肠道菌群及其代谢产物在非酒精性脂肪性肝病发生发展及治疗中的作用

李永强; 唐文娟; 周永健

doi:10.3969/j.issn.1001-5256.2023.08.006

肠道菌群及其代谢产物在非酒精性脂肪性肝病发生发展及治疗中的作用

DOI: 10.3969/j.issn.1001-5256.2023.08.006

广州市第一人民医院(华南理工大学附属第二医院)消化内科，广州消化疾病中心，广州 510180

基金项目:

国家自然科学基金 (82170585);

国家自然科学基金 (81970507);

广州市医学重点学科 (2021-2023);

广州市科技计划项目 (SL2022A03J01100);

广东省自然科学基金 (2021A1515011290)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：李永强负责论文的拟定及撰写; 唐文娟负责论文的修改; 周永健参与修改论文并最后定稿。

详细信息

通信作者:
周永健，eyzhouyongjian@scut.edu.cn (ORCID: 0000-0003-1721-7639)

计量
- 文章访问数: 570
- HTML全文浏览量: 141
- PDF下载量: 128
- 被引次数: 0
出版历程
- 收稿日期: 2023-05-04
- 录用日期: 2023-06-04
- 出版日期: 2023-08-20

Role of intestinal microbiota and metabolites in the development, progression, and treatment of nonalcoholic fatty liver disease

Department of Gastroenterology, Guangzhou First People's Hospital & The Second Affiliated Hospital of South China University of Technology; Guangzhou Digestive Disease Center, Guangzhou 510180, China

Research funding:

National Natural Science Foundation of China (NSFC) (82170585);

National Natural Science Foundation of China (NSFC) (81970507);

The Project of Key Medical Discipline in Guangzhou (2021-2023);

Guangzhou Planned Project of Science and Technology (SL2022A03J01100);

National Natural Science Foundation of Guangdong Province (2021A1515011290)

More Information

Corresponding author: ZHOU Yongjian, eyzhouyongjian@scut.edu.cn (ORCID: 0000-0003-1721-7639)

摘要

摘要: 非酒精性脂肪性肝病(NAFLD)是全世界最为常见的慢性肝病。肝脏与肠道之间有着紧密的结构及功能关系即“肠-肝轴”，其中肠道菌群可通过菌群易位、内源性乙醇的产生、胆汁酸和胆碱代谢的调节异常、内毒素血症等参与NAFLD的发生、发展。本文主要关注肠道菌群及代谢产物在NAFLD发生、发展及治疗中的作用进展。
- 非酒精性脂肪性肝病 /
- 胃肠道微生物组 /
- 治疗学
Abstract: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease around the world. There is a close structural and functional relationship between the liver and the intestine, namely "the gut-liver axis", in which intestinal microbiota can participate in the development and progression of NAFLD through microbial translocation, production of endogenous ethanol, abnormal regulation of bile acid metabolism and choline metabolism, and endotoxemia. This article reviews the role of intestinal microbiota and metabolites in the development, progression, and treatment of NAFLD.
- Non-alcoholic Fatty Liver Disease /
- Gastrointestinal Microbiome /
- Therapeutics

HTML全文

参考文献(50)

