PDF下载 ( 959 KB)
双歧杆菌对慢性肝病的干预作用及其机制
DOI: 10.12449/JCH260230
利益冲突声明：本文不存在任何利益冲突。
作者贡献声明：潘李轶负责文献检索，撰写文章；陈玉、黄钰雯、裴浩、吴凤兰、叶绿萍、王娜协助文献检索；陈月桥负责修改和审校文章。
-
摘要: 相较于传统慢性肝病（CLD）治疗方法，双歧杆菌具有干预靶点多、生物安全性高和宿主相容性好等特性，为干预CLD进展提供了微生态调控新策略。多项研究表明，双歧杆菌通过调节肠道菌群、保持抗氧化、促进能量消耗、减轻炎症、改善糖脂代谢和抗肿瘤等多个方面，调节肝脏稳态及治疗CLD。本文系统综述了国内外关于双歧杆菌治疗CLD的相关研究，探讨其不同作用机制，并对涉及的核转录因子红系2相关因子2和AMP活化的蛋白质激酶等相关信号通路与肝脏的交互作用进行阐述，以期为益生菌干预CLD病理提供依据，为CLD的综合治疗提供新思路。Abstract: Compared with traditional therapies for chronic liver disease （CLD）， Bifidobacterium has the characteristics of multi-target intervention， high biosafety， and good host compatibility and provides new strategies for intervention of CLD progression in terms of microecological regulation. Various studies have shown that Bifidobacterium regulates liver homeostasis and exerts a therapeutic effect on CLD by regulating intestinal flora， maintaining antioxidation， promoting energy consumption， alleviating inflammation， improving glycolipid metabolism， and exerting an antitumor effect. This article systematically reviews the studies on Bifidobacterium in the treatment of CLD in China and globally， explores their different mechanisms， and elaborates on the interaction between related signaling pathways （such as the nuclear factor erythroid 2-related factor 2 signaling pathway and the adenosine monophosphate-activated protein kinase signaling pathway） and the liver， in order to provide a basis for probiotic intervention in liver pathology， as well as new ideas for the comprehensive treatment of CLD.
-
Key words:
- Liver Diseases /
- Bifidobacterium /
- Signal Transduction
-
注： CLD，慢性肝病；occludin，闭合蛋白；IGF-1，胰岛素样生长因子1；LPS，脂多糖。
图 1 双歧杆菌通过肠道屏障干预CLD的过程
Figure 1. The process of Bifidobacterium intervening CLD through the intestinal barriers
注： CLD，慢性肝病；PGC-1α，过氧化物酶增殖激活受体-γ共激活因子-1α；Nrf2，核转录因子红系2相关因子2；ARE，抗氧化响应元件；HO-1，血红素加氧酶1；CAT，过氧化氢酶；SOD，超氧化物歧化酶；ROS，活性氧。
图 2 双歧杆菌通过抗氧化和消耗能量干预慢性肝病的过程
Figure 2. The process of Bifidobacterium intervening CLD through antioxidation and energy consumption
注： CLD，慢性肝病；LPS，脂多糖；MD-2，髓样分化蛋白2；TLR4，Toll样受体4；MyD88，髓分化因子88；IRAK，白细胞介素-1受体相关激酶；TRAM，易位关联膜蛋白1；TRIF，血清β干扰素TIR结构域衔接蛋白；TRAF，肿瘤坏死因子受体相关因子；IKK，kappa B 抑制因子激酶；IRF3，干扰素调节因子3；IL-6，白细胞介素-6；TNF-α，肿瘤坏死因子-α。
图 3 双歧杆菌通过相关炎症机制干预慢性肝病的过程
Figure 3. The process of Bifidobacterium intervening CLD through the related inflammatory mechanisms
-
[1] PAIK JM, KABBARA K, EBERLY KE, et al. Global burden of NAFLD and chronic liver disease among adolescents and young adults[J]. Hepatology, 2022, 75( 5): 1204- 1217. DOI: 10.1002/hep.32228. [2] TURRONI F, DURANTI S, MILANI C, et al. Bifidobacterium bifidum: A key member of the early human gut microbiota[J]. Microorganisms, 2019, 7( 11): 544. DOI: 10.3390/microorganisms7110544. [3] LI K, BIHAN M, METHÉ BA. Analyses of the stability and core taxonomic memberships of the human microbiome[J]. PLoS One, 2013, 8( 5): e63139. DOI: 10.1371/journal.pone.0063139. [4] XU Z, LIAO YS, FENG XL. The role of exercise in the prevention and treatment of liver diseases by regulating intestinal flora[J]. J Clin Hepatol, 2025, 41( 8): 1693- 1699. DOI: 10.12449/JCH250834.徐珍, 廖粤生, 冯晓露. 运动调控肠道菌群在肝脏疾病防治中的作用[J]. 