Changes in intestinal flora in patients with extrahepatic cholangiocarcinoma

Tao LI; Panliang WANG; Zibo YUAN; Quankai FENG; Jie LI

doi:10.3969/j.issn.1001-5256.2021.12.029

Volume 37 Issue 12

Dec. 2021

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Abstract

References

Article Navigation > Journal of Clinical Hepatology > 2021 > 37(12): 2883-2889

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Changes in intestinal flora in patients with extrahepatic cholangiocarcinoma

DOI: 10.3969/j.issn.1001-5256.2021.12.029

Tao LI^{1, 2, 3},
Panliang WANG^{2, 3},
Zibo YUAN^{1, 2, 3},
Quankai FENG^{1, 2, 3},
Jie LI^{1, 2, 3
,
,}

1.
Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
2.
Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou 450052, China
3.
Zhengzhou Key Laboratory of Organ Transplantation Technology and Application Engineering, Zhengzhou 450052, China

Research funding:

National Natural Science Foundation of China (81900596)

Received Date: 2021-07-30
Accepted Date: 2021-08-31
Published Date: 2021-12-20

Abstract

Abstract

Objective To investigate the changes in intestinal flora in patients with extrahepatic cholangiocarcinoma (ECC) and related influencing factors. Methods Fecal samples were collected from 16 patients with ECC who were hospitalized and treated in Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, from January to December 2020, and absolute quantitative bacterial 16S rRNA was used for sequencing. A comparison was made with 20 patients with common bile duct stones (CBDS group) and 10 healthy controls (normal group), and the three groups were compared in terms of the differences in intestinal flora and the association with clinical indices. A one-way analysis of variance was used for comparison of normally distributed data with homogeneity of variance between the three groups, the t-test was used for comparison between two groups; the Kruskal-Wallis H test was used for comparison of non-normally distributed data between the three groups, and the Nemenyi test was used for comparison between groups. The chi-square test or the Fisher's exact test were used for comparison of categorical data between the three groups, and a Spearman correlation analysis was used to investigate correlation. Results The ECC group had significantly higher levels of total bilirubin (TBil) and direct bilirubin (DBil) than the CBDS group and the normal group. The α diversity analysis showed that there were no significant differences in observed species, Chao1 Index, and Shannon Index between the three groups (all P > 0.05), while there were significant differences in Shannon Index and Simpson Index between the three groups. The ECC group had a similar species diversity to the normal group and a significantly greater species diversity than the CBDS group (P < 0.05), and the CBDS group had a significantly greater species diversity than the normal group (P < 0.05). The β diversity analysis showed that the structure of intestinal flora in the ECC group was significantly different from that in the normal group and the CBDS group (P < 0.05). The analysis of the difference in bacterial composition showed that Prevotella, Lactobacillus, Megasphaera, and Sutterella were significantly enriched in the ECC group. The correlation analysis showed that Prevotella was negatively correlated with the use of antibiotics, acid inhibitors, and liver-protecting drugs, and Lactobacillus, Megasphaera, and Sutterella were positively correlated with TBil and DBil. Conclusion There is a significant change in intestinal flora in patients with ECC, which is closely associated with liver function and the use of drugs.
- Extrahepatic Cholangiocarcinoma,
- Gastrointestinal Microbiome,
- Absolute Quantitative Sequencing

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非酒精性脂肪性肝病(NAFLD)是指除外过量饮酒和其他明确的损肝因素所致的肝细胞内脂肪沉积，全球2型糖尿病(T2DM)患者NAFLD患病率约为55.5%。NAFLD与高血糖、胰岛素抵抗、血脂异常等密切相关，T2DM合并NAFLD患者心血管疾病、肾脏病变等风险明显增加且更为严重^[1-3]。ALP是一种广泛存在于人体组织中的一种酶，研究^[4]显示ALP与胰岛素抵抗(IR)呈正相关，可导致基础状态下葡萄糖过剩，T2DM患者血清ALP活性升高，ALP增高是T2DM的独立危险因素。ALP在肝脏和骨骼中活性较高，通常作为胆汁淤积和骨代谢的指标，其在NAFLD中也可出现升高。在T2DM人群中，有关血清ALP与NAFLD关系的报道甚少，本研究旨在探讨ALP是否为T2DM合并NAFLD的危险因素，为相关疾病的早期防治提供一定的依据。

