Mechanistic and therapeutic advances in non-alcoholic fatty liver disease by targeting the gut microbiota

Abstract

Non-alcoholic fatty liver disease (NAFLD) is one of the most common metabolic diseases currently in the context of obesity worldwide, which contains a spectrum of chronic liver diseases, including hepatic steatosis, non-alcoholic steatohepatitis and hepatic carcinoma. In addition to the classical “Two-hit” theory, NAFLD has been recognized as a typical gut microbiota-related disease because of the intricate role of gut microbiota in maintaining human health and disease formation. Moreover, gut microbiota is even regarded as a “metabolic organ” that play complementary roles to that of liver in many aspects. The mechanisms underlying gut microbiota-mediated development of NAFLD include modulation of host energy metabolism, insulin sensitivity, and bile acid and choline metabolism. As a result, gut microbiota have been emerging as a novel therapeutic target for NAFLD by manipulating it in various ways, including probiotics, prebiotics, synbiotics, antibiotics, fecal microbiota transplantation, and herbal components. In this review, we summarized the most recent advances in gut microbiota-mediated mechanisms, as well as gut microbiota-targeted therapies on NAFLD.

Keywords

gut microbiota / NAFLD / obesity / insulin resistance / bile acids / probiotic

References

[1] Martinez KB, Leone V, Chang EB. Microbial metabolites in health and disease: navigating the unknown in search of function. J Biol Chem 2017; 292(21): 8553–8559

[2] Clarke G, Stilling RM, Kennedy PJ, Stanton C, Cryan JF, Dinan TG. Minireview: Gut microbiota: the neglected endocrine organ. Mol Endocrinol 2014; 28(8): 1221–1238

[3] Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Nielsen T, Pons N, Levenez F, Yamada T, Mende DR, Li J, Xu J, Li S, Li D, Cao J, Wang B, Liang H, Zheng H, Xie Y, Tap J, Lepage P, Bertalan M, Batto JM, Hansen T, Le Paslier D, Linneberg A, Nielsen HB, Pelletier E, Renault P, Sicheritz-Ponten T, Turner K, Zhu H, Yu C, Li S, Jian M, Zhou Y, Li Y, Zhang X, Li S, Qin N, Yang H, Wang J, Brunak S, Doré J, Guarner F, Kristiansen K, Pedersen O, Parkhill J, Weissenbach J, Bork P, Ehrlich SD, Wang J. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010; 464(7285): 59–65

[4] Claesson MJ, Cusack S, O’Sullivan O, Greene-Diniz R, de Weerd H, Flannery E, Marchesi JR, Falush D, Dinan T, Fitzgerald G, Stanton C, van Sinderen D, O’Connor M, Harnedy N, O’Connor K, Henry C, O’Mahony D, Fitzgerald AP, Shanahan F, Twomey C, Hill C, Ross RP, O’Toole PW. Composition, variability, and temporal stability of the intestinal microbiota of the elderly. Proc Natl Acad Sci USA 2011; 108(Suppl 1): 4586–4591

[5] He X, Ji G, Jia W, Li H. Gut microbiota and nonalcoholic fatty liver disease: insights on mechanism and application of metabolomics. Int J Mol Sci 2016; 17(3): 300

[6] Bordalo Tonucci L, Dos Santos KM, De Luces Fortes Ferreira CL, Ribeiro SM, De Oliveira LL, Martino HS. Gut microbiota and probiotics: focus on diabetes mellitus. Crit Rev Food Sci Nutr 2017; 57(11): 2296–2309

[7] Kvit KB, Kharchenko NV. Gut microbiota changes as a risk factor for obesity. Wiad Lek 2017; 70(2): 231–235

[8] Valsecchi C, Carlotta Tagliacarne S, Castellazzi A. Gut microbiota and obesity. J Clin Gastroenterol 2016; 50(Suppl 2): S157–S158

[9] Sanduzzi Zamparelli M, Compare D, Coccoli P, Rocco A, Nardone OM, Marrone G, Gasbarrini A, Grieco A, Nardone G, Miele L. The metabolic role of gut microbiota in the development of nonalcoholic fatty liver disease and cardiovascular disease. Int J Mol Sci 2016; 17(8): E1225

[10] Lambert JE, Parnell JA, Eksteen B, Raman M, Bomhof MR, Rioux KP, Madsen KL, Reimer RA. Gut microbiota manipulation with prebiotics in patients with non-alcoholic fatty liver disease: a randomized controlled trial protocol. BMC Gastroenterol 2015; 15(1): 169

[11] Mahana D, Trent CM, Kurtz ZD, Bokulich NA, Battaglia T, Chung J, Müller CL, Li H, Bonneau RA, Blaser MJ. Antibiotic perturbation of the murine gut microbiome enhances the adiposity, insulin resistance, and liver disease associated with high-fat diet. Genome Med 2016; 8(1): 48

