原发性肝癌患者肠道菌群特征及血清TBA、GRP78、MPO对其肠道菌群失调的预测效能

摘要/Abstract

摘要： 目的探究原发性肝癌(PLC)患者肠道菌群特征及血清总胆汁酸(TBA)、葡萄糖调节蛋白78(GRP78)、髓过氧化物酶(MPO)对其肠道菌群失调的预测效能。方法选取2020年1月至2023年2月在本院接受治疗的90名PLC患者为PLC组,并根据患者肠道菌群是否失调分为肠道菌群失调组(n=38)和肠道菌群未失调组(n=52),另选择同期90名体检健康者作为对照组。测定分析PLC组和对照组肠道菌群的数量及特征;酶比色法检测血清TBA水平;酶联免疫吸附试验检测血清GRP78、MPO水平;多因素logistic回归分析确定影响PLC患者肠道菌群失调的因素;受试者工作特征(ROC)曲线分析血清TBA、GRP78、MPO对PLC患者肠道菌群失调的预测效能。结果与对照组相比,PLC组患者肠道菌群中双歧杆菌、乳杆菌数量显著降低[(8.12±2.23)vs.(12.59±2.71)1gCFU/g,(6.53±1.47)vs.(17.04±4.02)1gCFU/g,均P＜0.001],而肠球菌、肠杆菌数量显著升高[(12.32±2.43)vs.(6.75±0.79)1gCFU/g,(16.56±3.49)vs.(7.02±1.68)1gCFU/g,均P＜0.001]。与对照组相比,PLC组血清TBA、GRP78、MPO表达水平呈上升趋势[(42.57±9.32)vs.(3.12±1.05)μmol/L,(154.33±21.54)vs.(60.13±14.42)ng/mL,(24.79±2.59)vs.(9.12±1.67)mg/L,均P＜0.001];肠道菌群失调组患者血清TBA、GRP78、MPO表达水平显著高于肠道菌群未失调组[(50.14±9.53)vs.(37.03±8.86)μmol/L,(174.64±23.64)vs.(139.48±17.35)ng/mL,(26.98±2.85)vs.(23.19±2.46)mg/L,均P＜0.001]。血清TBA、GRP78、MPO均是影响PLC患者发生肠道菌群失调的因素(P<0.05);血清TBA、GRP78、MPO及三者联合预测PLC患者肠道菌群失调的曲线下面积(AUC)分别为0.893、0.933、0.859、0.984,三者联合预测效能高于三个指标单独预测(Z_{三者联合-TBA}=3.133、Z_{三者联合-GRP78}=2.147、Z_{三者联合-MPO}=3.266,均P<0.05)。结论 PLC患者体内双歧杆菌、乳杆菌数量减少,肠球菌、肠杆菌数量增加,血清TBA、GRP78、MPO水平升高,三者与肠道菌群失调关系密切,且可能作为预测PLC患者发生肠道菌群失调的生物学指标。

