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肠道菌群代谢物TMAO与非酒精性脂肪性肝病的关系

李媛媛 宋亚贤 徐玉善 曾晓甫 袁惠 徐兆 江艳

李媛媛, 宋亚贤, 徐玉善, 曾晓甫, 袁惠, 徐兆, 江艳. 肠道菌群代谢物TMAO与非酒精性脂肪性肝病的关系[J]. 昆明医科大学学报, 2024, 45(2): 77-84. doi: 10.12259/j.issn.2095-610X.S20240210
引用本文: 李媛媛, 宋亚贤, 徐玉善, 曾晓甫, 袁惠, 徐兆, 江艳. 肠道菌群代谢物TMAO与非酒精性脂肪性肝病的关系[J]. 昆明医科大学学报, 2024, 45(2): 77-84. doi: 10.12259/j.issn.2095-610X.S20240210
Yuanyuan LI, Yaxian SONG, Yushan XU, Xiaofu ZENG, Hui YUAN, Zhao XU, Yan JIANG. The Association of Intestinal Flora Metabolite TMAO with Non-alcoholic Fatty Liver Disease[J]. Journal of Kunming Medical University, 2024, 45(2): 77-84. doi: 10.12259/j.issn.2095-610X.S20240210
Citation: Yuanyuan LI, Yaxian SONG, Yushan XU, Xiaofu ZENG, Hui YUAN, Zhao XU, Yan JIANG. The Association of Intestinal Flora Metabolite TMAO with Non-alcoholic Fatty Liver Disease[J]. Journal of Kunming Medical University, 2024, 45(2): 77-84. doi: 10.12259/j.issn.2095-610X.S20240210

肠道菌群代谢物TMAO与非酒精性脂肪性肝病的关系

doi: 10.12259/j.issn.2095-610X.S20240210
基金项目: 云南省科技厅-昆明医科大学应用基础研究联合专项基金资助项目(202001AY070001-195);云南省代谢性疾病临床医学研究中心资助项目(202102AA100056);云南省内分泌代谢性疾病临床医学中心资助项目(YWLCYXZXXYS20221005)
详细信息
    作者简介:

    李媛媛,(1993~ ),女,云南文山人,临床医学硕士,住院医师,主要从事内分泌与代谢工作

    宋亚贤与李媛媛对本文有同等贡献

    通讯作者:

    江艳,E-mail:jyan_6@126.com

  • 中图分类号: R589.2

The Association of Intestinal Flora Metabolite TMAO with Non-alcoholic Fatty Liver Disease

  • 摘要:   目的  检测NAFLD患者血清氧化三甲胺(TMAO)及其前体代谢物水平,及肠道中直肠真杆菌、多形拟杆菌、乳酸杆菌和双歧杆菌的表达量,探讨肠道菌群代谢物TMAO在NAFLD病程进展中的作用。  方法   随机选取118例受试者,分为NAFLD组86例和健康对照组32例,采用高效液相色谱串联质谱法检测受试者血清中TMAO及其前体代谢物的水平,qRT-PCR法检测粪便中目标细菌DNA的表达量。  结果  NAFLD患者血清TMAO、三甲胺(TMA)及胆碱水平明显升高(P<0.05),肝脏脂肪含量与TMAO的水平具有正相关性(P<0.05);NAFLD患者粪便中乳酸杆菌、直肠真杆菌表达量增加(P < 0.05),双歧杆菌、多形拟杆菌表达量减少(P < 0.05);血清TMAO水平与粪便中直肠真杆菌的数量呈正相关(r=0.280,P<0.05),与双歧杆菌的数量呈负相关(r=-0.332,P<0.05)。  结论  血清TMAO水平与NAFLD的严重程度呈正相关,NAFLD患者肠道菌群结构失衡,且与TMAO存在关联,推断肠道菌群可能通过代谢生成TMAO在NAFLD病程进展中起重要作用。
  • 图  1  肝脏右叶肋间切面图