[1]	XIAO J, WANG F, WONG NK, et al. Global liver disease burdens and research trends: Analysis from a Chinese perspective[J]. J Hepatol, 2019, 71(1): 212-221. DOI: 10.1016/j.jhep.2019.03.004.
[2]	KIM D, TOUROS A, KIM WR. Nonalcoholic fatty liver disease and metabolic syndrome[J]. Clin Liver Dis, 2018, 22(1): 133-140. DOI: 10.1016/j.cld.2017.08.010.
[3]	BUZZETTI E, PINZANI M, TSOCHATZIS EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)[J]. Metabolism, 2016, 65(8): 1038-1048. DOI: 10.1016/j.metabol.2015.12.012.
[4]	ECKBURG PB, BIK EM, BERNSTEIN CN, et al. Diversity of the human intestinal microbial flora[J]. Science, 2005, 308(5728): 1635-1638. DOI: 10.1126/science.1110591.
[5]	WANG B, JIANG X, CAO M, et al. Altered fecal microbiota correlates with liver biochemistry in nonobese patients with non-alcoholic fatty liver disease[J]. Sci Rep, 2016, 6: 32002. DOI: 10.1038/srep32002.
[6]	PARKS DJ, BLANCHARD SG, BLEDSOE RK, et al. Bile acids: natural ligands for an orphan nuclear receptor[J]. Science, 1999, 284(5418): 1365-1368. DOI: 10.1126/science.284.5418.1365.
[7]	CHIANG J. Bile acid metabolism and signaling in liver disease and therapy[J]. Liver Res, 2017, 1(1): 3-9. DOI: 10.1016/j.livres.2017.05.001.
[8]	CHÁVEZ-TALAVERA O, TAILLEUX A, LEFEBVRE P, et al. Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease[J]. Gastroenterology, 2017, 152(7): 1679-1694. e3. DOI: 10.1053/j.gastro.2017.01.055.
[9]	ARAB JP, KARPEN SJ, DAWSON PA, et al. Bile acids and nonalcoholic fatty liver disease: Molecular insights and therapeutic perspectives[J]. Hepatology, 2017, 65(1): 350-362. DOI: 10.1002/hep.28709.
[10]	CYPHERT HA, GE X, KOHAN AB, et al. Activation of the farnesoid X receptor induces hepatic expression and secretion of fibroblast growth factor 21[J]. J Biol Chem, 2012, 287(30): 25123-25138. DOI: 10.1074/jbc.M112.375907.
[11]	MINARD AY, TAN SX, YANG P, et al. mTORC1 is a major regulatory node in the FGF21 signaling network in adipocytes[J]. Cell Rep, 2016, 17(1): 29-36. DOI: 10.1016/j.celrep.2016.08.086.
[12]	DUTCHAK PA, KATAFUCHI T, BOOKOUT AL, et al. Fibroblast growth factor-21 regulates PPARγ activity and the antidiabetic actions of thiazolidinediones[J]. Cell, 2012, 148(3): 556-567. DOI: 10.1016/j.cell.2011.11.062.
[13]	MOURIES J, BRESCIA P, SILVESTRI A, et al. Microbiota-driven gut vascular barrier disruption is a prerequisite for non-alcoholic steatohepatitis development[J]. J Hepatol, 2019, 71(6): 1216-1228. DOI: 10.1016/j.jhep.2019.08.005.
[14]	LOU G, MA X, FU X, et al. GPBAR1/TGR5 mediates bile acid-induced cytokine expression in murine Kupffer cells[J]. PLoS One, 2014, 9(4): e93567. DOI: 10.1371/journal.pone.0093567.
[15]	WAHLSTRÖM A, SAYIN SI, MARSCHALL HU, et al. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism[J]. Cell Metab, 2016, 24(1): 41-50. DOI: 10.1016/j.cmet.2016.05.005.
[16]	HOUTEN SM, WATANABE M, AUWERX J. Endocrine functions of bile acids[J]. EMBO J, 2006, 25(7): 1419-1425. DOI: 10.1038/sj.emboj.7601049.
[17]	den BESTEN G, van EUNEN K, GROEN AK, et al. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism[J]. J Lipid Res, 2013, 54(9): 2325-2340. DOI: 10.1194/jlr.R036012.
[18]	CHAKRABORTI CK. New-found link between microbiota and obesity[J]. World J Gastrointest Pathophysiol, 2015, 6(4): 110-119. DOI: 10.4291/wjgp.v6.i4.110.