临床肝胆病杂志, 2025, 41( 8): 1693- 1699. DOI: 10.12449/JCH250834. [5] SHU X, WANG J, ZHAO L, et al. Bifidobacterium lactis TY-S01 protects against alcoholic liver injury in mice by regulating intestinal barrier function and gut microbiota[J]. Heliyon, 2023, 9( 7): e17878. DOI: 10.1016/j.heliyon.2023.e17878. [6] FANG DQ, SHI D, LV LX, et al. Bifidobacterium pseudocatenulatum LI09 and Bifidobacterium catenulatum LI10 attenuate D-galactosamine-induced liver injury by modifying the gut microbiota[J]. Sci Rep, 2017, 7( 1): 8770. DOI: 10.1038/s41598-017-09395-8. [7] WANG LL, JIAO T, YU QQ, et al. Bifidobacterium bifidum shows more diversified ways of relieving non-alcoholic fatty liver compared with Bifidobacterium adolescentis[J]. Biomedicines, 2021, 10( 1): 84. DOI: 10.3390/biomedicines10010084. [8] WANG W, SUN M, ZHENG YL, et al. Effects of Bifidobacterium infantis on cytokine-induced neutrophil chemoattractant and insulin-like growth factor-1 in the ileum of rats with endotoxin injury[J]. World J Gastroenterol, 2019, 25( 23): 2924- 2934. DOI: 10.3748/wjg.v25.i23.2924. [9] YIN JY, SHAN HY. Effect of probiotics combined with compound Glycyrrhizin glycoside for hepatitis B cirrhosis and its influences on gut microbiota and serum inflammatory factors[J]. Chin J Microecol, 2024, 36( 7): 803- 807, 812. DOI: 10.13381/j.cnki.cjm.202407009.殷景远, 单红艳. 微生态制剂联合复方甘草酸苷治疗肝炎肝硬化的效果及对肠道菌群和血清炎性因子水平的影响[J]. 中国微生态学杂志, 2024, 36( 7): 803- 807, 812. DOI: 10.13381/j.cnki.cjm.202407009. [10] YIN J, CHEN L, LIN YY, et al. Bifidobacterium bifidum reduces oxidative stress and alters gut flora to mitigate acute liver injury caused by N-acetyl-p-aminophenol[J]. BMC Microbiol, 2025, 25( 1): 87. DOI: 10.1186/s12866-025-03775-1. [11] BU GK, CHEN G, LI J, et al. Bifidobacterium bifidum BGN4 fractions ameliorate palmitic acid-induced hepatocyte ferroptosis by inhibiting SREBP1-CYP2E1 pathway[J]. J Investig Med, 2024, 72( 1): 67- 79. DOI: 10.1177/10815589231204058. [12] LI B, CHI XC, HUANG Y, et al. Bifidobacterium longum-derived extracellular vesicles prevent hepatocellular carcinoma by modulating the TGF-β1/smad signaling in mice[J]. Front Biosci, 2024, 29( 7): 241. DOI: 10.31083/j.fbl2907241. [13] YI HW, ZHU XX, HUANG XL, et al. Selenium-enriched Bifidobacterium longum protected alcohol and high fat diet induced hepatic injury in mice[J]. Chin J Nat Med, 2020, 18( 3): 169- 177. DOI: 10.1016/S1875-5364(20)30018-2. [14] PU R, ZHANG DC, QIU J, et al. Studies on radioprotective effect of Bifidobacterium on C57BL mice[J]. Chin J Microecol, 2007, 19( 4): 330- 332. DOI: 10.13381/j.cnki.cjm.2007.04.008.蒲荣, 张德纯, 邱建, 等. 双歧杆菌C57BL小鼠抗辐射能力的研究[J]. 中国微生态学杂志, 2007, 19( 4): 330- 332. DOI: 10.13381/j.cnki.cjm.2007.04.008. [15] LEE JY, KANG CH. Probiotics alleviate oxidative stress in H2O2-exposed hepatocytes and t-BHP-induced C57BL/6 mice[J]. Microorganisms, 2022, 10( 2): 234. DOI: 10.3390/microorganisms10020234. [16] BELOBORODOVA N, BAIRAMOV I, OLENIN A, et al. Effect of phenolic acids of microbial origin on production of reactive oxygen species in mitochondria and neutrophils[J]. J Biomed Sci, 2012, 19( 1): 89. DOI: 10.1186/1423-0127-19-89. [17] HOSSAIN M, PARK DS, RAHMAN MS, et al. Bifidobacterium longum DS0956 and Lactobacillus rhamnosus DS0508 culture-supernatant ameliorate obesity by inducing thermogenesis in obese-mice[J]. Benef Microbes, 2020, 11( 4): 361- 374. DOI: 10.3920/bm2019.0179. [18] HU