    A:NAFLD组;B:健康对照组。

    Figure  1.  Sagitta plane of right liver and kidney

    图  2  肝右肾矢状切面图

    A:NAFLD组;B:健康对照组。

    Figure  2.  Intercostal view of right lobe of liver

    图  3  肠道目标菌群PCR扩增曲线图

    A:直肠真杆菌;B:乳酸杆菌;C:多形拟杆菌;D:双歧杆菌;E:GAPDH。

    Figure  3.  The real-time PCR curve of the target intestinal flora

    表  1  引物及内参序列

    Table  1.   The sequences of primer and internal reference

    细菌名称序列(5′-3′)
    直肠真杆菌 F: GGGTGACCGGCCACATTGGG
    R: ATCAGACTTGCCGCACCGCC
    乳酸杆菌 F: AGCAGTAGGGAATCTTCCA
    R: CACCGCTACACATGGAG
    双歧杆菌 F:GATTCTGGCTCAGGATGAACGC
    R: CTGATAGGACGCGACCCAT
    多行拟杆菌 F: CCGCCTCCGTTAGCTGCGTG
    R: ACGTAGGCTGCACAGCCGGT
    GAPDH(内参) F: TCGGCATCATCGAAGGTCTG
    R: TGCCATTCAGTTCTGGCAGT
      F:上游引物 R:下游引物
    下载: 导出CSV

    表  2  2组受试者的一般临床指标比较 [M(P25P75) /$ \bar x \pm s $]

    Table  2.   Comparison of the general data between the two groups [M(P25P75) /$ \bar x \pm s $]

    临床指标NAFLD组(n=86)健康对照组(n=32)Z/tP
    性别(男/女) 49/37 12/20 3.543 0.060
    年龄(岁) 50.63±15.02 40.34±12.47 3.454 0.001*
    BMI(kg/m2 25.01±3.04 21.06±2.23 6.794 <0.001*
    腰围(cm) 93.5(84.75,102.25) 81.5(75.25,84.0) −5.911 <0.001*
    臀围(cm) 99.5(94.0,105.0) 93.0(89.25,95.75) −4.318 <0.001*
    FPG(mmol/L) 5.77(5.05,7.67) 4.96(4.09,5.25) −4.147 <0.001*
    HbA1C(%) 6.65(5.70,9.25) 5.45(5.33,5.58) −6.861 <0.001*
    HOMA-IR 2.46(0.52,3.82) 0.27(0.23,0.50) −6.435 <0.001*
    TC(mmol/L) 4.65±1.17 4.45±0.75 0.873 0.385
    TG(mmol/L) 2.25(1.64,3.33) 0.89(0.70,1.30) −5.203 <0.001*
    HDL-C(mmol/L) 1.03±0.26 1.34±0.33 −5.386 <0.001*
    LDL-C(mmol/L) 2.93±1.06 2.71±0.59 1.128 0.262
    AST(IU/L) 21.00(16.05,27.33) 21.35(14.60,25.28) −1.595 0.111
    ALT(IU/L) 23.75(15.68,36.90) 15.15(12.23,20.18) −3.562 <0.001*
    γ-GGT(U/L) 46.50(23.00,83.00) 18.50(13.25,27.50) −5.238 <0.001*
    TBA(µmol/L) 3.85(2.20,7.15) 1.6(0.95,3.10) −2.177 0.030*
    UA(µmol/L) 390.92±124.92 328.80±70.15 2.657 0.009*
    GFR(mL/min) 103.05(82.25,130.81) 84.86(69.03,107.11) −2.851 0.004*
      *P < 0.05。
    下载: 导出CSV

    表  3  2组受试者TMAO及其前体代谢物比较 [M(P25P75) /$ \bar x \pm s $]

    Table  3.   Comparison of TMAO and its precursor metabolites between the two groups [M(P25P75) /$ \bar x \pm s $]

    代谢物NAFLD组(n=86)健康对照组(n=32)Z/tP
    TMAO(ng/mL) 240.20(148.97,386.84) 136.94(100.40,246.37) −3.584 <0.001*
    TMA(ng/mL) 186.88(146.30,278.83) 141.84(114.62,231.03) −2.312 0.021*
    胆碱(ng/mL) 1882.20±442.22 1582.59±538.60 3.079 0.003*
    甜菜碱(ng/mL) 4121.55±973.57 4175.00±855.83 −0.274 0.785
    左旋肉碱(ng/mL) 7736.19±2334.51 8084.90±1703.53 −0.771 0.442
      *P < 0.05。
    下载: 导出CSV

    表  4  肝脏脂肪含量与TMAO、TMA及胆碱相关性

    Table  4.   Correlation between liver fat content and TMAO,TMA and choline

    项目(n=118)相关系数(rP
    TMAO0.2500.043*
    TMA0.1820.143
    胆碱0.1730.166
      *P < 0.05。
    下载: 导出CSV

    表  5  2组受试者4种肠道菌群表达量比较 [M(P25P75)]

