10-11易位蛋白2（TET2）介导的表观遗传与肠道微生物-免疫互作对自身免疫性肝炎的调控作用

王莉芬; 李玲; 刘光伟

doi:10.12449/JCH260327

10-11易位蛋白2（TET2）介导的表观遗传与肠道微生物-免疫互作对自身免疫性肝炎的调控作用

DOI: 10.12449/JCH260327

王莉芬¹,
李玲¹,
刘光伟^2, , ,

1.
河南中医药大学第一附属医院脾胃肝胆科，郑州 450000
2.
上海中医药大学附属龙华医院肝病科，上海 200032

基金项目:

河南省自然科学基金 (222300420490);

河南省科技研发计划联合基金 (222301420069);

2023年度河南省中医学“双一流”创建科学研究专项课题 (HSRP-DFCTCM-2023-7-24);

2023年度河南省卫生健康委国家中医药传承创新中心科研专项 (2023ZXZX1129)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：王莉芬负责拟定写作思路，撰写文章，调整文章架构和修改；李玲参与文献调研，整理分析及文章初稿校对；刘光伟指导文章撰写和修改。

详细信息

通信作者:
刘光伟， liuguangwei1975@163.com（ORCID： 0000-0002-6641-1625）

计量
- 文章访问数: 5
- HTML全文浏览量: 2
- PDF下载量: 0
- 被引次数: 0
出版历程
- 收稿日期: 2025-06-29
- 录用日期: 2025-07-30
- 出版日期: 2026-03-25

Regulatory effect of ten-eleven translocation 2-mediated epigenetics and the interaction between gut microbiota and immunity on autoimmune hepatitis

Lifen WANG¹,
Ling LI¹,
Guangwei LIU^{2
, ,
,}

1.
Department of Spleen，Stomach，Liver and Gallbladder，The First Affiliated Hospital of Henan University of Chinese Medicine，Zhengzhou 450000，China
2.
Department of Hepatology，Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine，Shanghai 200032，China

Research funding:

Henan Provincial Natural Science Foundation (222300420490);

Henan Provincial Joint Fund for Science and Technology Research (222301420069);

2023 Annual Special Research Project for the Creation of “Double First-Class” in Henan Province’s Traditional Chinese Medicine (HSRP-DFCTCM-2023-7-24);

2023 Research Project of Henan Provincial Health Commission for the National Center of Inheritance and Innovation of Traditional Chinese Medicine (2023ZXZX1129)

More Information

Corresponding author: LIU Guangwei， liuguangwei1975@163.com （ORCID： 0000-0002-6641-1625）

摘要

摘要: 10-11易位蛋白2（TET2）作为表观遗传调控核心酶，可通过介导DNA去甲基化动态调节CD4⁺ T细胞分化及功能。近年研究发现，TET2缺失可通过扰乱辅助性T细胞17/调节性T细胞之间的平衡，激活肠-肝轴炎症信号通路，从而促进自身免疫性肝炎（AIH）进展。本文系统综述了TET2在CD4⁺ T细胞和肠道微生物间的桥梁作用，深入探讨其通过肠道微生物-表观遗传-免疫网络驱动AIH的分子机制，并展望靶向TET2-菌群轴的潜在干预策略。
- 肝炎，自身免疫性 /
- 表观基因组学 /
- 胃肠道微生物组
Abstract: Ten-eleven translocation 2 （TET2）， as a core enzyme in epigenetic regulation， dynamically regulates the differentiation and function of CD4⁺ T cells by mediating DNA demethylation. Recent studies have shown that TET2 deficiency can promote the progression of autoimmune hepatitis （AIH） by disrupting the Th17/Treg balance and activating inflammatory signals along the gut-liver axis. This article systematically reviews the bridging role of TET2 between CD4⁺ T cells and gut microbiota， explores the molecular mechanisms by which it drives AIH through the gut microbiota-epigenetics-immunity network， and discusses the potential intervention strategies targeting the TET2-microbiota axis.
- Hepatitis， Autoimmune /
- Epigenomics /
- Gastrointestinal Microbiome

HTML全文

注： TET2，10-11易位蛋白2；TLR4，Toll样受体4；MyD88，髓系分化初级反应蛋白质88；NF-κB，核因子κB；miRNA，微RNA；5mC，5-甲基胞嘧啶；5hmC，5-羟甲基胞嘧啶；oxi-mC，氧化修饰胞嘧啶；5fC，5-甲酰基胞嘧啶；5caC，5-羧基胞嘧啶；TGF-β，转化生长因子β；IL，白细胞介素；Treg，调节性T细胞；Th17，辅助性T细胞17；HC，肝细胞；HSC，肝星状细胞；FOXP3，叉头框蛋白p3；STAT3，信号转导与转录激活因子3；RoRγt，视黄酸受体相关孤儿受体γt；GPR43，G蛋白偶联受体43；cAMP，环磷酸腺苷；PKA，环磷酸腺苷依赖性蛋白激酶A；AIH，自身免疫性肝炎。

