REFERENCES
1. Younossi Z, Anstee QM, Marietti M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2018;15:11-20.
2. European Association for the Study of the L, European Association for the Study of D, European Association for the Study of O. EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016;64:1388-402.
3. Eslam M, Sanyal AJ, George J; International Consensus P. MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease. Gastroenterology 2020;158:1999-2014 e1.
4. Eslam M, Newsome PN, Sarin SK, et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol 2020;73:202-9.
5. Eslam M, Sarin SK, Wong VW, et al. The Asian Pacific Association for the Study of the Liver clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease. Hepatol Int 2020; doi: 10.1007/s12072-020-10094-2.
6. Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 2010;52:1836-46.
7. Sender R, Fuchs S, Milo R. Are We Really Vastly Outnumbered? Revisiting the Ratio of Bacterial to Host Cells in Humans. Cell 2016;164:337-40.
8. De Filippis F, Pellegrini N, Vannini L, et al. High-level adherence to a Mediterranean diet beneficially impacts the gut microbiota and associated metabolome. Gut 2016;65:1812-21.
9. Yatsunenko T, Rey FE, Manary MJ, et al. Human gut microbiome viewed across age and geography. Nature 2012;486:222-7.
10. Backhed F, Ding H, Wang T, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A 2004;101:15718-23.
11. Backhed F, Manchester JK, Semenkovich CF, Gordon JI. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci U S A 2007;104:979-84.
12. Daniel H, Gholami AM, Berry D, et al. High-fat diet alters gut microbiota physiology in mice. ISME J 2014;8:295-308.
13. Le Roy T, Llopis M, Lepage P, et al. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut 2013;62:1787-94.
14. Wang R, Li H, Yang X, et al. Genetically Obese Human Gut Microbiota Induces Liver Steatosis in Germ-Free Mice Fed on Normal Diet. Front Microbiol 2018;9:1602.
15. Soderborg TK, Clark SE, Mulligan CE, et al. The gut microbiota in infants of obese mothers increases inflammation and susceptibility to NAFLD. Nat Commun 2018;9:4462.
16. Tsai MC, Liu YY, Lin CC, et al. Gut Microbiota Dysbiosis in Patients with Biopsy-Proven Nonalcoholic Fatty Liver Disease: A Cross-Sectional Study in Taiwan. Nutrients 2020;12.
17. Hoyles L, Fernandez-Real JM, Federici M, et al. Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women. Nat Med 2018;24:1070-80.
18. Shen F, Zheng RD, Sun XQ, Ding WJ, Wang XY, Fan JG. Gut microbiota dysbiosis in patients with non-alcoholic fatty liver disease. Hepatobiliary Pancreat Dis Int 2017;16:375-81.
19. Raman M, Ahmed I, Gillevet PM, et al. Fecal microbiome and volatile organic compound metabolome in obese humans with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2013;11:868-75 e1-3.
20. Loomba R, Seguritan V, Li W, et al. Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease. Cell Metab 2017;25:1054-62 e5.
21. Zhu L, Baker SS, Gill C, et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 2013;57:601-9.
22. Wang B, Jiang X, Cao M, et al. Altered Fecal Microbiota Correlates with Liver Biochemistry in Nonobese Patients with Non-alcoholic Fatty Liver Disease. Sci Rep 2016;6:32002.
23. Del Chierico F, Nobili V, Vernocchi P, et al. Gut microbiota profiling of pediatric nonalcoholic fatty liver disease and obese patients unveiled by an integrated meta-omics-based approach. Hepatology 2017;65:451-64.
24. Wong VW, Tse CH, Lam TT, et al. Molecular characterization of the fecal microbiota in patients with nonalcoholic steatohepatitis--a longitudinal study. PLoS One 2013;8:e62885.
25. Boursier J, Mueller O, Barret M, et al. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology 2016;63:764-75.
26. Schwimmer JB, Johnson JS, Angeles JE, et al. Microbiome Signatures Associated With Steatohepatitis and Moderate to Severe Fibrosis in Children With Nonalcoholic Fatty Liver Disease. Gastroenterology 2019;157:1109-22.