    Table  5.   Comparison of the expression levels of intestinal microbiota in the two groups [M(P25P75)]

    肠道菌群NAFLD组(n=86)健康对照组(n=32)ZP
    直肠真杆菌 3.24(1.64,10.60) 0.93(0.27,2.12) −4.240 <0.001*
    乳酸杆菌 9.71(0.16,26.26) 1.06(0.46,5.18) −2.450 0.014*
    多形拟杆菌 0.62(0.10,3.57) 2.80(0.35,11.08) −2.217 0.027*
    双歧杆菌 0.05(0.004,0.30) 1.18(0.26,2.90) −5.453 <0.001*
      *P < 0.05。
    下载: 导出CSV

    表  6  TMAO水平与4种肠道菌群表达量相关性(n=118)

    Table  6.   Correlation between TMAO and the expression levels of intestinal microflora(n=118)

    项目相关系数(rP
    直肠真杆菌 0.280 0.004*
    乳酸杆菌 0.163 0.097
    多形拟杆菌 −0.161 0.101
    双歧杆菌 −0.332 0.001*
      *P < 0.05。
    下载: 导出CSV

    表  7  饮食结构在2组间的差异

    Table  7.   Differences in dietary structure between the two groups

    是否按时就餐膳食搭配(荤/素)每日饮水量(ml)鸡蛋牛奶鱼类红肉动物内脏水果油腻油炸食物甜食饮料
    Z−0.473−3.251−0.136−0.091−0.226−3.500−0.882−0.313−0.898−0.073−0.482
    P0.6360.001*0.8920.9280.821<0.001*0.3780.7550.3690.9420.630
      *P < 0.05,食物种类食用频率均为每周次数。
    下载: 导出CSV

    表  8  肝脏脂肪含量与饮食结构的相关性(n=118)

    Table  8.   Correlation between liver fat content and diet structure(n=118)

