Overall, our results render relatively strong evidence to support that, compared with healthy individuals, it is possible that having IBD could contribute to the occurrence and development of AN. And the same positive causal association might be found for UC and CD on risk of AN. Such robust evidence adds to the substantial research base that has previously identified association of IBD with AN and may inform public health messages.
Current research referring to the association between IBD and AN remains controversial [7, 8, 10, 17]. Therefore, we conducted a two-sample MR to further explore their causality, which indicated a significant causal effect of IBD on AN. A recently published MR study found that AN was associated with an increased risk of a subsequent diagnosis of IBD, whereas the reverse was not observed and there was no causal relationship between IBD and AN [10]. In contrast, by leveraging summary statistics with update and larger sample sizes, we yielded more reliable results with consistency observed using different methods and under a series of sensitivity analyses compared to previous research.
Both IBD[18] and AN[19] are relapsing and multifactorial diseases in which genetics, immunity and gut microbiota play important roles. Several studies have suggested that changes in dietary patterns and gastrointestinal symptoms in IBD patients may be predisposing factors for AN[4, 20]. IBD positively reinforces eating disorder behaviors in patients with comorbid anorexia nervosa, contributing to the worsening of the eating disorder and providing barriers to its treatment. Likewise, psychopathology examinations revealed significantly elevated levels of anxiety, depression, and eating disorder psychopathology in the AN patients compared with healthy controls[21]. Intestinal inflammation alters brain function, including effects on induced mood disorders and appetite. In addition, significant gut microbial dysbiosis was both observed in patients with IBD and AN[22, 23]. Dysregulation of the gut microbiota affects the body's energy balance and neurohormone production, possibly affecting the central nervous system through many interactions along the gut-brain axis[24, 25]. Molecularly, it has been suggested that pro-inflammatory cytokines have an effect on anorexic properties by signaling the regulation of appetite[9, 26]. The causality prompts clinical practitioners to remain vigilant of the clinical manifestations of AN in patients with IBD. Timely screening IBD patients for mental and dietary status is of concern for early detection and treatment of AN.
The strength of the present study is that we performed two-sample MR approach and confirm the first positive causal effect for IBD on AN. Compared to previous MR studies, we adopted an updated and larger sample size data set and conducted a series of sensitivity analyses. We did not find any heterogeneity and multiple effects affecting the results between IBD and AN, which effectively avoided the interference of false negatives, and underpin the accuracy of our results. However, some limitations and deficiency existed in our study. MR analysis was restricted primarily to populations of European ancestry, and our findings may not be generalizable in all ethnicities. In addition, the largest GWAS summary data of AN were utilized in our study, but the quantity of SNPs was still insufficient. Limited number of SNPs possibly explaining the inconsistency of leave-one-out plots for UC and CD on AN in our study. Further prospective studies with larger sample sizes are needed to provide more adequate statistical power to validate the causal association. Moreover, observational epidemiology studies had shown a higher prevalence of AN and IBD comorbidities in young women. However, the published summary data we used do not have detailed in age and sex stratification. A more precise stratification analysis of age and gender in disease requires larger sample sizes and detailed GWAS data.