27. Caussy C, Tripathi A, Humphrey G, et al. A gut microbiome signature for cirrhosis due to nonalcoholic fatty liver disease. Nat Commun 2019;10:1406.
28. Qin N, Yang F, Li A, et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 2014;513:59-64.
29. Mouzaki M, Comelli EM, Arendt BM, et al. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology 2013;58:120-7.
30. Michail S, Lin M, Frey MR, et al. Altered gut microbial energy and metabolism in children with non-alcoholic fatty liver disease. FEMS Microbiol Ecol 2015;91:1-9.
31. Da Silva HE, Teterina A, Comelli EM, et al. Nonalcoholic fatty liver disease is associated with dysbiosis independent of body mass index and insulin resistance. Sci Rep 2018;8:1466.
32. Aron-Wisnewsky J, Vigliotti C, Witjes J, et al. Gut microbiota and human NAFLD: disentangling microbial signatures from metabolic disorders. Nat Rev Gastroenterol Hepatol 2020;17:279-97.
33. Bures J, Cyrany J, Kohoutova D, et al. Small intestinal bacterial overgrowth syndrome. World J Gastroenterol 2010;16:2978-90.
34. Wigg AJ, Roberts-Thomson IC, Dymock RB, McCarthy PJ, Grose RH, Cummins AG. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis. Gut 2001;48:206-11.
35. Miele L, Valenza V, La Torre G, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 2009;49:1877-87.
36. Rafiei R, Bemanian M, Rafiei F, et al. Liver disease symptoms in non-alcoholic fatty liver disease and small intestinal bacterial overgrowth. Rom J Intern Med 2018;56:85-9.
37. Saad RJ, Chey WD. Breath testing for small intestinal bacterial overgrowth: maximizing test accuracy. Clin Gastroenterol Hepatol 2014;12:1964-72. quiz e119-20
38. Ghoshal UC, Baba CS, Ghoshal U, et al. Low-grade small intestinal bacterial overgrowth is common in patients with non-alcoholic steatohepatitis on quantitative jejunal aspirate culture. Indian J Gastroenterol 2017;36:390-9.
39. Fei N, Bruneau A, Zhang X, et al. Endotoxin Producers Overgrowing in Human Gut Microbiota as the Causative Agents for Nonalcoholic Fatty Liver Disease. mBio 2020;11.
40. Volynets V, Kuper MA, Strahl S, et al. Nutrition, intestinal permeability, and blood ethanol levels are altered in patients with nonalcoholic fatty liver disease (NAFLD). Dig Dis Sci 2012;57:1932-41.
41. Giorgio V, Miele L, Principessa L, et al. Intestinal permeability is increased in children with non-alcoholic fatty liver disease, and correlates with liver disease severity. Dig Liver Dis 2014;46:556-60.
42. Luther J, Garber JJ, Khalili H, et al. Hepatic Injury in Nonalcoholic Steatohepatitis Contributes to Altered Intestinal Permeability. Cell Mol Gastroenterol Hepatol 2015;1:222-32.
43. Mouries J, Brescia P, Silvestri A, et al. Microbiota-driven gut vascular barrier disruption is a prerequisite for non-alcoholic steatohepatitis development. J Hepatol 2019;71:1216-28.
44. 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. Am J Pathol 2017;187:2698-710.
45. Guo S, Nighot M, Al-Sadi R, Alhmoud T, Nighot P, Ma TY. Lipopolysaccharide Regulation of Intestinal Tight Junction Permeability Is Mediated by TLR4 Signal Transduction Pathway Activation of FAK and MyD88. J Immunol 2015;195:4999-5010.
46. Pappo I, Becovier H, Berry EM, Freund HR. Polymyxin B reduces cecal flora, TNF production and hepatic steatosis during total parenteral nutrition in the rat. J Surg Res 1991;51:106-12.