[12] Sze MA, Schloss PD. Looking for a signal in the noise: revisiting obesity and the microbiome. MBio 2016; 7(4): e01018-16

[13] Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol 2013; 10(11): 686–690

[14] Wree A, Broderick L, Canbay A, Hoffman HM, Feldstein AE. From NAFLD to NASH to cirrhosis—new insights into disease mechanisms. Nat Rev Gastroenterol Hepatol 2013; 10(11): 627–636

[15] Liu W, Baker RD, Bhatia T, Zhu L, Baker SS. Pathogenesis of nonalcoholic steatohepatitis. Cell Mol Life Sci 2016; 73(10): 1969–1987

[16] Hoefert B. Über die bakterienbefunde im duodenalsaft von gesunden und kranken. Zschr Klin Med 1921; 92: 221–235 (In German)

[17] Dumas ME, Barton RH, Toye A, Cloarec O, Blancher C, Rothwell A, Fearnside J, Tatoud R, Blanc V, Lindon JC, Mitchell SC, Holmes E, McCarthy MI, Scott J, Gauguier D, Nicholson JK. Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proc Natl Acad Sci USA 2006; 103(33): 12511–12516

[18] Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology 1998; 114(4): 842–845

[19] Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature 2006; 444(7122): 1022–1023

[20] Cani PD, Delzenne NM. The role of the gut microbiota in energy metabolism and metabolic disease. Curr Pharm Des 2009; 15(13): 1546–1558

[21] Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, Liang S, Zhang W, Guan Y, Shen D, Peng Y, Zhang D, Jie Z, Wu W, Qin Y, Xue W, Li J, Han L, Lu D, Wu P, Dai Y, Sun X, Li Z, Tang A, Zhong S, Li X, Chen W, Xu R, Wang M, Feng Q, Gong M, Yu J, Zhang Y, Zhang M, Hansen T, Sanchez G, Raes J, Falony G, Okuda S, Almeida M, LeChatelier E, Renault P, Pons N, Batto JM, Zhang Z, Chen H, Yang R, Zheng W, Li S, Yang H, Wang J, Ehrlich SD, Nielsen R, Pedersen O, Kristiansen K, Wang J. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 2012; 490(7418): 55–60

[22] Delzenne NM, Cani PD, Everard A, Neyrinck AM, Bindels LB. Gut microorganisms as promising targets for the management of type 2 diabetes. Diabetologia 2015; 58(10): 2206–2217

[23] Escobedo G, López-Ortiz E, Torres-Castro I. Gut microbiota as a key player in triggering obesity, systemic inflammation and insulin resistance. Rev Invest Clin 2014; 66(5): 450–459

[24] Mehal WZ. The Gordian Knot of dysbiosis, obesity and NAFLD. Nat Rev Gastroenterol Hepatol 2013; 10(11): 637–644

[25] Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, Thaiss CA, Kau AL, Eisenbarth SC, Jurczak MJ, Camporez JP, Shulman GI, Gordon JI, Hoffman HM, Flavell RA. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 2012; 482(7384): 179–185

[26] DiBaise JK, Zhang H, Crowell MD, Krajmalnik-Brown R, Decker GA, Rittmann BE. Gut microbiota and its possible relationship with obesity. Mayo Clin Proc 2008; 83(4): 460–469

[27] Wieland A, Frank DN, Harnke B, Bambha K. Systematic review: microbial dysbiosis and nonalcoholic fatty liver disease. Aliment Pharmacol Ther 2015; 42(9): 1051–1063

[28] Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, Sogin ML, Jones WJ, Roe BA, Affourtit JP, Egholm M, Henrissat B, Heath AC, Knight R, Gordon JI. A core gut microbiome in obese and lean twins. Nature 2009; 457(7228): 480–484

[29] Bäckhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, Semenkovich CF, Gordon JI. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA 2004; 101(44): 15718–15723

[30] Dutton S, Trayhurn P. Regulation of angiopoietin-like protein 4/fasting-induced adipose factor (Angptl4/FIAF) expression in mouse white adipose tissue and 3T3-L1 adipocytes. Br J Nutr 2008; 100(1): 18–26

[31] Bäckhed F, Manchester JK, Semenkovich CF, Gordon JI. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci USA 2007; 104(3): 979–984

[32] Hong YH, Nishimura Y, Hishikawa D, Tsuzuki H, Miyahara H, Gotoh C, Choi KC, Feng DD, Chen C, Lee HG, Katoh K, Roh SG, Sasaki S. Acetate and propionate short chain fatty acids stimulate adipogenesis via GPCR43. Endocrinology 2005; 146(12): 5092–5099

[33] Polyzos SA, Kountouras J, Zavos C. Nonalcoholic fatty liver disease: the pathogenetic roles of insulin resistance and adipocytokines. Curr Mol Med 2009; 9(3): 299–314

[34] Samuel BS, Shaito A, Motoike T, Rey FE, Backhed F, Manchester JK, Hammer RE, Williams SC, Crowley J, Yanagisawa M, Gordon JI. 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 USA 2008; 105(43): 16767–16772