1. 资料与方法

1.1 研究对象

选取2016年7月—2018年12月在本院内分泌科就诊的T2DM患者599例(其中男320例，女279例)，平均年龄(63.32±11.30)岁。T2DM诊断符合1999年世界卫生组织糖尿病的诊断标准及分型标准^[5]。根据超声检查结果将患者分为NAFLD组和非NAFLD组，NAFLD的诊断符合《非酒精性脂肪性肝病防治指南(2018年更新版)》^[2]。排除标准：(1)1型糖尿病、特殊类型糖尿病、糖尿病急性严重代谢紊乱、急性感染；(2)骨骼系统疾病、慢性肾脏疾病；(3)病毒性肝炎、自身免疫性肝炎、肝豆状核变性、肝硬化等慢性肝病及肝脏恶性肿瘤、胆道疾病；(4)过度饮酒：饮酒折合乙醇量男性＞30 g/d(＞210 g/周)，女性＞20 g/d(＞140 g/周)；(5)服用噻唑烷二酮类药物、糖皮质激素、降脂药、丙戊酸钠、奥氮平等；(6)垂体前叶功能减退、甲状腺功能减退、性腺功能减退、甲状旁腺功能亢进、炎症性肠病、全胃肠外营养等全身性疾病^[2]。

1.2 NAFLD超声分级标准

(1) 肝区近场回声弥漫性增强(强于肾脏和脾脏)远场回声逐渐衰减；(2)肝内管道结构显示不清；(3)肝脏轻至中度肿大，边缘角圆钝；(4)彩色多普勒血流显象提示肝内彩色血流信号减少或不易显示，但肝内血管走向正常；(5)肝右叶包膜及横膈回声显示不清或不完整。具备上述第1项及第2~4项中一项者为轻度脂肪肝；具备上述第1项及第2~4项中两项者为中度脂肪肝；具备上述第1项以及2~4项中两项和第5项者为重度脂肪肝^[6]。

1.3 研究方法

1.3.1 一般资料测量

采用统一标准测量T2DM患者一般临床资料包括身高、体质量、腰围(WC)、收缩压(SBP)和舒张压(DBP)；收集患者性别、年龄、糖尿病病程、吸烟史、高血压病史。

1.3.2 生化指标检测

所有受试者于试验前一晚禁食12 h，于第2日清晨空腹状态下抽取静脉血检测血清ALP、糖化血红蛋白(HbA1c)、空腹血糖(FPG)、空腹胰岛素(FIns)、空腹C肽(FC-P)、尿酸(SUA)、GGT、ALT、AST、TC、TG、HDL-C、LDL-C。BMI=体质量/身高²(kg/m²)；稳态模型评估胰岛素抵抗指数(HOMA-IR)=空腹血糖×空腹胰岛素/22.5。

1.3.3 肝脏彩超检测

使用LOGIQ-9全身彩色多普勒诊断仪器，由超声科专业医生对受试者行空腹状态下腹部超声检查，观察其大小形态、肝脏回声及血流情况等。

1.4 统计学方法

采用SPSS 22.0对资料行统计分析。正态分布计量资料以x±s表示，两组间比较采用t检验，多组间比较使用单因素方差分析；非正态分布计量资料以M(P₂₅~P₇₅)表示，两组间比较采用非参数Mann Whitney U检验，多组间比较使用Kruskal-Wallis H秩和检验；计数资料组间比较采用χ²检验。采用Pearson相关分析法和Spearman相关分析法进行相关性分析。采用二元Logistic回归分析T2DM发生NAFLD的影响因素。P＜0.05为差异具有统计学意义。

2. 结果

2.1 两组一般资料及生化指标比较

NAFLD组高血压病史所占比例、SBP、DBP、BMI、WC、FIns、FC-P、SUA、LDL-C、TG、TC、HOMA-IR、ALT、AST、GGT、ALP均高于非NAFLD组(P值均＜0.05)。NAFLD组年龄、HDL-C低于非NAFLD组(P值均＜0.05)。两组间性别、病程、有吸烟史者所占比例、HbA1c、FPG比较，差异均无统计学意义(P值均＞0.05)(表 1)。