47. Pappo I, Bercovier H, Berry EM, Haviv Y, Gallily R, Freund HR. Polymyxin B reduces total parenteral nutrition-associated hepatic steatosis by its antibacterial activity and by blocking deleterious effects of lipopolysaccharide. JPEN J Parenter Enteral Nutr 1992;16:529-32.
48. Sharifnia T, Antoun J, Verriere TG, et al. Hepatic TLR4 signaling in obese NAFLD. Am J Physiol Gastrointest Liver Physiol 2015;309:G270-8.
49. Harte AL, da Silva NF, Creely SJ, et al. Elevated endotoxin levels in non-alcoholic fatty liver disease. J Inflamm (Lond) 2010;7:15.
50. Cani PD, Amar J, Iglesias MA, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007;56:1761-72.
51. Kudo H, Takahara T, Yata Y, Kawai K, Zhang W, Sugiyama T. Lipopolysaccharide triggered TNF-alpha-induced hepatocyte apoptosis in a murine non-alcoholic steatohepatitis model. J Hepatol 2009;51:168-75.
52. Machado MV, Cortez-Pinto H. Gut microbiota and nonalcoholic fatty liver disease. Ann Hepatol 2012;11:440-9.
53. Abu-Shanab A, Quigley EM. The role of the gut microbiota in nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 2010;7:691-701.
54. Feldstein AE, Canbay A, Angulo P, et al. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology 2003;125:437-43.
55. Canbay A, Friedman S, Gores GJ. Apoptosis: the nexus of liver injury and fibrosis. Hepatology 2004;39:273-8.
56. Zhao P, Sun X, Chaggan C, et al. An AMPK-caspase-6 axis controls liver damage in nonalcoholic steatohepatitis. Science 2020;367:652-60.
57. Garcia-Martinez I, Santoro N, Chen Y, et al. Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9. J Clin Invest 2016;126:859-64.
58. An P, Wei LL, Zhao S, et al. Hepatocyte mitochondria-derived danger signals directly activate hepatic stellate cells and drive progression of liver fibrosis. Nat Commun 2020;11:2362.
59. Gomes MT, Campos PC, Pereira Gde S, Bartholomeu DC, Splitter G, Oliveira SC. TLR9 is required for MAPK/NF-kappaB activation but does not cooperate with TLR2 or TLR6 to induce host resistance to Brucella abortus. J Leukoc Biol 2016;99:771-80.
60. Kawasaki A, Karasudani Y, Otsuka Y, et al. Synthesis of diaminopimelic acid containing peptidoglycan fragments and tracheal cytotoxin (TCT) and investigation of their biological functions. Chemistry 2008;14:10318-30.
61. Yuan L, Bambha K. Bile acid receptors and nonalcoholic fatty liver disease. World J Hepatol 2015;7:2811-8.
62. Ridlon JM, Kang DJ, Hylemon PB. Bile salt biotransformations by human intestinal bacteria. J Lipid Res 2006;47:241-59.
63. Dawson PA, Karpen SJ. Intestinal transport and metabolism of bile acids. J Lipid Res 2015;56:1085-99.
64. Ferslew BC, Xie G, Johnston CK, et al. Altered Bile Acid Metabolome in Patients with Nonalcoholic Steatohepatitis. Dig Dis Sci 2015;60:3318-28.
65. Kalhan SC, Guo L, Edmison J, et al. Plasma metabolomic profile in nonalcoholic fatty liver disease. Metabolism 2011;60:404-13.
66. Mouzaki M, Wang AY, Bandsma R, et al. Bile Acids and Dysbiosis in Non-Alcoholic Fatty Liver Disease. PLoS One 2016;11:e0151829.
67. Appleby RN, Moghul I, Khan S, et al. Non-alcoholic fatty liver disease is associated with dysregulated bile acid synthesis and diarrhea: A prospective observational study. PLoS One 2019;14:e0211348.
68. Yara S IT, Miyazaki T, Murakami M, et al. Circulating bile acid profiles in Japanese patients with NASH. GastroHep 2019;1:302-10.