图 1 肠道微生物-TET2-CD4⁺T细胞轴驱动AIH发展的分子机制

Figure 1. Molecular mechanism of the gut microbiota-TET2-CD4⁺T cell axis driving the development of AIH

下载: 全尺寸图片幻灯片

参考文献(49)

[1]	HARTL J, MIQUEL R, ZACHOU K, et al. Features and outcome of AIH patients without elevation of IgG[J]. JHEP Rep, 2020, 2( 3): 100094. DOI: 10.1016/j.jhepr.2020.100094.
[2]	STOELINGA AEC, BIEWENGA M, DRENTH JPH, et al. Diagnostic criteria and long-term outcomes in AIH-PBC variant syndrome under combination therapy[J]. JHEP Rep, 2024, 6( 7): 101088. DOI: 10.1016/j.jhepr.2024.101088.
[3]	LAPIERRE P, ALVAREZ F. Type 2 autoimmune hepatitis: Genetic susceptibility[J]. Front Immunol, 2022, 13: 1025343. DOI: 10.3389/fimmu.2022.1025343.
[4]	WANG L, CAO ZM, ZHANG LL, et al. The role of gut microbiota in some liver diseases: From an immunological perspective[J]. Front Immunol, 2022, 13: 923599. DOI: 10.3389/fimmu.2022.923599.
[5]	CHEN HR, HAN ZY, FAN YY, et al. CD4⁺ T-cell subsets in autoimmune hepatitis: A review[J]. Hepatol Commun, 2023, 7( 10): e0269. DOI: 10.1097/HC9.0000000000000269.
[6]	SHEN MY, ZHOU LY, FAN XL, et al. Metabolic reprogramming of CD4⁺ T cells by mesenchymal stem cell-derived extracellular vesicles attenuates autoimmune hepatitis through mitochondrial protein transfer[J]. Int J Nanomedicine, 2024, 19: 9799- 9819. DOI: 10.2147/IJN.S472086.
[7]	VUERICH M, WANG N, KALBASI A, et al. Dysfunctional immune regulation in autoimmune hepatitis: From pathogenesis to novel therapies[J]. Front Immunol, 2021, 12: 746436. DOI: 10.3389/fimmu.2021.746436.
[8]	MUSCATE F, WOESTEMEIER A, GAGLIANI N. Functional heterogeneity of CD4⁺ T cells in liver inflammation[J]. Semin Immunopathol, 2021, 43( 4): 549- 561. DOI: 10.1007/s00281-021-00881-w.
[9]	SIRBE C, SIMU G, SZABO I, et al. Pathogenesis of autoimmune hepatitis-cellular and molecular mechanisms[J]. Int J Mol Sci, 2021, 22( 24): 13578. DOI: 10.3390/ijms222413578.
[10]	ZHANG KH, LI JC, SHI Z, et al. Ginsenosides regulates innate immunity to affect immune microenvironment of AIH through hippo-YAP/TAZ signaling pathway[J]. Front Immunol, 2022, 13: 851560. DOI: 10.3389/fimmu.2022.851560.
[11]	LI YY. Modern epigenetics methods in biological research[J]. Methods, 2021, 187: 104- 113. DOI: 10.1016/j.ymeth.2020.06.022.
[12]	ÄIJÖ T, THEOFILATOS D, CHENG M, et al. TET proteins regulate T cell and iNKT cell lineage specification in a TET2 catalytic dependent manner[J]. Front Immunol, 2022, 13: 940995. DOI: 10.3389/fimmu.2022.940995.
[13]	GIOULBASANI M, ÄIJÖ T, LIU SY, et al. Concomitant loss of TET2 and TET3 results in T cell expansion and genomic instability in mice[J]. Commun Biol, 2024, 7( 1): 1606. DOI: 10.1038/s42003-024-07312-0.
[14]	CONG BY, ZHANG Q, CAO XT. The function and regulation of TET2 in innate immunity and inflammation[J]. Protein Cell, 2021, 12( 3): 165- 173. DOI: 10.1007/s13238-020-00796-6.
[15]	ZACHOU K, ARVANITI P, LYBEROPOULOU A, et al. Altered DNA methylation pattern characterizes the peripheral immune cells of patients with autoimmune hepatitis[J]. Liver Int, 2022, 42( 6): 1355- 1368. DOI: 10.1111/liv.15176.
[16]	BAESSLER A, NOVIS CL, SHEN ZL, et al. Tet2 coordinates with Foxo1 and Runx1 to balance T follicular helper cell and T helper 1 cell differentiation[J]. Sci Adv, 2022, 8( 24): eabm4982. DOI: 10.1126/sciadv.abm4982.
[17]	BAESSLER A, FUCHS B, PERKINS B, et al. Tet2 deletion in CD4⁺ T cells disrupts Th1 lineage commitment in memory cells and enhances T follicular helper cell recall responses to viral rechallenge[J]. Proc Natl Acad Sci USA, 2023, 120( 36): e2218324120. DOI: 10.1073/pnas.2218-324120.