JM, KYROU I, TAN BK, et al. Short-chain fatty acid acetate stimulates adipogenesis and mitochondrial biogenesis via GPR43 in brown adipocytes[J]. Endocrinology, 2016, 157( 5): 1881- 1894. DOI: 10.1210/en.2015-1944. [19] RAHMAN MS, KANG I, LEE Y, et al. Bifidobacterium longum subsp. infantis YB0411 Inhibits Adipogenesis in 3T3-L1 Pre-adipocytes and Reduces High-Fat-Diet-Induced Obesity in Mice[J]. J Agric Food Chem, 2021, 69( 21): 6032- 6042. DOI: 10.1021/acs.jafc.1c01440. [20] RAHMAN MS, LEE Y, PARK DS, et al. Bifidobacterium bifidum DS0908 and Bifidobacterium longum DS0950 culture-supernatants ameliorate obesity-related characteristics in mice with high-fat diet-induced obesity[J]. J Microbiol Biotechnol, 2023, 33( 1): 96- 105. DOI: 10.4014/jmb.2210.10046. [21] VENTURA-CLAPIER R, GARNIER A, VEKSLER V. Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha[J]. Cardiovasc Res, 2008, 79( 2): 208- 217. DOI: 10.1093/cvr/cvn098. [22] CHENG CF, KU HC, LIN H. PGC-1α as a pivotal factor in lipid and metabolic regulation[J]. Int J Mol Sci, 2018, 19( 11): 3447. DOI: 10.3390/ijms19113447. [23] TORRES-FUENTES C, GOLUBEVA AV, ZHDANOV AV, et al. Short-chain fatty acids and microbiota metabolites attenuate ghrelin receptor signaling[J]. FASEB J, 2019, 33( 12): 13546- 13559. DOI: 10.1096/fj.201901433R. [24] GUO WL, CUI SM, TANG X, et al. Intestinal microbiomics and hepatic metabolomics insights into the potential mechanisms of probiotic Bifidobacterium pseudolongum CCFM1253 preventing acute liver injury in mice[J]. J Sci Food Agric, 2023, 103( 12): 5958- 5969. DOI: 10.1002/jsfa.12665. [25] MOYA-PÉREZ A, NEEF A, SANZ Y. Bifidobacterium pseudocatenulatum CECT 7765 reduces obesity-associated inflammation by restoring the lymphocyte-macrophage balance and gut microbiota structure in high-fat diet-fed mice[J]. PLoS One, 2015, 10( 7): e0126976. DOI: 10.1371/journal.pone.0126976. [26] YAN Y, LIU CY, ZHAO SM, et al. Probiotic Bifidobacterium lactis V9 attenuates hepatic steatosis and inflammation in rats with non-alcoholic fatty liver disease[J]. AMB Express, 2020, 10( 1): 101. DOI: 10.1186/s13568-020-01038-y. [27] LEE DY, SHIN JW, SHIN YJ, et al. Lactobacillus plantarum and Bifidobacterium longum alleviate liver injury and fibrosis in mice by regulating NF-κB and AMPK signaling[J]. J Microbiol Biotechnol, 2024, 34( 1): 149- 156. DOI: 10.4014/jmb.2310.10006. [28] DONG JH, PING LJ, MENG YY, et al. Bifidobacterium longum BL-10 with antioxidant capacity ameliorates lipopolysaccharide-induced acute liver injury in mice by the nuclear factor-κB pathway[J]. J Agric Food Chem, 2022, 70( 28): 8680- 8692. DOI: 10.1021/acs.jafc.2c02950. [29] FONTANA L, PLAZA-DÍAZ J, ROBLES-BOLÍVAR P, et al. Bifidobacterium breve CNCM I-4035, Lactobacillus paracasei CNCM I-4034 and Lactobacillus rhamnosus CNCM I-4036 modulate macrophage gene expression and ameliorate damage markers in the liver of Zucker-Leprfa/fa rats[J]. Nutrients, 2021, 13( 1): 202. DOI: 10.3390/nu13010202. [30] SONG JG, DAI J, CHEN XP, et al. Bifidobacterium mitigates autoimmune hepatitis by regulating IL-33-induced Treg/Th17 imbalance via the TLR2/4 signaling pathway[J]. Histol Histopathol, 2024, 39( 5): 623- 632. DOI: 10.14670/HH-18-669. [31] LI CHO E EN, ANG CZ, QUEK J, et