69. Chen J, Zheng M, Liu J, et al; Chinese NAFLD Clinical Research Network (CNAFLD CRN). Ratio of Conjugated Chenodeoxycholic to Muricholic Acids is Associated with Severity of Nonalcoholic Steatohepatitis. Obesity (Silver Spring) 2019;27:2055-66.
70. Pols TW, Noriega LG, Nomura M, Auwerx J, Schoonjans K. The bile acid membrane receptor TGR5: a valuable metabolic target. Dig Dis 2011;29:37-44.
71. Fiorucci S, Biagioli M, Zampella A, Distrutti E. Bile Acids Activated Receptors Regulate Innate Immunity. Front Immunol 2018;9:1853.
72. Molinaro A, Wahlstrom A, Marschall HU. Role of Bile Acids in Metabolic Control. Trends Endocrinol Metab 2018;29:31-41.
73. Kawamata Y, Fujii R, Hosoya M, et al. A G protein-coupled receptor responsive to bile acids. J Biol Chem 2003;278:9435-40.
74. Thomas C, Gioiello A, Noriega L, et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab 2009;10:167-77.
75. Keitel V, Donner M, Winandy S, Kubitz R, Haussinger D. Expression and function of the bile acid receptor TGR5 in Kupffer cells. Biochem Biophys Res Commun 2008;372:78-84.
76. Higuchi H, Bronk SF, Takikawa Y, et al. The bile acid glycochenodeoxycholate induces trail-receptor 2/DR5 expression and apoptosis. J Biol Chem 2001;276:38610-8.
77. Higuchi H, Grambihler A, Canbay A, Bronk SF, Gores GJ. Bile acids up-regulate death receptor 5/TRAIL-receptor 2 expression via a c-Jun N-terminal kinase-dependent pathway involving Sp1. J Biol Chem 2004;279:51-60.
78. Faubion WA, Guicciardi ME, Miyoshi H, et al. Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas. J Clin Invest 1999;103:137-45.
79. Qiao L, Studer E, Leach K, et al. Deoxycholic acid (DCA) causes ligand-independent activation of epidermal growth factor receptor (EGFR) and FAS receptor in primary hepatocytes: inhibition of EGFR/mitogen-activated protein kinase-signaling module enhances DCA-induced apoptosis. Mol Biol Cell 2001;12:2629-45.
80. Ibrahim S, Dayoub R, Krautbauer S, et al. Bile acid-induced apoptosis and bile acid synthesis are reduced by over-expression of Augmenter of Liver Regeneration (ALR) in a STAT3-dependent mechanism. Exp Cell Res 2019;374:189-97.
81. Schaap FG, Trauner M, Jansen PL. Bile acid receptors as targets for drug development. Nat Rev Gastroenterol Hepatol 2014;11:55-67.
82. Claudel T, Staels B, Kuipers F. The Farnesoid X receptor: a molecular link between bile acid and lipid and glucose metabolism. Arterioscler Thromb Vasc Biol 2005;25:2020-30.
83. Mudaliar S, Henry RR, Sanyal AJ, et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 2013;145:574-82 e1.
84. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015;385:956-65.
85. Younossi ZM, Ratziu V, Loomba R, et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2019;394:2184-96.
86. Siddiqui MS, Van Natta ML, Connelly MA, et al. Impact of obeticholic acid on the lipoprotein profile in patients with non-alcoholic steatohepatitis. J Hepatol 2020;72:25-33.
87. Pencek R, Marmon T, Roth JD, Liberman A, Hooshmand-Rad R, Young MA. Effects of obeticholic acid on lipoprotein metabolism in healthy volunteers. Diabetes Obes Metab 2016;18:936-40.
88. Pockros PJ, Fuchs M, Freilich B, et al. CONTROL: A randomized phase 2 study of obeticholic acid and atorvastatin on lipoproteins in nonalcoholic steatohepatitis patients. Liver Int 2019;39:2082-93.
89. Patel K, Harrison SA, Elkhashab M, et al. Cilofexor, a Nonsteroidal FXR Agonist, in Patients With Noncirrhotic NASH: A Phase 2 Randomized Controlled Trial. Hepatology 2020;72:58-71.
