Xiao Sinan, Su Kairong, Gao Hongliang, Qiao Chenyang, Sha Sumei, Liu Xin, Shi Haitao
Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
The Second Department of Gastroenterology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China.
Mediators Inflamm. 2025 Jul 28;2025:1675577. doi: 10.1155/mi/1675577. eCollection 2025.
Beyond intestinal inflammation, inflammatory bowel disease (IBD) is associated with many extraintestinal manifestations, particularly arthritis. However, systematic evidence regarding causal relationships between IBD and clinically prevalent arthritis subtypes remains limited. We conducted bidirectional two-sample Mendelian randomization (MR) analyses to assess causal associations between IBD (Crohn's disease [CD], ulcerative colitis [UC]) and seven arthritis subtypes: rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), osteoarthritis (OA), reactive arthritis (ReA), gout and pyogenic arthritis (PA). A two-step MR (TSMR) analyses was subsequently performed to evaluate potential mediators across four domains: metabolites of gut microbiota, serum biochemical indicators, inflammatory/immune factors, and nutritional/metabolic indicators in IBD-AS/PsA/ReA pathways. MR analysis revealed that IBD increased the risk of AS (OR = 1.21, 95% CI: 1.11-1.32, < 0.001), PsA (OR = 1.18, 95% CI: 1.05-1.33, = 0.007), and ReA (OR = 1.11, 95% CI: 1.04-1.18, = 0.003). Subgroup analyses revealed CD increased the risk of AS (OR = 1.16, 95% CI: 1.07-1.27, < 0.001) and UC increased the risk of ReA (OR = 1.14, 95% CI: 1.04-1.24, = 0.005). The first step of the mediation MR showed that IBD was associated with increased butyrate levels, decreased serotonin levels, increased C-reactive protein (CRP), increased interleukin-6 (IL-6), increased percentage of neutrophils, decreased percentage of lymphocytes, and decreased total body bone mineral density, but the second step of the analysis revealed no significant evidence that the above factors were mediators of the causal effects of IBD on AS, PsA, and ReA. This study establishes the causal effect of IBD on AS, PsA, and ReA. The absence of significant mediation effects suggests that IBD-associated gut dysbiosis, systemic inflammation, and calcium metabolic disturbances may not directly drive arthritis pathogenesis, challenging their utility as predictive biomarkers for arthritis development in IBD patients.
除肠道炎症外，炎症性肠病（IBD）还与许多肠外表现相关，尤其是关节炎。然而，关于IBD与临床常见关节炎亚型之间因果关系的系统性证据仍然有限。我们进行了双向两样本孟德尔随机化（MR）分析，以评估IBD（克罗恩病[CD]、溃疡性结肠炎[UC]）与七种关节炎亚型之间的因果关联：类风湿关节炎（RA）、强直性脊柱炎（AS）、银屑病关节炎（PsA）、骨关节炎（OA）、反应性关节炎（ReA）、痛风和化脓性关节炎（PA）。随后进行了两步MR（TSMR）分析，以评估IBD-AS/PsA/ReA通路中四个领域的潜在介导因素：肠道微生物群代谢物、血清生化指标、炎症/免疫因子以及营养/代谢指标。MR分析显示，IBD增加了患AS（比值比[OR]=1.21，95%置信区间[CI]：1.11-1.32，P<0.001）、PsA（OR=1.18，95%CI：1.05-1.33，P=0.007）和ReA（OR=1.11，95%CI：1.04-1.18，P=0.003）的风险。亚组分析显示，CD增加了患AS的风险（OR=1.16，95%CI：1.07-1.27，P<0.001），UC增加了患ReA的风险（OR=1.14，95%CI：1.04-1.24，P=0.005）。中介MR的第一步显示，IBD与丁酸盐水平升高、血清素水平降低、C反应蛋白（CRP）升高、白细胞介素-6（IL-6）升高、中性粒细胞百分比升高、淋巴细胞百分比降低以及全身骨密度降低有关，但分析的第二步没有发现显著证据表明上述因素是IBD对AS、PsA和ReA因果效应的介导因素。本研究确立了IBD对AS、PsA和ReA的因果效应。缺乏显著的中介效应表明，IBD相关的肠道生态失调、全身炎症和钙代谢紊乱可能不会直接驱动关节炎的发病机制，这对它们作为IBD患者关节炎发展预测生物标志物的效用提出了挑战。