关键词: 原发性肝癌, 总胆汁酸, 葡萄糖调节蛋白78, 髓过氧化物酶, 肠道菌群

Abstract: Objective To investigate the characteristics of gut microbiota in patients with primary liver cancer (PLC) and the predictive efficacy of serum total bile acid (TBA), glucose regulatory protein 78 (GRP78), and myeloperoxidase (MPO) on their gut microbiota dysbiosis. Methods Ninety PLC patients who received treatment in our hospital from January 2020 to February 2023 were selected as the PLC group, and were separated into dysbiosis group (n=38) and non-dysbiosis group (n=52) based on whether the patient had gut microbiota dysbiosis. Additionally, 90 healthy individuals who underwent physical examination during the same period were included as the control group. The quantity and characteristics of gut microbiota in the PLC group and control group were measured and analyzed. Enzyme colorimetric method was applied to detect serum TBA level. Enzyme linked immunosorbent assay (ELISA) was applied to detect serum levels of GRP78 and MPO. Multivariate logistic analysis was applied to analyze the factors affecting gut microbiota imbalance in PLC patients. Receiver operating characteristic (ROC) curve was applied to analyze the predictive efficacy of serum TBA, GRP78, and MPO for gut microbiota dysbiosis in PLC patients. Results The numbers of bifidobacteria and lactobacilli in the PLC group were lower than those in the control group [(8.12±2.23) vs (12.59±2.71) 1gCFU/g, (6.53±1.47) vs (17.04±4.02) 1gCFU/g, all P<0.001], while the numbers of Enterococcus and Enterobacterium were higher than those in the control group [(12.32±2.43) vs (6.75±0.79) 1gCFU/g, (16.56±3.49) vs (7.02±1.68) 1gCFU/g, all P<0.001]. Compared with the control group, the expression levels of serum TBA, GRP78, and MPO in the PLC group showed an upward trend [(42.57±9.32) vs (3.12±1.05) μmol/L, (154.33±21.54) vs (60.13±14.42) ng/mL, (24.79±2.59) vs (9.12±1.67) mg/L, all P<0.001]. The expression levels of serum TBA, GRP78, and MPO in the dysbiosis group were obviously higher than those in the non dysbiosis group [(50.14±9.53) vs (37.03±8.86) μmol/L, (174.64±23.64) vs (139.48±17.35) ng/mL, (26.98±2.85) vs (23.19±2.46) mg/L, all P<0.001]. Serum TBA, GRP78, and MPO were all factors that affected the occurrence of intestinal microbiota imbalance in PLC patients (P<0.05). The area under the curve (AUC) of serum TBA, GRP78, MPO, and their combined prediction for gut microbiota dysbiosis in PLC patients was 0.893, 0.933, 0.859, and 0.984, respectively. The combined predictive efficacy of the three indicators was higher than that of the three indicators alone (Z_{triple combination-TBA}=3.133, Z_{triple combination-GRP78}=2.147, Z_{triple combination-MPO}=3.266, all P<0.05). Conclusion The numbers of Bifidobacterium and Lactobacillus in PLC patients decrease, while the numbers of Enterococcus and Enterobacterium increase. The serum levels of TBA, GRP78, and MPO also increase, and these three factors are closely related to intestinal dysbiosis and may serve as biological indicators for predicting the occurrence of intestinal dysbiosis in PLC patients.

Key words: Primary liver carcinoma, Total bile acid, Glucose-regulated protein 78, Myeloperoxidase, Intestinal microbiota

庞武, 刘袁君, 葛明刚, 朱宇, 龚程. 原发性肝癌患者肠道菌群特征及血清TBA、GRP78、MPO对其肠道菌群失调的预测效能[J]. 肝脏, 2025, 30(10): 1349-1353.

PANG Wu, LIU Yuan-jun, GE Ming-gang, ZHU Yu, GONG Cheng. Characteristics of gut microbiota in patients with primary liver cancer and predictive efficacy of serum TBA, GRP78, and MPO for gut microbiota dysbiosis[J]. Chinese Hepatolgy, 2025, 30(10): 1349-1353.