90. Pedrosa M, Seyedkazemi S, Francque S, et al. A randomized, double-blind, multicenter, phase 2b study to evaluate the safety and efficacy of a combination of tropifexor and cenicriviroc in patients with nonalcoholic steatohepatitis and liver fibrosis: Study design of the TANDEM trial. Contemp Clin Trials 2020;88:105889.
91. Friedman ES, Li Y, Shen TD, et al. FXR-Dependent Modulation of the Human Small Intestinal Microbiome by the Bile Acid Derivative Obeticholic Acid. Gastroenterology 2018;155:1741-52 e5.
92. Yajima M, Karaki SI, Tsuruta T, et al. Diversity of the intestinal microbiota differently affects non-neuronal and atropine-sensitive ileal contractile responses to short-chain fatty acids in mice. Biomed Res 2016;37:319-28.
93. Wolever TM, Brighenti F, Royall D, Jenkins AL, Jenkins DJ. Effect of rectal infusion of short chain fatty acids in human subjects. Am J Gastroenterol 1989;84:1027-33.
94. McNeil NI. The contribution of the large intestine to energy supplies in man. Am J Clin Nutr 1984;39:338-42.
95. Samuel BS, Shaito A, Motoike T, et al. Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc Natl Acad Sci U S A 2008;105:16767-72.
96. Musso G, Gambino R, Cassader M. Obesity, diabetes, and gut microbiota: the hygiene hypothesis expanded? Diabetes Care 2010;33:2277-84.
97. 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. Liver Int 2011;31:1285-97.
98. Tolhurst G, Heffron H, Lam YS, et al. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes 2012;61:364-71.
99. Ge H, Li X, Weiszmann J, et al. Activation of G protein-coupled receptor 43 in adipocytes leads to inhibition of lipolysis and suppression of plasma free fatty acids. Endocrinology 2008;149:4519-26.
100. Zhao S, Jang C, Liu J, et al. Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate. Nature 2020;579:586-91.
101. Hanson RW, Ballard FJ. The relative significance of acetate and glucose as precursors for lipid synthesis in liver and adipose tissue from ruminants. Biochem J 1967;105:529-36.
102. den Besten G, Lange K, Havinga R, et al. Gut-derived short-chain fatty acids are vividly assimilated into host carbohydrates and lipids. Am J Physiol Gastrointest Liver Physiol 2013;305:G900-10.
103. Weidemann MJ, Hems R, Williams DL, Spray GH, Krebs HA. Gluconeogenesis from propionate in kidney and liver of the vitamin B12-deficient rat. Biochem J 1970;117:177-81.
104. Iannucci LF, Sun J, Singh BK, et al. Short chain fatty acids induce UCP2-mediated autophagy in hepatic cells. Biochem Biophys Res Commun 2016;480:461-7.
105. Singh R, Kaushik S, Wang Y, et al. Autophagy regulates lipid metabolism. Nature 2009;458:1131-5.
106. Sinha RA, You SH, Zhou J, et al. Thyroid hormone stimulates hepatic lipid catabolism via activation of autophagy. J Clin Invest 2012;122:2428-38.
107. Gao Z, Yin J, Zhang J, et al. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes 2009;58:1509-17.
108. den Besten G, Bleeker A, Gerding A, et al. Short-Chain Fatty Acids Protect Against High-Fat Diet-Induced Obesity via a PPARgamma-Dependent Switch From Lipogenesis to Fat Oxidation. Diabetes 2015;64:2398-408.
109. Waldecker M, Kautenburger T, Daumann H, Busch C, Schrenk D. Inhibition of histone-deacetylase activity by short-chain fatty acids and some polyphenol metabolites formed in the colon. J Nutr Biochem 2008;19:587-93.
110. Juanola O, Ferrusquia-Acosta J, Garcia-Villalba R, et al. Circulating levels of butyrate are inversely related to portal hypertension, endotoxemia, and systemic inflammation in patients with cirrhosis. FASEB J 2019;33:11595-605.
