Zhang Yuan, Huang Longbin, Yue Ningning, Mai Zhiliang, Kong Chen, Tian Chengmei, Wei Dao-Ru, Yao Jun, Wang Lisheng, Li Defeng
Department of Gastroenterology, Shenzhen People's Hospital (the Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People's Republic of China.
Department of Medical Administration, Huizhou Institute for Occupational Health, Huizhou, Guangdong, People's Republic of China.
J Inflamm Res. 2025 Jul 31;18:10313-10329. doi: 10.2147/JIR.S528072. eCollection 2025.
Although cytokines have been implicated in the development of ulcerative colitis (UC), the potential mediating role of metabolite levels in this association remains unclear.
Utilizing data from genome-wide association studies (GWAS) encompassing 91 circulating cytokines, 1400 blood metabolites, and 178,689 UC cases, we performed a two-sample Mendelian randomization (MR) analysis to investigate the effect of metabolites mediated cytokines on the development of UC. A two-step MR analysis was conducted to quantitatively evaluate the mediation effect. Additionally, dextran sodium sulfate (DSS)-induced colitis mice were used to further confirm our results.
Mendelian randomization (MR) analysis indicated that macrophage colony-stimulating factor (M-CSF) had a causal and positive relationship with aconitate (OR: 1.10, 95% CI: 1.00-1.20, p = 0.043, IVW beta 1 = 0.095). Moreover, MR analysis revealed that high level of aconitate were associated with reduced risk of UC (OR: 0.44, 95% CI: 0.24-0.80, p = 0.008, IVW beta 2 = -0.818). In addition, MR analysis showed M-CSF had an inverse correlation with the disease onset of UC (OR: 0.31, 95% CI: 0.15-0.80, p = 0.002, IVW beta all = -1.16). Furthermore, the mediation effect of aconitate mediated M-CSF on the risk of UC was -0.0777 (95% CI: -0.154 to -0.0018, p = 0.045), accounting for 6.69% of the total effect, and indicating a modest contribution to the protective effect of M-CSF against UC. Subsequently, as an in vivo validation model, DSS-induced colitis was employed to demonstrate that M-CSF treatment significantly ameliorated weight loss, disease activity index (DAI) scores, colon shortening, and histological damage. Additionally, M-CSF treatment also significantly reduced M1 macrophage infiltration, elevated levels of aconitate as well as itaconate, and decreased the levels of pro-inflammatory cytokines in colitis. These results demonstrated that aconitate inhibited the expression of pro-inflammatory cytokines through its enzymatic conversion into the immunometabolite itaconate by aconitate decarboxylase 1 (Acod1), and downregulated the levels of M1 macrophages, thereby ameliorating colitis.
These findings suggest that M-CSF is an important anti-inflammatory cytokine in UC, which may be a promising therapeutic target in the treatment of UC.
尽管细胞因子与溃疡性结肠炎（UC）的发病有关，但代谢物水平在这种关联中的潜在介导作用仍不清楚。
利用来自全基因组关联研究（GWAS）的数据，包括91种循环细胞因子、1400种血液代谢物和178,689例UC病例，我们进行了两样本孟德尔随机化（MR）分析，以研究代谢物介导的细胞因子对UC发病的影响。进行了两步MR分析以定量评估中介效应。此外，使用葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠进一步证实我们的结果。
孟德尔随机化（MR）分析表明，巨噬细胞集落刺激因子（M-CSF）与乌头酸呈因果正相关（OR：1.10，95%CI：1.00-1.20，p = 0.043，IVWβ1 = 0.095）。此外，MR分析显示，高水平的乌头酸与UC风险降低相关（OR：0.44，95%CI：0.24-0.80，p = 0.008，IVWβ2 = -0.818）。此外，MR分析显示M-CSF与UC的疾病发作呈负相关（OR：0.31，95%CI：0.15-0.80，p = 0.002，IVWβ全 = -1.16）。此外，乌头酸介导的M-CSF对UC风险的中介效应为-0.0777（95%CI：-0.154至-0.0018，p = 0.045），占总效应的6.69%，表明对M-CSF对UC的保护作用有适度贡献。随后，作为体内验证模型，采用DSS诱导的结肠炎来证明M-CSF治疗显著改善了体重减轻、疾病活动指数（DAI）评分、结肠缩短和组织学损伤。此外，M-CSF治疗还显著减少了M1巨噬细胞浸润，提高了乌头酸以及衣康酸的水平，并降低了结肠炎中促炎细胞因子的水平。这些结果表明，乌头酸通过其被乌头酸脱羧酶1（Acod1）酶促转化为免疫代谢物衣康酸来抑制促炎细胞因子的表达，并下调M1巨噬细胞的水平，从而改善结肠炎。
这些发现表明，M-CSF是UC中的一种重要抗炎细胞因子，可能是治疗UC的一个有前景的治疗靶点。