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参考文献

[1] Zheng Y, Li Y, Feng J, et al. Cellular based immunotherapy for primary liver cancer[J]. J Exp Clin Cancer Res, 2021, 40(1):250.
[2] Chen W, Chiang C L, Dawson L A. Efficacy and safety of radiotherapy for primary liver cancer[J]. Chin Clin Oncol, 2021, 10(1):9.
[3] 王飞雪, 于君. 肠道菌群与原发性肝癌[J]. 实用肝脏病杂志, 2020, 23(6):769-772.
[4] 宋少娟, 苏国华. 血清总胆汁酸、胆碱酯酶和前白蛋白检测在肝病诊断中应用探析[J]. 医学信息, 2021, 34(23):9-11.
[5] 李斐, 郭珊, 曹献芹. 脓性胆管炎患者肠道菌群失调与血清TBA、IL-17表达的相关性分析[J]. 中国病原生物学杂志, 2023, 18(2):220-223.
[6] Ninkovic S, Harrison S J, Quach H. Glucose-regulated protein 78 (GRP78) as a potential novel biomarker and therapeutic target in multiple myeloma[J]. Expert Rev Hematol, 2020, 13(11):1201-1210.
[7] 梁亚鹏, 张浩, 蔡华忠, 等. 脓毒症患者血清FABP4、GRP78表达及与肠道菌群失调的相关性[J]. 中国病原生物学杂志, 2023, 18(10):1175-1178.
[8] Ndrepepa G. Myeloperoxidase-a bridge linking inflammation and oxidative stress with cardiovascular disease[J]. Clin Chim Acta, 2019, 493:36-51.
[9] 朱国民, 廖福全, 郑伟华. 溃疡性结肠炎患者血清IL-1β、C反应蛋白及髓过氧化物酶水平与肠道菌群的关系[J]. 中国微生态学杂志, 2023, 35(12):1434-1438.
[10] 中华人民共和国国家卫生健康委员会医政医管局. 原发性肝癌诊疗规范(2019年版)[J]. 传染病信息, 2020, 33(6):481-500.
[11] 张秀荣. 肠道菌群粪便涂片检查图谱[M]. 北京:人民军医出版社, 2000:1-25.
[12] 《中华消化杂志》编委会, 王兴鹏, 刘志华. 肠道菌群失调诊断治疗建议[J]. 中华消化杂志, 2009, 29(5):335-337.
[13] 鲜林峰, 方乐天, 刘文斌, 等. 原发性肝癌流行现状、主要发病机制及防控策略[J]. 中国癌症防治杂志, 2022, 14(3):320-328.
[14] 王潇, 陈华春, 严家栋, 等. 肠道菌群与肿瘤临床治疗相关性研究概述[J]. 中外医学研究, 2024, 22(2):158-162.
[15] 李亚桐, 赵中华, 张润南, 等. 肠道菌群对肝癌治疗效果的影响研究进展[J]. 山东医药, 2023, 63(35):92-95.
[16] Schwabe R F, Greten T F. Gut microbiome in HCC - mechanisms, diagnosis and therapy[J]. J Hepatol, 2020, 72(2):230-238.
[17] 李慧, 康纯嘉, 董赛男, 等. TLR4和肠道菌群在原发性肝癌进展中动态变化及与其预后的关系[J]. 实用癌症杂志, 2023, 38(9):1414-1417.
[18] 汤莉, 吴伶莉. 原发性肝癌患者肠道菌群变化与内毒素和炎性因子水平的关系[J]. 中国微生态学杂志, 2021, 33(10):1162-1165.
[19] Brock W J, Beaudoin J J, Slizgi J R, et al. Bile acids as potential biomarkers to assess liver impairment in polycystic kidney disease[J]. Int J Toxicol, 2018, 7(2):144-154.
[20] 王宏伟, 田丽丽, 徐尚倩, 等. CG、TBA联合AFP在原发性肝癌鉴别中的临床价值研究[J]. 内蒙古医科大学学报, 2023, 45(5):469-474.
[21] Ibrahim I M, Abdelmalek D H, Elfiky A A. GRP78: A cell's response to stress[J]. Life Sci, 2019, 226:156-163.
[22] 苏博, 钱国武, 闫振宇, 等. 葡萄糖调节蛋白78在原发性肝癌患者癌组织中表达及其与预后的关系[J]. 中国老年学杂志, 2023, 43(1):159-162.
[23] Chen S, Chen H, Du Q, et al. Targeting myeloperoxidase (MPO) mediated oxidative stress and inflammation for reducing brain ischemia injury: potential application of natural compounds[J]. Front Physiol, 2020, 11:433.
[24] Lazarević-Pasti T, Leskovac A, Vasić V. Myeloperoxidase inhibitors as potential drugs[J]. Curr Drug Metab, 2015, 16(3):168-190.
[25] 白燕鸥, 刘旭. 肠易激综合征与肠道菌群失调相关性研究进展[J]. 临床军医杂志, 2023, 51(3):327-330.
[26] 辛勇, 王青梅. 上消化道出血患者肠道菌群失调与胃肠激素变化的相关性[J]. 实验与检验医学, 2021, 39(2):411-414+443.