111. Zhai S, Qin S, Li L, Zhu L, Zou Z, Wang L. Dietary butyrate suppresses inflammation through modulating gut microbiota in high-fat diet-fed mice. FEMS Microbiol Lett 2019;366.
112. Sun B, Jia Y, Hong J, et al. Sodium Butyrate Ameliorates High-Fat-Diet-Induced Non-alcoholic Fatty Liver Disease through Peroxisome Proliferator-Activated Receptor alpha-Mediated Activation of beta Oxidation and Suppression of Inflammation. J Agric Food Chem 2018;66:7633-42.
113. Baumann A, Jin CJ, Brandt A, et al. Oral Supplementation of Sodium Butyrate Attenuates the Progression of Non-Alcoholic Steatohepatitis. Nutrients 2020;12.
114. Cope K, Risby T, Diehl AM. Increased gastrointestinal ethanol production in obese mice: implications for fatty liver disease pathogenesis. Gastroenterology 2000;119:1340-7.
115. Dawes EA, Foster SM. The formation of ethanol in Escherichia coli. Biochim Biophys Acta 1956;22:253-65.
116. Nair S, Cope K, Risby TH, Diehl AM. Obesity and female gender increase breath ethanol concentration: potential implications for the pathogenesis of nonalcoholic steatohepatitis. Am J Gastroenterol 2001;96:1200-4.
117. Baker SS, Baker RD, Liu W, Nowak NJ, Zhu L. Role of alcohol metabolism in non-alcoholic steatohepatitis. PLoS One 2010;5:e9570.
118. 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. Gut 2016;65:1564-71.
119. Gaitantzi H, Meyer C, Rakoczy P, et al. Ethanol sensitizes hepatocytes for TGF-beta-triggered apoptosis. Cell Death Dis 2018;9:51.
120. Parlesak A, Schafer C, Schutz T, Bode JC, Bode C. Increased intestinal permeability to macromolecules and endotoxemia in patients with chronic alcohol abuse in different stages of alcohol-induced liver disease. J Hepatol 2000;32:742-7.
121. Wang Z, Klipfell E, Bennett BJ, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011;472:57-63.
122. Mehedint MG, Zeisel SH. Choline’s role in maintaining liver function: new evidence for epigenetic mechanisms. Curr Opin Clin Nutr Metab Care 2013;16:339-45.
123. Yao ZM, Vance DE. Reduction in VLDL, but not HDL, in plasma of rats deficient in choline. Biochem Cell Biol 1990;68:552-8.
124. Stephenson K, Kennedy L, Hargrove L, et al. Updates on Dietary Models of Nonalcoholic Fatty Liver Disease: Current Studies and Insights. Gene Expr 2018;18:5-17.
125. Dumas ME, Barton RH, Toye A, et al. Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proc Natl Acad Sci U S A 2006;103:12511-6.
126. Koeth RA, Wang Z, Levison BS, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 2013;19:576-85.
127. Chen YM, Liu Y, Zhou RF, et al. Associations of gut-flora-dependent metabolite trimethylamine-N-oxide, betaine and choline with non-alcoholic fatty liver disease in adults. Sci Rep 2016;6:19076.
128. Leon-Mimila P, Villamil-Ramirez H, Li XS, et al. Trimethylamine N-oxide levels are associated with NASH in obese subjects with type 2 diabetes. Diabetes Metab 2020; doi: 10.1016/j.diabet.2020.07.010.
129. Barrea L, Annunziata G, Muscogiuri G, et al. Trimethylamine-N-oxide (TMAO) as Novel Potential Biomarker of Early Predictors of Metabolic Syndrome. Nutrients 2018;10.
130. De Chiara F, Thomsen KL, Habtesion A, et al. Ammonia Scavenging Prevents Progression of Fibrosis in Experimental Nonalcoholic Fatty Liver Disease. Hepatology 2020;71:874-92.
131. De Chiara F, Heeboll S, Marrone G, et al. Urea cycle dysregulation in non-alcoholic fatty liver disease. J Hepatol 2018;69:905-15.