    项目(n=118)相关系数(rP
    膳食搭配(荤/素) 0.345 0.004*
    鱼类(每周次数) −0.289 0.019*
      *P < 0.05。
    下载: 导出CSV
  • [1] 张金俊,吕梦,陈浩,等. 我国成人非酒精性脂肪性肝病患病率的meta分析[J]. 职业与健康,2023,39(21):3000-3003.
    [2] Xiao S Y,Xie W H,Zhang Y H,et al. Changing epidemiology of cirrhosis from 2010 to 2019: Results from the Global Burden Disease study 2019[J]. Ann Med,2023,55(2):2252326. doi: 10.1080/07853890.2023.2252326
    [3] Fang J,Yu C H,Li X J,et al. Gut dysbiosis in nonalcoholic fatty liver disease: Pathogenesis,diagnosis,and therapeutic implications[J]. Front Cell Infect Microbiol,2022,8(12):997018.
    [4] Nawrot M,Peschard S,Lestavel S,et al. Intestine-liver crosstalk in type 2 diabetes and non-alcoholic fatty liver disease[J]. Metabolism,2021,10(123):154844.
    [5] Wang Z,Klipfell E,Bennett B J. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease[J]. Nature,2011,472(7341):57-63. doi: 10.1038/nature09922
    [6] Janeiro M H,Ramírez M J,Milagro F I,et al. Implication of Trimethylamine N-Oxide (TMAO) in disease: Potential biomarker or new therapeutic target[J]. Nutrients,2018,10(10):1398. doi: 10.3390/nu10101398
    [7] Jalandra R,Dalal N,Yadav A K,et al. Emerging role of trimethylamine-N-oxide (TMAO) in colorectal cancer[J]. Appl Microbiol Biotechnol,2021,105(20):7651-7660. doi: 10.1007/s00253-021-11582-7
    [8] Tang W H,Wang Z,Kennedy D J. Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease[J]. Circ Res,2015,116(3):448-455. doi: 10.1161/CIRCRESAHA.116.305360
    [9] Le ó n-Mimila P,Villamil-Ramírez H,Li X S,et al. Trimethylamine N-oxide levels are associated with NASH in obese subjects with type 2 diabetes[J]. Diabetes Metab,2021,47(2):101183. doi: 10.1016/j.diabet.2020.07.010
    [10] 中华医学会肝脏病学分会脂肪肝和酒精性肝病学组. 非酒精性脂肪性肝病诊疗指南[J]. 中国肝脏病杂志(电子版),2010,2(4):43-48. doi: 10.3969/j.issn.1674-7380.2010.04.013
    [11] Motamed N,Faraji A H,Khonsari M R,et al. Fatty liver index (FLI) and prediction of new cases of non-alcoholic fatty liver disease: A population-based study of northern Iran[J]. Clin Nutr,2020,39(2):468-474. doi: 10.1016/j.clnu.2019.02.024
    [12] Xia M F,Lin H D,Yan H M,et al. The association of liver fat content and serum alanine aminotransferase with bone mineral density in middle-aged and elderly Chinese men and postmenopausal women[J]. J Transl Med,2016,13(14):11.
    [13] 薛平燕,江艳,徐玉善,等. 肠道菌群结构在非酒精性脂肪性肝病患者中的改变[J]. 昆明医科大学学报,2020,41(11):62-67. doi: 10.12259/j.issn.2095-610X.S20201120
    [14] Eslam M,Sanyal A J,George J,et al. MAFLD: A consensus-driven proposed nomenclature for metabolic associated fatty liver disease[J]. Gastroenterology,2020,158(7):1999-2014. doi: 10.1053/j.gastro.2019.11.312
    [15] Angelico F,Baratta F,Pastori D,et al. Statins and non-alcoholic fatty liver disease[J]. Liver Int,2019,39(9):1787. doi: 10.1111/liv.14134
    [16] Polyzos S A,Kountouras J,Mantzoros C S. Obesity and nonalcoholic fatty liver disease: From pathophysiology to therapeutics[J]. Metabolism,2019,3(92):82-97.
    [17] Cusi K,Isaacs S,Barb D,et al. American association of clinical endocrinology clinical practice guideline for the diagnosis and management of nonalcoholic fatty liver disease in primary care and endocrinology clinical settings: Co-Sponsored by the American association for the study of liver diseases(AASLD)[J]. Endocr Pract,2022,28(5):528-562. doi: 10.1016/j.eprac.2022.03.010
    [18] Hemmati M,Kashanipoor S,Mazaheri P,et al. Importance of gut microbiota metabolites in the development of cardiovascular diseases (CVD)[J]. Life Sci,2023,15(329):121947.
    [19] Saaoud F,Liu L,Xu K,et al. Aorta- and liver-generated TMAO enhances trained immunity for increased inflammation via ER stress/mitochondrial ROS/glycolysis pathways[J]. JCI Insight,2023,8(1):e158183. doi: 10.1172/jci.insight.158183
    [20] Flores-Guerrero J L,Post A,Dijk P R,et al. Circulating trimethylamine-N-oxide is associated with all-cause mortality in subjects with nonalcoholic fatty liver disease[J]. Liver Int,2021,41(10):2371-2382. doi: 10.1111/liv.14963
    [21] Chen Y M,Liu Y,Zhou R F,et al. Associations of gut-flora-dependent metabolite trimethylamine-N-oxide,betaine and choline with non-alcoholic fatty liver disease in adults[J]. Sci Rep,2016,8(6):19076.
    [22] Gao X,Liu X F,Xu J,et al. Dietary trimethylamine N-oxide exacerbates impaired glucose tolerance in mice fed a high fat diet[J]. J Biosci Bioeng,2014,118(4):476-481. doi: 10.1016/j.jbiosc.2014.03.001
    [23] Yu D X,Shu X O,Xiang Y B,et al. Higher dietary choline intake is associated with lower risk of nonalcoholic fatty liver in normal-weight Chinese women[J]. J Nutr,2014,144(12):2034-2040. doi: 10.3945/jn.114.197533
    [24] Ji Y,Yin Y,Sun L J,et al. The molecular and mechanistic insights based on gut-liver axis: Nutritional target for non-alcoholic fatty liver disease (NAFLD) Improvement[J]. Int J Mol Sci,2020,21(9):3066. doi: 10.3390/ijms21093066
    [25] Muralitharan R R,Marques F Z. Diet-related gut microbial metabolites and sensing in hypertension[J]. J Hum Hypertens,2021,35(2):162-169. doi: 10.1038/s41371-020-0388-3
    [26] Cho C E,Taesuwan S,Malysheva O V,et al. Trimethylamine-N-oxide (TMAO) response to animal source foods varies among healthy young men and is influenced by their gut microbiota composition: Arandomized controlled trial[J]. Mol Nutr Food Res,2017,61(1):1600324. doi: 10.1002/mnfr.201600324
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出版历程
  • 收稿日期:  2023-10-07
  • 网络出版日期:  2024-02-22
  • 刊出日期:  2024-02-25

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