis compared with conventional observational studies. Secondly, our study was limited to individuals of European ancestry for minimizing the population structure bias. Thirdly, there was no pleiotropy observed suggesting that the results were robust. However, there are also limitations. Firstly, the results of this study might not be appropriate to other ancestry besides European. Secondly, the large OR and CI were observed due to the limited sample size possibly. Therefore, in order to verify the accuracy of our results, future studies with larger sample GWAS datasets are needed.