132. Thomsen KL, De Chiara F, Rombouts K, et al. Ammonia: A novel target for the treatment of non-alcoholic steatohepatitis. Med Hypotheses 2018;113:91-7.
133. Richardson AJ, McKain N, Wallace RJ. Ammonia production by human faecal bacteria, and the enumeration, isolation and characterization of bacteria capable of growth on peptides and amino acids. BMC Microbiol 2013;13:6.
134. Wiest R, Albillos A, Trauner M, Bajaj JS, Jalan R. Targeting the gut-liver axis in liver disease. J Hepatol 2017;67:1084-103.
135. Jiang C, Xie C, Li F, et al. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J Clin Invest 2015;125:386-402.
136. Wu WC, Zhao W, Li S. Small intestinal bacteria overgrowth decreases small intestinal motility in the NASH rats. World J Gastroenterol 2008;14:313-7.
137. Gangarapu V, Ince AT, Baysal B, et al. Efficacy of rifaximin on circulating endotoxins and cytokines in patients with nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol 2015;27:840-5.
138. Paolella G, Mandato C, Pierri L, Poeta M, Di Stasi M, Vajro P. Gut-liver axis and probiotics: their role in non-alcoholic fatty liver disease. World J Gastroenterol 2014;20:15518-31.
139. Hu H, Lin A, Kong M, et al. Intestinal microbiome and NAFLD: molecular insights and therapeutic perspectives. J Gastroenterol 2020;55:142-58.
140. Jayakumar S, Loomba R. Review article: emerging role of the gut microbiome in the progression of nonalcoholic fatty liver disease and potential therapeutic implications. Aliment Pharmacol Ther 2019;50:144-58.
141. Perdomo CM, Fruhbeck G, Escalada J. Impact of Nutritional Changes on Nonalcoholic Fatty Liver Disease. Nutrients 2019;11.
142. Xiao MW, Lin SX, Shen ZH, Luo WW, Wang XY. Systematic Review with Meta-Analysis: The Effects of Probiotics in Nonalcoholic Fatty Liver Disease. Gastroenterol Res Pract 2019;2019:1484598.
143. Ma YY, Li L, Yu CH, Shen Z, Chen LH, Li YM. Effects of probiotics on nonalcoholic fatty liver disease: a meta-analysis. World J Gastroenterol 2013;19:6911-8.
144. Alisi A, Carpino G, Nobili V. Paediatric nonalcoholic fatty liver disease. Curr Opin Gastroenterol 2013;29:279-84.
145. Liu Q, Liu Y, Li F, et al. Probiotic culture supernatant improves metabolic function through FGF21-adiponectin pathway in mice. J Nutr Biochem 2020;75:108256.
146. 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 Nutr Biochem 2014;25:81-90.
147. Malaguarnera G, Leggio F, Vacante M, et al. Probiotics in the gastrointestinal diseases of the elderly. J Nutr Health Aging 2012;16:402-10.
148. Asgharian A, Askari G, Esmailzade A, Feizi A, Mohammadi V. The Effect of Symbiotic Supplementation on Liver Enzymes, C-reactive Protein and Ultrasound Findings in Patients with Non-alcoholic Fatty Liver Disease: A Clinical Trial. Int J Prev Med 2016;7:59.
149. Song Y, Garg S, Girotra M, et al. Microbiota dynamics in patients treated with fecal microbiota transplantation for recurrent Clostridium difficile infection. PLoS One 2013;8:e81330.
150. Kelly CR, Khoruts A, Staley C, et al. Effect of Fecal Microbiota Transplantation on Recurrence in Multiply Recurrent Clostridium difficile Infection: A Randomized Trial. Ann Intern Med 2016;165:609-16.
151. Zhou D, Pan Q, Shen F, et al. Total fecal microbiota transplantation alleviates high-fat diet-induced steatohepatitis in mice via beneficial regulation of gut microbiota. Sci Rep 2017;7:1529.
152. Porras D, Nistal E, Martinez-Florez S, Gonzalez-Gallego J, Garcia-Mediavilla MV, Sanchez-Campos S. Intestinal Microbiota Modulation in Obesity-Related Non-alcoholic Fatty Liver Disease. Front Physiol 2018;9:1813.
