In the current research, bidirectional MR analysis was conducted on genome-wide association summary data to evaluate the causal relationships between systemic inflammation regulators and IBD and its subtypes. This analytical approach enabled the distinction of upstream and downstream links in the disease chain, and no bidirectional causal relationships were found. To minimize pleiotropic effects, MR-Egger and MRPRESSO were utilized to evaluate the reliability of the MR analysis.
Regarding MIF, a retrospective analysis of 42 individuals with IBD (18 UC, 24 CD) revealed significantly higher serum levels of MIF in the IBD group relative to the control group(14). In an animal experiment(15), the severity of DSS-induced colitis was considerably elevated in MIF transgenic mice relative to wild-type mice. MIF mRNA and protein levels in the colonic mucosa and serum of mice were significantly upregulated. The elevated levels of MIF in IBD patients may promote the localization of macrophages in the intestinal mucosa, resulting in the generation of inflammatory factors, including TNFα, IFN-γ, and IL-1β, within the intestinal mucosa. It has been demonstrated that MIF gene mutations are associated with various autoimmune diseases, such as rheumatoid arthritis(16), glomerulonephritis(17), and chronic colitis(18, 19). A meta-analysis involving 2084 IBD patients and 2288 controls in an Asian population found that the MIF-173 G/C polymorphism is a risk factor for IBD(20). These findings imply the significance of MIF in the development of IBD, and the exacerbating effect of MIF in IBD patients aligns with the findings of this study.
Additionally, IL-13 is an anti-inflammatory cytokine implicated in several physiological and pathological processes, including cell proliferation, apoptosis, inflammation, and immune responses. It has been linked with multiple inflammatory diseases such as asthma(21), atopic dermatitis(14), and IBD(22). Studies have reported notably elevated levels of IL-13 in individuals with IBD and its subtype CD(23) and UC relative to the control group. As a vital Th2 cytokine, IL-13 participates in multiple immune reactions and tissue repair processes. IL-13 can inhibit the differentiation and function of Treg cells, reduce intestinal mucosal tolerance, promote Th17 immune response, and increase levels of pro-inflammatory factors, including IL-17 and IL-22(24). IL-13 can also stimulate B cell differentiation into IgE-producing plasma cells, induce infiltration and activation of mast cells and eosinophils, enhance Th2 immune response, and exacerbate fibrosis and damage to intestinal tissues(25, 26). Animal experiments have shown that blocking IL-13 can reduce intestinal inflammation and fibrosis in colitis mice. Therefore, findings of this study are consistent with previous studies suggesting that higher levels of IL-13 may be involved in the pathogenesis of IBD. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), belonging to the TNF superfamily, triggers apoptosis of self-reactive T cells and other inflammatory cells in various transformed cell lines(27).
Prior research indicated that TRAIL induces apoptosis in human intestinal epithelial cells under inflammatory conditions but not under normal non-inflammatory conditions. This finding suggests the potential involvement of TRAIL in the pathogenesis of intestinal inflammation(28). Furthermore, mice with TRAIL-R knockout (KO) displayed an increased incidence of dextran sodium sulfate (DSS)-induced colitis, suggesting the potential involvement of the TRAIL/TRAIL-R pathway in regulating autoimmune colitis(29). Accumulating evidence from various animal models of autoimmune diseases, including rheumatoid arthritis and experimental autoimmune encephalomyelitis (EAE), suggests that blocking or deficiency of TRAIL enhances disease activity and increases joint inflammation(30, 31). Recent studies have further demonstrated that administration of TRAIL effectively inhibits autoimmune inflammation through apoptosis-independent pathways(32), activation of Escherichia coli-associated T cell pathways(33), and activation of colon T cell pathways(33). All these outcomes imply a novel immune regulatory role of TRAIL in autoimmune diseases, aligning with the results of this research.
The reverse MR findings of this study support the influence of IBD and its subtypes on multiple levels of inflammatory factors. CXCL9 and CXCL12, both members of the chemokine family, play important roles in inflammation, angiogenesis, hematopoiesis, and embryonic development. They do so by affecting the activation and/or migration of leukocytes, endothelial cells, hematopoietic progenitor cells, and stem cells(34). Elevated expressions of CXCL9 and CXCL12 have been observed in various autoimmune diseases, including IBD, rheumatoid arthritis(35), Behcet's disease(36), and multiple sclerosis(37). These elevated expressions are positively correlated with disease activity and/or severity, which support the findings of the study. IL-10, as an anti-inflammatory cytokine, regulates inflammatory response in various diseases, including multiple sclerosis, systemic lupus erythematosus, and IBD(38, 39). Elevated IL-10 mRNA expression has been observed in active IBD and UC patients(6), suggesting that IL-10 is a crucial regulatory component in controlling IBD inflammation(40). Prior research has identified heightened expression of stem cell factor (SCF) in inflamed intestinal mucosal tissue. An animal experiment demonstrated that stem cell factors alone could improve intestinal mucosal regeneration after indomethacin-induced injury(41). This indicates the potential promotion of intestinal repair and healing in the intestine of IBD patients through the upregulation of SCF and IL-10. Tumor necrosis factor (TNF) is critically involved in the process of IBD, including cell apoptosis, fibrosis, and immune cell migration. TNF is categorized into two subtypes, TNF-α and TNF-β. TNF-α is involved in the deterioration of IBD, as significantly elevated levels of TNF-α have been observed in individuals with IBD relative to healthy controls. The TNF-α antibody infliximab has been clinically proven to be effective in IBD patients(42, 43). TNF-β triggers the activation of multiple signaling pathways, such as NF-κB and MAPK, which promote inflammatory response, cell survival, and angiogenesis(44). However, there is limited literature regarding the association of TNF-β with CD. The evidence of this research shows reduced circulating levels of TNF-β in CD patients, but further research is necessary to fully understand the potential molecular pathways.
This study has several strengths. Firstly, the robustness of the genetic instrumental variables facilitated a comprehensive MR analysis for the first time, examining the association between inflammatory factors and the risk of IBD. The function of inflammatory factors in the occurrence and development of IBD is intricate and potentially interactive. However, MR analysis effectively isolated the correlation between IBD and inflammatory factors solely from a genetic perspective, eliminating the influence of their interactions. This innovative approach holds substantial significance in discerning whether genetic susceptibility to IBD induces changes in circulating inflammatory factors and whether the levels of inflammatory factors impact the risk of IBD. The study utilized a less stringent threshold (5 x 10− 6) instead of the common standard (5 x 10− 8) for genome-wide significance P-value to explore low-frequency variants in the European population. This allowed for the investigation of more potential associations and an expanded understanding of genetic influences on the studied traits.
Furthermore, the GWAS summary data only included individuals of European ancestry, implying that the results may not fully represent the entire population. Therefore, caution should be exercised when applying these findings to racially and ethnically diverse populations.