al. Global prevalence of non-alcoholic fatty liver disease in type 2 diabetes mellitus: An updated systematic review and meta-analysis[J]. Gut, 2023, 72( 11): 2138- 2148. DOI: 10.1136/gutjnl-2023-330110. [32] QIAN X, SI Q, LIN GP, et al. Bifidobacterium adolescentis is effective in relieving type 2 diabetes and may be related to its dominant core genome and gut microbiota modulation capacity[J]. Nutrients, 2022, 14( 12): 2479. DOI: 10.3390/nu14122479. [33] ZHANG JL, WANG SB, ZENG Z, et al. Anti-diabetic effects of Bifidobacterium animalis 01 through improving hepatic insulin sensitivity in type 2 diabetic rat model[J]. J Funct Foods, 2020, 67: 103843. DOI: 10.1016/j.jff.2020.103843. [34] HANCHANG W, DISSOOK S, WONGMANEE N, et al. Antidiabetic effect of Bifidobacterium animalis TISTR 2591 in a rat model of type 2 diabetes[J]. Probiotics Antimicrob Proteins, 2025, 17( 6): 4298- 4313. DOI: 10.1007/s12602-024-10377-2. [35] MA QT, LI YQ, LI PF, et al. Research progress in the relationship between type 2 diabetes mellitus and intestinal flora[J]. Biomed Pharmacother, 2019, 117: 109138. DOI: 10.1016/j.biopha.2019.109138. [36] JIANG T, LI Y, LI LY, et al. Bifidobacterium longum 070103 fermented milk improve glucose and lipid metabolism disorders by regulating gut microbiota in mice[J]. Nutrients, 2022, 14( 19): 4050. DOI: 10.3390/nu14194050. [37] ZHA AD, QI M, DENG YK, et al. Gut Bifidobacterium pseudocatenulatum protects against fat deposition by enhancing secondary bile acid biosynthesis[J]. Imeta, 2024, 3( 6): e261. DOI: 10.1002/imt2.261. [38] DEV K, BEGUM J, BISWAS A, et al. Hepatic transcriptome analysis reveals altered lipid metabolism and consequent health indices in chicken supplemented with dietary Bifidobacterium bifidum and mannan-oligosaccharides[J]. Sci Rep, 2021, 11( 1): 17895. DOI: 10.1038/s41598-021-97467-1. [39] LIANG X, ZHENG XM, WANG P, et al. Bifidobacterium animalis subsp. lactis F1-7 alleviates lipid accumulation in atherosclerotic mice via modulating bile acid metabolites to downregulate intestinal FXR[J]. J Agric Food Chem, 2024, 72( 5): 2585- 2597. DOI: 10.1021/acs.jafc.3c05709. [40] JENA PK, SHENG LL, NAGAR N, et al. Synbiotics Bifidobacterium infantis and milk oligosaccharides are effective in reversing cancer-prone nonalcoholic steatohepatitis using western diet-fed FXR knockout mouse models[J]. J Nutr Biochem, 2018, 57: 246- 254. DOI: 10.1016/j.jnutbio.2018.04.007. [41] BRAY F, LAVERSANNE M, SUNG H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2024, 74( 3): 229- 263. DOI: 10.3322/caac.21834. [42] SONG Q, ZHANG X, LIU WX, et al. Bifidobacterium pseudolongum-generated acetate suppresses non-alcoholic fatty liver disease-associated hepatocellular carcinoma[J]. J Hepatol, 2023, 79( 6): 1352- 1365. DOI: 10.1016/j.jhep.2023.07.005. [43] YOON JH, GWAK GY, LEE HS, et al. Enhanced epidermal growth factor receptor activation in human cholangiocarcinoma cells[J]. J Hepatol, 2004, 41( 5): 808- 814. DOI: 10.1016/j.jhep.2004.07.016. [44] ZHANG NN, ZHU WW, ZHANG SW, et al. A novel Bifidobacterium/Klebsiella ratio in characterization analysis of the gut and bile microbiota of CCA patients[J]. Microb Ecol, 2023, 87( 1): 5. DOI: 10.1007/s00248-023-02318-3. [45] GUO B, XIE N, WANG Y. Cooperative