[19]	MOUZAKI M, LOOMBA R. Insights into the evolving role of the gut microbiome in nonalcoholic fatty liver disease: rationale and prospects for therapeutic intervention[J]. Therap Adv Gastroenterol, 2019, 12: 1756284819858470. DOI: 10.1177/1756284819858470.
[20]	SVEGLIATI-BARONI G, SACCOMANNO S, RYCHLICKI C, et al. Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis[J]. Liver Int, 2011, 31(9): 1285-1297. DOI: 10.1111/j.1478-3231.2011.02462.x.
[21]	SMITH PM, HOWITT MR, PANIKOV N, et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis[J]. Science, 2013, 341(6145): 569-573. DOI: 10.1126/science.1241165.
[22]	ZHOU D, PAN Q, XIN FZ, et al. Sodium butyrate attenuates high-fat diet-induced steatohepatitis in mice by improving gut microbiota and gastrointestinal barrier[J]. World J Gastroenterol, 2017, 23(1): 60-75. DOI: 10.3748/wjg.v23.i1.60.
[23]	SHARIFNIA T, ANTOUN J, VERRIERE TG, et al. Hepatic TLR4 signaling in obese NAFLD[J]. Am J Physiol Gastrointest Liver Physiol, 2015, 309(4): G270-G278. DOI: 10.1152/ajpgi.00304.2014.
[24]	CECCARELLI S, PANERA N, MINA M, et al. LPS-induced TNF-α factor mediates pro-inflammatory and pro-fibrogenic pattern in non-alcoholic fatty liver disease[J]. Oncotarget, 2015, 6(39): 41434-41452. DOI: 10.18632/oncotarget.5163.
[25]	NIGHOT M, AL-SADI R, GUO S, et al. Lipopolysaccharide-induced increase in intestinal epithelial tight permeability is mediated by toll-like receptor 4/Myeloid differentiation primary response 88 (MyD88) activation of myosin light chain kinase expression[J]. Am J Pathol, 2017, 187(12): 2698-2710. DOI: 10.1016/j.ajpath.2017.08.005.
[26]	HARTE AL, da SILVA NF, CREELY SJ, et al. Elevated endotoxin levels in non-alcoholic fatty liver disease[J]. J Inflamm (Lond), 2010, 7: 15. DOI: 10.1186/1476-9255-7-15.
[27]	ENGSTLER AJ, AUMILLER T, DEGEN C, et al. Insulin resistance alters hepatic ethanol metabolism: studies in mice and children with non-alcoholic fatty liver disease[J]. Gut, 2016, 65(9): 1564-1571. DOI: 10.1136/gutjnl-2014-308379.
[28]	ZHU L, BAKER SS, GILL C, et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH[J]. Hepatology, 2013, 57(2): 601-609. DOI: 10.1002/hep.26093.
[29]	BAKER SS, BAKER RD, LIU W, et al. Role of alcohol metabolism in non-alcoholic steatohepatitis[J]. PLoS One, 2010, 5(3): e9570. DOI: 10.1371/journal.pone.0009570.
[30]	CHEN X, ZHANG Z, LI H, et al. Endogenous ethanol produced by intestinal bacteria induces mitochondrial dysfunction in non-alcoholic fatty liver disease[J]. J Gastroenterol Hepatol, 2020, 35(11): 2009-2019. DOI: 10.1111/jgh.15027.
[31]	MIR H, MEENA AS, CHAUDHRY KK, et al. Occludin deficiency promotes ethanol-induced disruption of colonic epithelial junctions, gut barrier dysfunction and liver damage in mice[J]. Biochim Biophys Acta, 2016, 1860(4): 765-774. DOI: 10.1016/j.bbagen.2015.12.013.
[32]	HARTMANN P, SEEBAUER CT, MAZAGOVA M, et al. Deficiency of intestinal mucin-2 protects mice from diet-induced fatty liver disease and obesity[J]. Am J Physiol Gastrointest Liver Physiol, 2016, 310(5): G310-322. DOI: 10.1152/ajpgi.00094.2015.
[33]	CORBIN KD, ZEISEL SH. Choline metabolism provides novel insights into nonalcoholic fatty liver disease and its progression[J]. Curr Opin Gastroenterol, 2012, 28(2): 159-165. DOI: 10.1097/MOG.0b013e32834e7b4b.
[34]	YE JZ, LI YT, WU WR, et al. Dynamic alterations in the gut microbiota and metabolome during the development of methionine-choline-deficient diet-induced nonalcoholic steatohepatitis[J]. World J Gastroenterol, 2018, 24(23): 2468-2481. DOI: 10.3748/wjg.v24.i23.2468.
