IBD is characterized by inflammation caused by excessive host immune response and mucosal barrier disruption [15]. The gut harbors a substantial community of commensal microorganisms. Most of these bacteria are beneficial and contribute to food metabolism, immune response, and elimination of pathogens [16]. However, some bacteria can promote pathological changes and disease development in specific environmental or genetic conditions [16]. Several defense mechanisms of the gut defend against IBD-induced intestinal inflammation. The pancreas also exerts a significant role in fighting intestinal inflammation. The pancreas performs digestive and endocrine functions. The pancreas secretes secretory phospholipase A2, pancreatic lipase, and glycoprotein 2 to protect the gut and maintain the flora through bacterial lysis [17]. Conversely, the gut can influence pancreatic endocrine function through vasoactive intestinal peptides such as secretin, glucagon-releasing peptide, and growth inhibitor [18].
Dysbiosis of the intestinal flora due to IBD can affect pancreatic function and increase the venture of pancreatic disease. Previous studies showed that IBD patients have a higher risk of pancreatitis [19], pancreatic cancer [20], and type II diabetes [21]. In addition, intestinal bacteria can be transferred to the pancreas under pathologic conditions [22]. Increased intestinal microorganisms and weakened epithelial barrier function in IBD can cause or exacerbate pancreatitis and even contribute to acute necrotizing pancreatitis [23]. Various proteases released by the pancreas can maintain gut homeostasis. Neurons activated by gut microbes also regulate pancreatic function. Intestinal disruption is critical for the development of pancreatitis. IBD can contribute to irreversible intestinal dysfunction and exacerbate the risk of pancreatitis. AP is a rare extra-intestinal manifestation (EIM) in patients with IBD; however, its incidence is higher in IBD patients. A study of 11,909 patients with IBD and 47,636 patients without IBD showed that the overall incidence of AP was 3.56 folds higher in the IBD cohort than in the control cohort. After adjustment for multiple Influencing factors, the adjusted hazard ratio in the IBD cohort was 2.93-fold higher [24].
AP is one of the most prevalent pancreatic disorders in IBD [25]. The causes of AP in IBD patients include medications and biliary lithiasis. Some APs caused by pathogenesis similar to IBD or systemic inflammation are also recognized as extra-intestinal manifestations of IBD [26]. IBD and its two subtypes contribute to the risk of AP. In one study, 70 percent of EIMs occurred after the diagnosis of IBD, and very few EIMs occurred before the diagnosis [27]. A retrospective study of 3,960 patients with IBD showed that only 0.3% had AP before being diagnosed with IBD [28]. A case report showed that presymptomatic CD was diagnosed in a 16-year-old child patient just after the onset of idiopathic acute pancreatitis, which was likely an EIM of CD [29]. Autoimmune pancreatitis is classified as type 1 or type 2 in adults, whereas pediatric autoimmune pancreatitis (AIP) shows similar features to type II AIP in adults. Approximately 30% of AIP is related to IBD or other autoimmune diseases. However, there is a lack of AIP-related genome-wide association data, and we did not validate it. A study found that 56% of CD patients developed CP [30]. An autopsy study found that 53% of 86 UC patients had chronic interstitial pancreatitis [31].
Myosin IXB mediates tight junction assembly and actin filament remodeling to regulate mucosal barrier function [32]; its gene is strongly related to intestinal permeability impairment and IBD [32–34]. Several subtypes are associated with UC, CD, and pancreatitis, predicting a solid association and similar mechanisms between IBD and pancreatitis [35]. Recent studies found an immune imbalance in both pancreatitis and IBD, as evidenced by abnormally elevated IL-1β, IL-6, and IL-10, which may contribute to the elevated risk of pancreatitis in IBD patients [36]. MUC1 is a transmembrane glycoprotein usually low-expressed on pancreatic ductal epithelia and over-expressed on colonic epithelium. MUC1-specific T cells in IBD mice migrated toward the colon and pancreas, increasing MUC1 expression in the pancreatic ductal epithelium. This result suggests that IBD can promote pancreatitis development through MUC1 in mice [37].
IBD and pancreatitis are diseases with diversified pathogenesis. Genetic diversity may be central to identify the genetic relationships among species. A clinical study revealed an association between IBD and pancreatitis; however, the findings may be affected by sample size and residual confounding [38]. Moreover, the underlying genetic risk remains unexplained. Therefore, further studies are needed to uncover biological evidence of how IBD influences pancreatitis risk. Our study first verified the causal relationship between IBD and pancreatitis using an MR method. We found that IBD raises the risk of AP and CP. CD was causally related to AP and CP. UC had a causal relationship with AP and AAP. Moreover, all sensitivity analyses predicted no heterogeneity and horizontal pleiotropy, minimizing bias. Importantly, our study provides a theoretical foundation for preventing and treating pancreatitis in IBD patients.
Our study has some limitations. First, there are no genome-wide association data for pancreatitis in Asian populations and other ethnic groups; we found a causal relationship between IBD and pancreatitis only in a European population. Second, we used genome-wide association study summary data, which may influence quality assurance and selectivity criteria heterogeneity.