effect of Bifidobacteria lipoteichoic acid combined with 5-fluorouracil on hepatoma-22 cells growth and apoptosis[J]. Bull Cancer, 2015, 102( 3): 204- 212. DOI: 10.1016/j.bulcan.2014.09.003. [46] WANG CD, MA YP, HU QW, et al. Bifidobacterial recombinant thymidine kinase-ganciclovir gene therapy system induces FasL and TNFR2 mediated antitumor apoptosis in solid tumors[J]. BMC Cancer, 2016, 16: 545. DOI: 10.1186/s12885-016-2608-3. [47] FU GF, LI X, HOU YY, et al. Bifidobacterium longum as an oral delivery system of endostatin for gene therapy on solid liver cancer[J]. Cancer Gene Ther, 2005, 12( 2): 133- 140. DOI: 10.1038/sj.cgt.7700758. [48] WANG LL, HU LJ, XU Q, et al. Bifidobacteria exert species-specific effects on constipation in BALB/c mice[J]. Food Funct, 2017, 8( 10): 3587- 3600. DOI: 10.1039/c6fo01641c. [49] LI SJ, ZHUGE AX, XIA JF, et al. Bifidobacterium longum R0175 protects mice against APAP-induced liver injury by modulating the Nrf2 pathway[J]. Free Radic Biol Med, 2023, 203: 11- 23. DOI: 10.1016/j.freeradbiomed.2023.03.026. [50] ISHIDA K, KAJI K, SATO S, et al. Sulforaphane ameliorates ethanol plus carbon tetrachloride-induced liver fibrosis in mice through the Nrf2-mediated antioxidant response and acetaldehyde metabolization with inhibition of the LPS/TLR4 signaling pathway[J]. J Nutr Biochem, 2021, 89: 108573. DOI: 10.1016/j.jnutbio.2020.108573. [51] YU JS, CHEN WC, TSENG CK, et al. Sulforaphane suppresses hepatitis C virus replication by up-regulating heme oxygenase-1 expression through PI3K/Nrf2 pathway[J]. PLoS One, 2016, 11( 3): e0152236. DOI: 10.1371/journal.pone.0152236. [52] YUN SW, SHIN YJ, MA XY, et al. Lactobacillus plantarum and Bifidobacterium longum alleviate high-fat diet-induced obesity and depression/cognitive impairment-like behavior in mice by upregulating AMPK activation and downregulating adipogenesis and gut dysbiosis[J]. Nutrients, 2024, 16( 22): 3810. DOI: 10.3390/nu16223810. [53] TODA K, YAMAUCHI Y, TANAKA A, et al. Heat-killed Bifidobacterium breve B-3 enhances muscle functions: Possible involvement of increases in muscle mass and mitochondrial biogenesis[J]. Nutrients, 2020, 12( 1): 219. DOI: 10.3390/nu12010219. [54] LU J, SHATAER D, YAN HZ, et al. Probiotics and non-alcoholic fatty liver disease: Unveiling the mechanisms of Lactobacillus plantarum and Bifidobacterium bifidum in modulating lipid metabolism, inflammation, and intestinal barrier integrity[J]. Foods, 2024, 13( 18): 2992. DOI: 10.3390/foods13182992. [55] LV HH, TAO FY, PENG LL, et al. In vitro probiotic properties of Bifidobacterium animalis subsp. lactis SF and its alleviating effect on non-alcoholic fatty liver disease[J]. Nutrients, 2023, 15( 6): 1355. DOI: 10.3390/nu15061355. [56] ZENG QW, QI ZH, HE X, et al. Bifidobacterium pseudocatenulatum NCU-08 ameliorated senescence via modulation of the AMPK/Sirt1 signaling pathway and gut microbiota in mice[J]. Food Funct, 2024, 15( 8): 4095- 4108. DOI: 10.1039/d3fo04575g. [57] GAO WK, WANG G, YUAN H, et al. Gram-positive probiotics improves acetaminophen-induced hepatotoxicity by inhibiting leucine and Hippo-YAP pathway[J]. Cell Biosci, 2025, 15( 1): 32. DOI: 10.1186/s13578-025-01370-5. -
下载:
本文二维码
图(3)
计量
- 文章访问数: 6
- HTML全文浏览量: 2
- PDF下载量: 2
- 被引次数: 0