[35]	BARREA L, ANNUNZIATA G, MUSCOGIURI G, et al. Trimethylamine- N-oxide (TMAO) as novel potential biomarker of early predictors of metabolic syndrome[J]. Nutrients, 2018, 10(12): 1971. DOI: 10.3390/nu10121971.
[36]	ROMANO KA, MARTINEZ-DEL CAMPO A, KASAHARA K, et al. Metabolic, epigenetic, and transgenerational effects of gut bacterial choline consumption[J]. Cell Host Microbe, 2017, 22(3): 279-290. e7. DOI: 10.1016/j.chom.2017.07.021.
[37]	GAO X, LIU X, 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.
[38]	JÄGER R, MOHR AE, CARPENTER KC, et al. International society of sports nutrition position stand: probiotics[J]. J Int Soc Sports Nutr, 2019, 16(1): 62. DOI: 10.1186/s12970-019-0329-0.
[39]	ZHAO Z, WANG C, ZHANG L, et al. Lactobacillus plantarum NA136 improves the non-alcoholic fatty liver disease by modulating the AMPK/Nrf2 pathway[J]. Appl Microbiol Biotechnol, 2019, 103(14): 5843-5850. DOI: 10.1007/s00253-019-09703-4.
[40]	BRISKEY D, HERITAGE M, JASKOWSKI LA, et al. Probiotics modify tight-junction proteins in an animal model of nonalcoholic fatty liver disease[J]. Therap Adv Gastroenterol, 2016, 9(4): 463-472. DOI: 10.1177/1756283X16645055.
[41]	ALISI A, BEDOGNI G, BAVIERA G, et al. Randomised clinical trial: The beneficial effects of VSL#3 in obese children with non-alcoholic steatohepatitis[J]. Aliment Pharmacol Ther, 2014, 39(11): 1276-1285. DOI: 10.1111/apt.12758.
[42]	SEPIDEH A, KARIM P, HOSSEIN A, et al. Effects of multistrain probiotic supplementation on glycemic and inflammatory indices in patients with nonalcoholic fatty liver disease: a double-blind randomized clinical trial[J]. J Am Coll Nutr, 2016, 35(6): 500-505. DOI: 10.1080/07315724.2015.1031355.
[43]	ZVENIGORODSKAIA LA, CHERKASHOVA EA, SAMSONOVA NG, et al. Advisability of using probiotics in the treatment of atherogenic dyslipidemia[J]. Eksp Klin Gastroenterol, 2011, (2): 37-43.
[44]	SHAVAKHI A, MINAKARI M, FIROUZIAN H, et al. Effect of a probiotic and metformin on liver aminotransferases in non-alcoholic steatohepatitis: a double blind randomized clinical trial[J]. Int J Prev Med, 2013, 4(5): 531-537.
[45]	PACHIKIAN BD, ESSAGHIR A, DEMOULIN JB, et al. Prebiotic approach alleviates hepatic steatosis: implication of fatty acid oxidative and cholesterol synthesis pathways[J]. Mol Nutr Food Res, 2013, 57(2): 347-359. DOI: 10.1002/mnfr.201200364.
[46]	CANI PD, POSSEMIERS S, van de WIELE T, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability[J]. Gut, 2009, 58(8): 1091-1103. DOI: 10.1136/gut.2008.165886.
[47]	RASO GM, SIMEOLI R, IACONO A, et al. Effects of a Lactobacillus paracasei B21060 based synbiotic on steatosis, insulin signaling and toll-like receptor expression in rats fed a high-fat diet[J]. J Nutr Biochem, 2014, 25(1): 81-90. DOI: 10.1016/j.jnutbio.2013.09.006.
[48]	MALAGUARNERA M, VACANTE M, ANTIC T, et al. Bifidobacterium longum with fructo-oligosaccharides in patients with non alcoholic steatohepatitis[J]. Dig Dis Sci, 2012, 57(2): 545-553. DOI: 10.1007/s10620-011-1887-4.
[49]	LE ROY T, LLOPIS M, LEPAGE P, et al. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice[J]. Gut, 2013, 62(12): 1787-1794. DOI: 10.1136/gutjnl-2012-303816.
[50]	XUE L, DENG Z, LUO W, et al. Effect of fecal microbiota transplantation on non-alcoholic fatty liver disease: a randomized clinical trial[J]. Front Cell Infect Microbiol, 2022, 12: 759306. DOI: 10.3389/fcimb.2022.759306.