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儿童溃疡性结肠炎手术治疗的预测标志物分析

  • 黄柳芳 ,
  • 吴博 ,
  • 王莹
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  • 上海交通大学医学院附属新华医院儿消化营养科 上海市儿科医学研究所 上海市小儿消化与营养重点实验室(上海 200092)
*具有同等贡献
王莹 电子信箱:wangying_ssmu@126.com

收稿日期: 2024-01-23

  录用日期: 2024-07-01

  网络出版日期: 2025-02-12

基金资助

国家自然科学基金资助项目(82370525);上海市“科技创新行动计划”医学创新研究专项项目(22Y31900600);上海市自然科学基金资助项目(22ZR1441100);上海市“医苑新星”杰出青年医学人才项目(20234Z0004)

An analysis of predictive markers for surgical treatment of ulcerative colitis in children

  • HUANG Liufang ,
  • WU Bo ,
  • WANG Ying
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  • Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University;Shanghai Institute of Pediatric Research;Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai 200092, China

Received date: 2024-01-23

  Accepted date: 2024-07-01

  Online published: 2025-02-12

摘要

目的 分析铁死亡相关基因对溃疡性结肠炎(UC)患儿手术治疗风险的预测价值。方法 选取GEO数据库数据集GSE150961中331例UC患儿为研究对象,在诊断性结肠镜检查时获取病变直肠组织标本,诊断后随访1年,其中21例患儿进展到施行结肠切除术治疗,作为手术组;310例患儿为非手术组。筛选在两组患儿诊断时获得的病变直肠组织中差异表达的铁死亡相关基因,研究其对UC手术治疗风险的预测价值,以及与免疫细胞浸润、炎症因子、肠道上皮屏障功能相关基因表达的相关性。结果 非手术组310例,男158例,女152例,平均年龄(12.9±3.2)岁;手术组21例,男12例,女9例,平均年龄(13.6±2.7)岁。筛选出在两组患儿病变直肠组织中差异表达的铁死亡相关基因2个,包括溶质载体家族7成员5(SLC7A5)和Bcl2/腺病毒E1B相互作用蛋白3(BNIP3)。与非手术组相比,手术组病变直肠组织中SLC7A5BNIP3表达水平明显升高(P均<0.001)。多因素logistic回归分析表明SLC7A5BNIP3为UC患儿进展为手术治疗的危险因素(P均<0.01)。受试者工作特征曲线(ROC)结果显示,SLC7A5BNIP3预测UC患儿手术治疗的曲线下面积(AUC)为0.938和0.867,SLC7A5BNIP3联合预测的AUC为0.949(P均<0.05)。相关性分析结果表明,SLC7A5BNIP3表达水平与记忆B细胞、巨噬细胞M0、中性粒细胞比例呈正相关(r=0.14~0.47,P均<0.05),与初始B细胞、静息CD4+记忆T细胞、调节性T细胞、巨噬细胞M2比例呈负相关(r=-0.13~-0.35,P均<0.05),与炎症因子CXCL1CXCL8TNFIL1BTLR2NLRP3IL23A表达水平呈显著正相关(r=0.12~0.53,P均<0.05),与肠道上皮屏障功能相关基因OCLNTJP1TJP2DSG2CDH1MARVELD2水平呈负相关(r=-0.13~-0.42,P均<0.05)。结论 铁死亡相关基因SLC7A5BNIP3在手术治疗的UC患儿诊断时获取的病变直肠组织中表达水平升高,是UC患儿手术治疗的风险因素和预测因子。

本文引用格式

黄柳芳 , 吴博 , 王莹 . 儿童溃疡性结肠炎手术治疗的预测标志物分析[J]. 临床儿科杂志, 2025 , 43(2) : 120 -127 . DOI: 10.12372/jcp.2025.24e0051