153. Vrieze A, Van Nood E, Holleman F, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 2012;143:913-6 e7.
154. Garcia-Lezana T, Raurell I, Bravo M, et al. Restoration of a healthy intestinal microbiota normalizes portal hypertension in a rat model of nonalcoholic steatohepatitis. Hepatology 2018;67:1485-98.
155. Day CP, Saksena S. Non-alcoholic steatohepatitis: definitions and pathogenesis. J Gastroenterol Hepatol 2002;17 Suppl 3:S377-84.
156. Hardy T, Oakley F, Anstee QM, Day CP. Nonalcoholic Fatty Liver Disease: Pathogenesis and Disease Spectrum. Annu Rev Pathol 2016;11:451-96.
157. Powell EE, Cooksley WG, Hanson R, Searle J, Halliday JW, Powell LW. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology 1990;11:74-80.
158. Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 2010;51:1972-8.
159. Sanyal A, Poklepovic A, Moyneur E, Barghout V. Population-based risk factors and resource utilization for HCC: US perspective. Curr Med Res Opin 2010;26:2183-91.
160. Kim GA, Lee HC, Choe J, et al. Association between non-alcoholic fatty liver disease and cancer incidence rate. J Hepatol 2017; doi: 10.1016/j.jhep.2017.09.012.
161. Pais R, Fartoux L, Goumard C, et al. Temporal trends, clinical patterns and outcomes of NAFLD-related HCC in patients undergoing liver resection over a 20-year period. Aliment Pharmacol Ther 2017;46:856-63.
162. Tsuchida T, Lee YA, Fujiwara N, et al. A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer. J Hepatol 2018;69:385-95.
163. Raza S, Rajak S, Anjum B, Sinha RA. Molecular links between non-alcoholic fatty liver disease and hepatocellular carcinoma. Hepatoma Res 2019;5:42.
164. Hirsova P, Bohm F, Dohnalkova E, et al. Hepatocyte apoptosis is tumor promoting in murine nonalcoholic steatohepatitis. Cell Death Dis 2020;11:80.
165. Michelotti GA, Machado MV, Diehl AM. NAFLD, NASH and liver cancer. Nat Rev Gastroenterol Hepatol 2013;10:656-65.
166. Cholankeril G, Patel R, Khurana S, Satapathy SK. Hepatocellular carcinoma in non-alcoholic steatohepatitis: Current knowledge and implications for management. World J Hepatol 2017;9:533-43.
167. Ponziani FR, Bhoori S, Castelli C, et al. Hepatocellular Carcinoma Is Associated With Gut Microbiota Profile and Inflammation in Nonalcoholic Fatty Liver Disease. Hepatology 2019;69:107-20.
168. Chen YH, Wu WK, Wu MS. Microbiota-Associated Therapy for Non-Alcoholic Steatohepatitis-Induced Liver Cancer: A Review. Int J Mol Sci 2020;21.
169. Dapito DH, Mencin A, Gwak GY, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 2012;21:504-16.
170. Yuan D, Huang S, Berger E, et al. Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS. Cancer Cell 2017;31:771-89 e6.
171. Loo TM, Kamachi F, Watanabe Y, et al. Gut Microbiota Promotes Obesity-Associated Liver Cancer through PGE2-Mediated Suppression of Antitumor Immunity. Cancer Discov 2017;7:522-38.
172. Wang X, Fu X, Van Ness C, Meng Z, Ma X, Huang W. Bile Acid Receptors and Liver Cancer. Curr Pathobiol Rep 2013;1:29-35.
173. Chen T, Xie G, Wang X, et al. Serum and urine metabolite profiling reveals potential biomarkers of human hepatocellular carcinoma. Mol Cell Proteomics 2011;10:M110 004945.
175. Knisely AS, Strautnieks SS, Meier Y, et al. Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency. Hepatology 2006;44:478-86.
176. Ma C, Han M, Heinrich B, et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science 2018;360.