表 1 两组一般资料及生化指标比较

Table 1. Comparison of general data between groups

项目	non-NAFLD组(n=313)	NAFLD组(n=286)	统计值	P值
男性[例(%)]	179(57.2)	141(49.3)	χ²= 3.737	0.053
年龄(岁)	64.28±11.15	62.27±11.38	t=2.184	0.029
病程(月)	120(36~192)	120(36~159)	Z=-1.365	0.172
BMI(kg/m²)	23.51±2.99	26.49±3.18	t=-11.842	＜0.001
吸烟史[例(%)]	67(21.4)	60(21.0)	χ²=0.016	0.898
高血压病史[例(%)]	174(55.6)	191(66.8)	χ²=7.864	0.005
SBP(mmHg)	133.63±15.27	136.44±15.58	t=-2.226	0.026
DBP(mmHg)	78.62±8.77	81.47±9.58	t=-3.800	＜0.001
WC(cm)	87.46±9.88	94.54±8.98	t=-9.150	＜0.001
HbA1c(%)	8.89±2.13	8.93±1.73	t=-0.279	0.781
FPG(mmol/L)	9.69±3.71	9.50±3.12	t=0.684	0.495
FIns(μIU/L)	6.25(3.62~11.14)	10.05(5.41~16.72)	Z=-6.173	＜0.001
FC-P(μg/L)	1.74±0.96	2.18±1.04	t=-5.419	＜0.001
SUA(μmol/L)	269.37±84.92	305.03±91.13	t=-4.957	＜0.001
LDL-C(mmol/L)	2.54±0.86	2.72±0.75	t=-2.702	0.007
HDL-C(mmol/L)	1.09(0.88~1.34)	0.95(0.81~1.14)	Z=-5.273	＜0.001
TG(mmol/L)	1.28(0.96~1.79)	1.86(1.43~2.69)	Z=-9.376	＜0.001
TC(mmol/L)	4.61±1.10	4.86±0.98	t=-3.016	0.003
HOMA-IR	2.77(1.41~4.44)	3.92(2.19~6.71)	Z=-5.794	＜0.001
ALT(U/L)	14.80(11.05~21.90)	20.20(14.68~30.40)	Z=-6.737	＜0.001
AST(U/L)	14.70(11.35~17.95)	16.90(12.38~23.33)	Z=-4.389	＜0.001
GGT(U/L)	19.00(14.30~28.00)	27.60(20.00~43.55)	Z=-7.764	＜0.001
ALP(U/L)	69.73±19.94	74.71±23.03	t=-2.833	0.005

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2.2 NAFLD严重程度与各指标相关性分析

随着脂肪肝严重程度的加重，T2DM合并NAFLD患者BMI、WC、FIns、HOMA-IR、ALT、AST、GGT、ALP水平均明显升高(P值均＜0.05)(表 2)。相关性分析显示，NAFLD的脂肪肝严重程度(轻、中、重)与年龄(r_s=0.140，P=0.018)、BMI(r_s=0.239，P＜0.001)、WC(r_s=0.222，P＜0.001)、FIns(r_s=0.191，P=0.001)、HOMA-IR(r_s=0.218，P＜0.001)、ALT(r_s=0.188，P=0.001)、AST(r_s=0.279，P＜0.001)、GGT(r_s=0.202，P=0.001)、ALP(r_s=0.361，P＜0.001)水平呈正相关。