Abstract

Objective To analyze the predictive value of ferroptosis-related genes for the surgical treatment risk of children with ulcerative colitis (UC). Methods A total of 331 children with UC were selected from the GSE150961 dataset in the GEO database as the research subject. The rectal biopsy specimens were obtained from UC children during diagnostic colonoscopy, and the children followed up for 1 year after diagnosis. Among them, 21 children progressed to colectomy treatment and served as the surgical group, while 310 children served as the non-surgical group. The differentially expressed ferroptosis-related genes in the rectal tissues of the two groups of children were screened out, and their predictive values for the risk of surgical treatment were investigated. Their correlations with immune cell infiltration, inflammatory factors, and genes related to intestinal epithelial barrier function were examined. Results The non-surgical group consisted of 310 cases, including 158 males and 152 females, with an average age of 12.9±3.2 years; the surgical group consisted of 21 cases, including 12 males and 9 females, with an average age of 13.6±2.7 years. Two genes, solute carrier family 7 member 5 (SLC7A5) and Bcl2/adenovirus E1B interacting protein 3 (BNIP3), were screened out as differentially expressed ferroptosis-related genes in the rectal tissues of the two groups of children. Compared with the non-surgical group, the expression levels of SLC7A5 and BNIP3 in the rectal tissues of the surgical group were significantly increased (P<0.001). The results of multivariate Logistic regression analysis showed that SLC7A5 and BNIP3 were risk factors for the progression of UC children to require colectomy treatment (P<0.01). The results of the receiver operating characteristic (ROC) curve showed that the areas under the curve (AUC) of SLC7A5 and BNIP3 in predicting colectomy treatment of children with UC were 0.938 and 0.867, respectively, the AUC of the combined prediction of SLC7A5 and BNIP3 was 0.949 (P<0.05). The results of correlation analysis showed that the levels of SLC7A5 and BNIP3 were positively correlated with the proportions of memory B cells, macrophage M0, and neutrophils (r=0.14-0.47, P<0.05), and negatively correlated with the proportions of naive B cells, resting CD4+ memory T cells, regulatory T cells, and macrophage M2 (r=-0.13 to -0.35, P<0.05), and were significantly positively correlated with the expression levels of inflammatory factors CXCL1, CXCL8, TNF, IL1B, TLR2, NLRP3, and IL23A (r=0.12-0.53, P<0.05), and negatively correlated with the levels of genes related to intestinal epithelial barrier function OCLN, TJP1, TJP2, DSG2, CDH1, and MARVELD2 (r=-0.13 to -0.42, P<0.05). Conclusions The expression levels of ferroptosis-related genes SLC7A5 and BNIP3 were increased in the rectal tissues obtained at diagnosis of children with UC requiring colectomy treatment, and they were both risk factors and predictors for colectomy treatment of children with UC.