[18]	CHEN J, LIU W, ZHU WJ. FOXP3⁺ Treg cells are associated with pathological process of autoimmune hepatitis by activating methylation modification in autoimmune hepatitis patients[J]. Med Sci Monit, 2019, 25: 6204- 6212. DOI: 10.12659/MSM.915408.
[19]	PRETI M, SCHLOTT L, LÜBBERING D, et al. Failure of thymic deletion and instability of autoreactive Tregs drive autoimmunity in immune-privileged liver[J]. JCI Insight, 2021, 6( 6): e141462. DOI: 10.1172/jci.insight.141462.
[20]	OHKURA N, SAKAGUCHI S. Transcriptional and epigenetic basis of Treg cell development and function: Its genetic anomalies or variations in autoimmune diseases[J]. Cell Res, 2020, 30( 6): 465- 474. DOI: 10.1038/s41422-020-0324-7.
[21]	BAI L, HAO XL, KEITH J, et al. DNA methylation in regulatory T cell differentiation and function: Challenges and opportunities[J]. Biomolecules, 2022, 12( 9): 1282. DOI: 10.3390/biom12091282.
[22]	YUE XJ, LIO CJ, SAMANIEGO-CASTRUITA D, et al. Loss of TET2 and TET3 in regulatory T cells unleashes effector function[J]. Nat Commun, 2019, 10( 1): 2011. DOI: 10.1038/s41467-019-09541-y.
[23]	PACINI G, PAOLINO S, ANDREOLI L, et al. Epigenetics, pregnancy and autoimmune rheumatic diseases[J]. Autoimmun Rev, 2020, 19( 12): 102685. DOI: 10.1016/j.autrev.2020.102685.
[24]	WANG QX, SELMI C, ZHOU XM, et al. Epigenetic considerations and the clinical reevaluation of the overlap syndrome between primary biliary cirrhosis and autoimmune hepatitis[J]. J Autoimmun, 2013, 41: 140- 145. DOI: 10.1016/j.jaut.2012.10.004.
[25]	MIGITA K, KOMORI A, KOZURU H, et al. Circulating microRNA profiles in patients with type-1 autoimmune hepatitis[J]. PLoS One, 2015, 10( 11): e 0136908.10.1371/journal.pone. 0136908.
[26]	PANDEY SP, BENDER MJ, MCPHERSON AC, et al. Tet2 deficiency drives liver microbiome dysbiosis triggering Tc1 cell autoimmune hepatitis[J]. Cell Host Microbe, 2022, 30( 7): 1003- 1019. DOI: 10.1016/j.chom.2022.05.006.
[27]	ZHANG GL, WU SS, XIA GT. miR-326 sponges TET2 triggering imbalance of Th17/Treg differentiation to exacerbate pyroptosis of hepatocytes in concanavalin A-induced autoimmune hepatitis[J]. Ann Hepatol, 2024, 29( 2): 101183. DOI: 10.1016/j.aohep.2023.101183.
[28]	TORP AUSTVOLL C, GALLO V, MONTAG D. Health impact of the Anthropocene: The complex relationship between gut microbiota, epigenetics, and human health, using obesity as an example[J]. Glob Health Epidemiol Genom, 2020, 5: e2. DOI: 10.1017/gheg.2020.2.
[29]	SUN HJ, GUO YK, WANG HD, et al. Gut commensal Parabacteroides distasonis alleviates inflammatory arthritis[J]. Gut, 2023, 72( 9): 1664- 1677. DOI: 10.1136/gutjnl-2022-327756.
[30]	LIU JZ, GUO M, YUAN XB, et al. Gut microbiota and their metabolites: The hidden driver of diabetic nephropathy? Unveiling gut microbe’s role in DN[J]. J Diabetes, 2025, 17( 4): e70068. DOI: 10.1111/1753-0407.70068.
[31]	TZENG HT, LEE WC. Impact of transgenerational nutrition on nonalcoholic fatty liver disease development: Interplay between gut microbiota, epigenetics and immunity[J]. Nutrients, 2024, 16( 9): 1388. DOI: 10.3390/nu16091388.
[32]	SZABO G, BALA S, PETRASEK J, et al. Gut-liver axis and sensing microbes[J]. Dig Dis, 2010, 28( 6): 737- 744. DOI: 10.1159/000324281.
[33]	WANG H, WANG GD, BANERJEE N, et al. Aberrant gut microbiome contributes to intestinal oxidative stress, barrier dysfunction, inflammation and systemic autoimmune responses in MRL/lpr mice[J]. Front Immunol, 2021, 12: 651191. DOI: 10.3389/fimmu.2021.651191.