表 2 轻中重度NAFLD患者临床资料比较

Table 2. Comparison of general data among groups in patients with NAFLD

项目	轻度NAFLD组(n=111)	中度NAFLD组(n=105)	重度NAFLD组(n=70)	统计值	P值
男性[例(%)]	58(52.3)	56(53.3)	27(38.6)	χ²=4.294	0.117
年龄(岁)	60.5±10.6	63.0±12.0	64.1±11.4	F=2.538	0.081
病程(月)	120(36~168)	108(29~144)	120(33~156)	χ²=0.442	0.802
BMI(kg/m²)	25.48±2.59	26.88±2.99¹⁾	27.52±3.83¹⁾	F=10.731	＜0.001
SBP(mmHg)	136.16±15.64	134.51±14.55	139.76±16.66	F=2.429	0.090
DBP(mmHg)	81.10±9.33	81.57±9.68	81.91±9.92	F=0.163	0.849
WC(cm)	92.17±7.37	95.33±8.38¹⁾	97.12±11.14¹⁾	F=7.502	0.001
HbA1c(%)	8.79±1.72	8.90±1.67	9.22±1.85	F=1.388	0.251
FPG(mmol/L)	9.35±3.04	9.28±3.12	10.06±3.21	F=1.551	0.214
FIns(μIU/L)	7.38(4.61~14.94)	10.25(5.69~16.22)	11.65(7.53~19.62)¹⁾	χ²=10.512	0.005
FC-P(μg/L)	2.12±1.07	2.19±1.00	2.28±1.05	F=0.524	0.593
SUA(μmol/L)	293.99±82.32	321.08±88.00	298.46±105.81	F=2.654	0.072
LDL-C(mmol/L)	2.76±0.73	2.66±0.77	2.76±0.77	F=0.603	0.548
HDL-C(mmol/L)	0.95(0.82~1.14)	0.93(0.80~1.11)	0.99(0.82~1.21)	χ²=1.749	0.417
TG(mmol/L)	1.84(1.37~2.87)	1.77(1.47~2.59)	1.92(1.45~3.16)	χ²=0.679	0.712
TC(mmol/L)	4.83±0.96	4.74±0.91	5.10±1.08	F=2.956	0.054
HOMA-IR	3.32(1.83~5.55)	3.90(2.34~6.51)	5.47(2.96~9.53)¹⁾	χ²=14.183	0.001
ALT(U/L)	18.00(13.60~27.60)	22.00(15.10~31.30)	23.95(16.00~42.23)¹⁾	χ²=10.453	0.005
AST(U/L)	14.00(11.50~18.40)	18.40(13.00~25.30)¹⁾	20.05(14.25~27.08)¹⁾	χ²=22.423	＜0.001
GGT(U/L)	23.00(17.00~38.80)	27.90(21.05~39.50)	34.50(21.65~55.43)¹⁾	χ²=11.791	0.003
ALP(U/L)	65.72±16.63	73.71±20.94¹⁾	90.44±26.58¹⁾²⁾	F=29.920	＜0.001
注：与轻度NAFLD组比较，1)P＜0.01；与中度NAFLD组比较，2)P＜0.01。

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2.3 T2DM合并NAFLD患者ALP与临床指标的相关性分析

相关分析显示，T2DM合并NAFLD患者ALP与HbA1c、FPG、HOMA-IR、TC、ALT、AST、GGT呈正相关(P值均＜0.05)(表 3)。

表 3 NAFLD患者ALP与临床各指标的相关性分析

Table 3. Correlation analysis between ALP and clinical indicators in patients with NAFLD

项目	r或r_s值	P值
HbA1c	0.149	0.012
FPG	0.146	0.014
HOMA-IR	0.132	0.025
TC	0.151	0.011
ALT	0.210	＜0.001
AST	0.192	0.001
GGT	0.297	＜0.001

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2.4 T2DM患者NAFLD影响因素的Logistic回归分析

以是否出现NAFLD为因变量，以年龄、BMI、高血压病史、FPG、FC-P、TC、TG、HDL-C、LDL-C、SUA、HOMA-IR、ALP为自变量，行二元Logistic回归分析，结果显示，年龄、BMI、FC-P、LDL-C、TG、ALP均为T2DM患者发生NAFLD的影响因素(表 4)。

表 4 Logistic回归分析NAFLD的影响因素

Table 4. Logistic regression analysis of the influencing factors for NAFLD

因素	β值	SE	Wald	OR	95%CI	P值
年龄	-0.030	0.010	8.527	0.971	0.951~0.990	0.003
BMI	0.298	0.037	63.596	1.347	1.252~1.450	＜0.001
FC-P	0.267	0.111	5.807	1.307	1.051~1.624	0.016
LDL-C	1.332	0.470	8.023	3.787	1.507~9.516	0.005
TG	0.685	0.167	16.803	1.984	1.430~2.752	＜0.001
ALP	0.013	0.005	7.444	1.013	1.004~1.023	0.006