参考文献

[1] Godala M, Gaszyńska E, Zatorski H, et al. Dietary interventions in inflammatory bowel disease[J]. Nutrients, 2022, 14(20): 4261.
[2] 王恩会, 韩丽娜, 孙梅. 儿童炎症性肠病治疗现状和进展[J]. 国际儿科学杂志, 2017, (4): 241-244.
  Wang EH, Han LN, Sun M. Current status and progress of the pediatric inflammatory bowel disease treatment[J]. Guoji Erkexue Zazhi, 2017, (4): 241-244.
[3] 中华医学会儿科学分会消化学组, 中华医学会儿科学分会临床营养学组. 儿童炎症性肠病诊断和治疗专家共识[J]. 中华儿科杂志, 2019, (7): 501-507.
  Subspecialty Group of Gastroenterology, the Society of Pediatrics, Chinese Medical Association; Subspecialty Group of Clinical Nutrition, the Society of Pediatrics, Chinese Medical Association. Expert consensus on the diagnosis and management of pediatric inflammatory bowel disease[J]. Zhonghua Erke Zazhi, 2019, (7): 501-517.
[4] 郭世博. 儿童溃疡性结肠炎临床特征分析及信号调节蛋白α在其进展中的作用研究[D]. 中国人民解放军空军军医大学, 2022.
  Guo SB. Clinical characteristics of ulcerative colitis in children and the role of signal-regulating protein α in its progression[D]. Air Force Medical University, 2022.
[5] Nakase H, Sato N, Mizuno N, et al. The influence of cytokines on the complex pathology of ulcerative colitis[J]. Autoimmun Rev, 2022, 21(3): 103017.
[6] Turner D, Ruemmele FM, Orlanski-Meyer E, et al. Management of paediatric ulcerative colitis, part 1: ambulatory care-an evidence-based guideline from European Crohn's and Colitis Organization and European Society of Paediatric Gastroenterology, Hepatology and Nutrition[J]. J Pediatr Gastroenterol Nutr, 2018, 67(2): 257-291.
[7] Phillips MR, Brenner E, Purcell LN, et al. Pediatric inflammatory bowel disease for general surgeons[J]. Surg Clin North Am, 2022, 102(5): 913-927.
[8] Adamina M, Gerasimidis K, Sigall-Boneh R, et al. Perioperative dietary therapy in inflammatory bowel disease[J]. J Crohns Colitis, 2020, 14(4): 431-444.
[9] Stockwell BR, Friedmann Angeli JP, Bayir H, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease[J]. Cell, 2017, 171(2): 273-285.
[10] Wang S, Liu W, Wang J, et al. Curculigoside inhibits ferroptosis in ulcerative colitis through the induction of GPX4[J]. Life Sci, 2020, 259: 118356.
[11] 龚卓之, 曹增, 姚梦茜, 等. 从铁死亡探讨溃疡性结肠炎不同时期的发病机制及相关天然药物筛选[J]. 中草药, 2023, 54(7): 2187-2196.
  Gong ZZ, Cao Z, Yao MX, et al. Discussion on pathogenesis of ulcerative colitis at different stages from ferroptosis and screening of related natural drug[J]. Zhongcaoyao, 2023, 54 (7): 2187-2196.
[12] Hyams JS, Davis S, Mack DR, et al. Factors associated with early outcomes following standardised therapy in children with ulcerative colitis (PROTECT): a multicentre inception cohort study[J]. Lancet Gastroenterol Hepatol, 2017, 2(12): 855-868.
[13] Mo A, Nagpal S, Gettler K, et al. Stratification of risk of progression to colectomy in ulcerative colitis via measured and predicted gene expression[J]. Am J Hum Genet, 2021, 108(9): 1765-1779.
[14] Shen W, Song Z, Zhong X, et al. Sangerbox: a comprehensive, interaction-friendly clinical bioinformatics analysis platform[J]. iMeta, 2022, 1(3): e36.
[15] Lin Z, Xu Y, Guan L, et al. Seven ferroptosis-specific expressed genes are considered as potential biomarkers for the diagnosis and treatment of cigarette smoke-induced chronic obstructive pulmonary disease[J]. Ann Transl Med, 2022, 10(6): 331.
[16] Oliveira SB, Monteiro IM. Diagnosis and management of inflammatory bowel disease in children[J]. BMJ, 2017, 357: j2083.
[17] Haberman Y, Karns R, Dexheimer PJ, et al. Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response[J]. Nat Commun, 2019, 10(1): 38.
[18] Li Q, Liu H, Jin Y, et al. Analysis of a new therapeutic target and construction of a prognostic model for breast cancer based on ferroptosis genes[J]. Comput Biol Med, 2023, 165: 107370.
[19] Field JT, Gordon JW. BNIP3 and Nix: atypical regulators of cell fate[J]. Biochim Biophys Acta Mol Cell Res, 2022, 1869(10): 119325.
[20] 伍晓涵, 刘占举. 溃疡性结肠炎最新发病机制的认识[J]. 中国中西医结合消化杂志, 2023, 31(04): 237-42.
  Wu XH, Liu ZJ. Recent advances in the pathogenesis of ulcerative colitis[J]. Zhongguo Zhongxiyi Jiehe Xiaohua Zazhi, 2023, 31 (4): 237-242.
[21] 余飞浩, 吴甜甜, 栾思宇, 等. 苦参素干预AKT/mTOR通路调节记忆性B细胞治疗溃疡性结肠炎作用机制研究[J]. 时珍国医国药, 2023, 34(3): 537-541.
  Yu FH, Wu TT, Luan SY, et al. Study on the mechanism of matrine interfering with AKT/mTOR pathway to regulate memory B cells in the treatment of ulcerative colitis[J]. Shizhen Guoyi Guoyao, 2023, 34 (03): 537-541.
[22] 颜湘冀, 张玉洁, 张明真. 中性粒细胞在溃疡性结肠炎中的作用机制及靶向治疗策略[J]. 右江医学, 2021, 49(2): 87-91.
  Yan XJ, Zhang YJ, Zhang MZ. Mechanism of action and targeted therapy strategy of neutrophils in ulcerative colitis[J]. Youjiang Yixue, 2021, 49 (2): 87-91.
[23] Guan Q. A comprehensive review and update on the pathogenesis of inflammatory bowel disease[J]. J Immunol Res, 2019, 2019: 1-16.
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