[34]	CHEN Y, GAN YM, ZHONG HJ, et al. Gut microbe and hepatic macrophage polarization in non-alcoholic fatty liver disease[J]. Front Microbiol, 2023, 14: 1285473. DOI: 10.3389/fmicb.2023.1285473.
[35]	ZHANG HX, LIU M, LIU X, et al. Bifidobacterium animalis ssp. lactis 420 mitigates autoimmune hepatitis through regulating intestinal barrier and liver immune cells[J]. Front Immunol, 2020, 11: 569104. DOI: 10.3389/fimmu.2020.569104.
[36]	KANG YB, KUANG XY, YAN H, et al. A novel synbiotic alleviates autoimmune hepatitis by modulating the gut microbiota-liver axis and inhibiting the hepatic TLR4/NF-κB/NLRP3 signaling pathway[J]. mSystems, 2023, 8( 2): e01127-22. DOI: 10.1128/msystems.01127-22.
[37]	WOO V, ALENGHAT T. Epigenetic regulation by gut microbiota[J]. Gut Microbes, 2022, 14( 1): 2022407. DOI: 10.1080/19490976.2021.2022407.
[38]	LV JL, HAO PD, ZHOU Y, et al. Role of the intestinal flora-immunity axis in the pathogenesis of rheumatoid arthritis-mechanisms regulating short-chain fatty acids and Th17/Treg homeostasis[J]. Mol Biol Rep, 2025, 52( 1): 617. DOI: 10.1007/s11033-025-10714-w.
[39]	LYON P, STRIPPOLI V, FANG B, et al. B vitamins and one-carbon metabolism: Implications in human health and disease[J]. Nutrients, 2020, 12( 9): 2867. DOI: 10.3390/nu12092867.
[40]	ANSARI I, RADDATZ G, GUTEKUNST J, et al. The microbiota programs DNA methylation to control intestinal homeostasis and inflammation[J]. Nat Microbiol, 2020, 5( 4): 610- 619. DOI: 10.1038/s41564-019-0659-3.
[41]	FERENC K, SOKAL-DEMBOWSKA A, HELMA K, et al. Modulation of the gut microbiota by nutrition and its relationship to epigenetics[J]. Int J Mol Sci, 2024, 25( 2): 1228. DOI: 10.3390/ijms25021228.
[42]	AMES SR, LOTOSKI LC, AZAD MB. Comparing early life nutritional sources and human milk feeding practices: Personalized and dynamic nutrition supports infant gut microbiome development and immune system maturation[J]. Gut Microbes, 2023, 15( 1): 2190305. DOI: 10.1080/19490976.2023.2190305.
[43]	ALIPOUR B, HOMAYOUNI-RAD A, VAGHEF-MEHRABANY E, et al. Effects of Lactobacillus casei supplementation on disease activity and inflammatory cytokines in rheumatoid arthritis patients: A randomized double-blind clinical trial[J]. Int J Rheum Dis, 2014, 17( 5): 519- 527. DOI: 10.1111/1756-185X.12333.
[44]	MA ZY, AKHTAR M, PAN H, et al. Fecal microbiota transplantation improves chicken growth performance by balancing jejunal Th17/Treg cells[J]. Microbiome, 2023, 11( 1): 137. DOI: 10.1186/s40168-023-01569-z.
[45]	CHEN L, RUAN GC, CHENG Y, et al. The role of Th17 cells in inflammatory bowel disease and the research progress[J]. Front Immunol, 2022, 13: 1055914. DOI: 10.3389/fimmu.2022.1055914.
[46]	WU Q, GE Z, LV C, et al. Interacting roles of gut microbiota and T cells in the development of autoimmune hepatitis[J]. Front Immunol, 2025, 16: 1584001. DOI: 10.3389/fimmu.2025.1584001.
[47]	MA HL, GAO WS, SUN XX, et al. STAT5 and TET2 cooperate to regulate FOXP3-TSDR demethylation in CD4⁺ T cells of patients with colorectal cancer[J]. J Immunol Res, 2018, 2018: 6985031. DOI: 10.1155/2018/6985031.
[48]	GHORESCHI K, LAURENCE A, YANG XP, et al. T helper 17 cell heterogeneity and pathogenicity in autoimmune disease[J]. Trends Immunol, 2011, 32( 9): 395- 401. DOI: 10.1016/j.it.2011.06.007.
[49]	HU X, ZOU YL, COPLAND DA, et al. Epigenetic drug screen identified IOX1 as an inhibitor of Th17-mediated inflammation through targeting TET2[J]. EBioMedicine, 2022, 86: 104333. DOI: 10.1016/j.ebiom.2022.104333.