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3. 讨论

ALP是一种常见的广泛存在于微生物和动植物中的酶，在人体内有四种ALP同工酶，包括组织非特异性ALP(TNAP)、肠型ALP、生殖细胞型ALP以及胎盘型ALP。TNAP主要在肝脏、肾脏和骨骼组织中表达，占血清总ALP活性的90%以上^[7]。在小鼠3T3-L1前脂肪细胞中的研究^[8]发现，TNAP水平在脂肪生成过程中升高，但在脂肪生成开始加入TNAP抑制剂后，TNAP活性和脂质积累均减少；同时在原代培养的人前脂肪细胞中也观察到类似现象。此外，更多证据表明ALP活性存在于大鼠脂肪组织、兔前脂肪细胞和人脂肪细胞中，TNAP敲除小鼠也表现出脂肪量的减少。TNAP除了参与调节脂肪细胞内脂质积累，也在肝细胞和肾上腺细胞的脂质积累中发挥作用，提示TNAP可能参与了多种不同类型细胞中的脂质积累^[9-10]。一项研究^[11]纳入了14 393例无糖尿病的高血压病患者，平均随访4.5年后发现血清ALP升高与IR相关，并且增加了糖尿病的患病风险。本研究结果显示，在T2DM合并NAFLD的患者中，ALP与HbA1c、FPG、HOMA-IR、TC、ALT、AST、GGT呈正相关，提示ALP增加可能与IR、血脂异常等多种致NAFLD风险密切相关。

据估计，2016年—2030年我国NAFLD的患病人数将从2.46亿人增加至约3.14亿人，NAFLD患病率的迅速增长导致高血糖、IR、血脂异常、肝硬化、肝癌和亚临床炎症的增加，加剧如糖尿病、肥胖、心血管疾病和癌症等非传染性疾病的负担^{[1, 12]}。本研究发现，NAFLD组BMI、WC、FIns、FC-P、LDL-C、TG、TC、HOMA-IR、ALP水平均高于非NAFLD组。随着脂肪肝严重程度的加重，T2DM合并NAFLD患者ALP水平均明显升高；NAFLD的脂肪肝严重程度与ALP水平呈正相关。Logistic回归分析表明，在调整了相关的NAFLD危险因素之后，年龄、BMI、FC-P、LDL-C、TG、ALP均为T2DM患者发生NAFLD的影响因素。NAFLD是肝脏能量代谢不平衡的表现，肝脏有将能量氧化为CO₂或输出为极低密度脂蛋白的能力，但是过多的能量主要以碳水化合物和脂肪的形式进入肝脏后，导致TG在肝脏中的积累，因此NAFLD在肥胖者中广泛存在^[13]。迄今为止，IR被认为是NAFLD发病及进展的主要机制。在IR状态下，肝脏失去在胰岛素作用下抑制肝葡萄糖生成的能力并且通过激活Notch信号通路增强脂肪从头合成。脂肪在肝脏的积累是由于游离脂肪酸(FFA)的摄取、合成、输出和氧化受损造成的。在NAFLD患者中，因为脂肪组织抑制脂肪分解的功能受损，所以肝脏脂肪变性的数量与血浆游离FFA水平的增加相关^[14]。FFA导致JNK信号通路的激活，从而引起细胞应激、炎症、凋亡和线粒体功能障碍。此外，JNK信号通路使PPARγ磷酸化，加剧了脂毒性和肝炎症^[15]。近年研究^[16]表明，C肽也与NAFLD密切相关，可能与IR和C肽本身生物功能有关。本研究中年龄较长者NAFLD的发生率较低，考虑随着年龄的增长，脂肪组织储存脂肪能力下降、肝纤维化比例升高以及接受更长久的T2DM治疗干预等原因对结果造成一定的影响^[17]。

综上所述，血清ALP水平与血糖、IR、脂代谢紊乱密切相关，ALP是T2DM合并NAFLD的危险因素，ALP可能参与了T2DM和NAFLD的发生发展。能否进行预防性用药干预ALP水平使NAFLD得到缓解，值得后续进一步研究。另外，本研究样本量偏少，为单中心横断面研究，可能存在选择偏倚，可进一步扩大样本量证实，ALP在NAFLD中的具体作用机制也需更加深入的研究。

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Changes in intestinal flora in patients with extrahepatic cholangiocarcinoma

DOI: 10.3969/j.issn.1001-5256.2021.12.029