[35] Wong JM, de Souza R, Kendall CW, Emam A, Jenkins DJ. Colonic health: fermentation and short chain fatty acids. J Clin Gastroenterol 2006; 40(3): 235–243

[36] Kimura I, Inoue D, Maeda T, Hara T, Ichimura A, Miyauchi S, Kobayashi M, Hirasawa A, Tsujimoto G. Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc Natl Acad Sci USA 2011; 108(19): 8030–8035

[37] Yadav H, Lee JH, Lloyd J, Walter P, Rane SG. Beneficial metabolic effects of a probiotic via butyrate-induced GLP-1 hormone secretion. J Biol Chem 2013; 288(35): 25088–25097

[38] Leung C, Rivera L, Furness JB, Angus PW. The role of the gut microbiota in NAFLD. Nat Rev Gastroenterol Hepatol 2016; 13(7): 412–425

[39] Kant P, Hull MA. Excess body weight and obesity—the link with gastrointestinal and hepatobiliary cancer. Nat Rev Gastroenterol Hepatol 2011; 8(4): 224–238

[40] Pagano G, Pacini G, Musso G, Gambino R, Mecca F, Depetris N, Cassader M, David E, Cavallo-Perin P, Rizzetto M. Nonalcoholic steatohepatitis, insulin resistance, and metabolic syndrome: further evidence for an etiologic association. Hepatology 2002; 35(2): 367–372

[41] Cani PD, Delzenne NM. Gut microflora as a target for energy and metabolic homeostasis. Curr Opin Clin Nutr Metab Care 2007; 10(6): 729–734

[42] Perry RJ, Peng L, Barry NA, Cline GW, Zhang D, Cardone RL, Petersen KF, Kibbey RG, Goodman AL, Shulman GI. Acetate mediates a microbiome-brain-β-cell axis to promote metabolic syndrome. Nature 2016; 534(7606): 213–217

[43] Fialho A, Fialho A, Thota P, McCullough AJ, Shen B. Small intestinal bacterial overgrowth is associated with non-alcoholic fatty liver disease. J Gastrointestin Liver Dis 2016; 25(2): 159–165 doi:10.15403/jgld.2014.1121.252.iwg

[44] Wu WC, Zhao W, Li S. Small intestinal bacteria overgrowth decreases small intestinal motility in the NASH rats. World J Gastroenterol 2008; 14(2): 313–317

[45] 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 α in the pathogenesis of non-alcoholic steatohepatitis. Gut 2001; 48(2): 206–211

[46] Saito T, Hayashida H, Furugen R. Comment on: Cani et al. (2007) Metabolic endotoxemia initiates obesity and insulin resistance: Diabetes 56:1761–1772. Diabetes 2007; 56(12): e20 DOI:10.2337/db07-1181

[47] Brun P, Castagliuolo I, Di Leo V, Buda A, Pinzani M, Palù G, Martines D. Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol 2007; 292(2): G518–G525

[48] Bluemel S, Williams B, Knight R, Schnabl B. Precision medicine in alcoholic and nonalcoholic fatty liver disease via modulating the gut microbiota. Am J Physiol Gastrointest Liver Physiol 2016; 311(6): G1018–G1036

[49] Kessoku T, Imajo K, Honda Y, Kato T, Ogawa Y, Tomeno W, Higurashi T, Yoneda M, Shimakawa M, Tanaka Y, Kawahara T, Saito S, Haruki U, Wada K, Nakajima A, Tanaka Y. Characteristics of fecal microbiota in Japanese patients with nonalcoholic fatty liver disease: a connection among gut-permeability, endotoxin and NAFLD. Gastroenterology 2017; 152(5): S1200

[50] Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmée E, Cousin B, Sulpice T, Chamontin B, Ferrières J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007; 56(7): 1761–1772

[51] Bilzer M, Roggel F, Gerbes AL. Role of Kupffer cells in host defense and liver disease. Liver Int 2006; 26(10): 1175–1186

[52] Stams AJ, Plugge CM. Electron transfer in syntrophic communities of anaerobic bacteria and archaea. Nat Rev Microbiol 2009; 7(8): 568–577

[53] Kim JJ, Sears DD. TLR4 and Insulin Resistance. Gastroenterol Res Pract 2010; 2010: 212563

[54] Farrell GC. Signalling links in the liver: knitting SOCS with fat and inflammation. J Hepatol 2005; 43(1): 193–196

[55] Alisi A, Manco M, Devito R, Piemonte F, Nobili V. Endotoxin and plasminogen activator inhibitor-1 serum levels associated with nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr 2010; 50(6): 645–649

[56] Creely SJ, McTernan PG, Kusminski CM, Fisher M, Da Silva NF, Khanolkar M, Evans M, Harte AL, Kumar S. Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Am J Physiol Endocrinol Metab 2007; 292(3): E740–E747

[57] Li Z, Yang S, Lin H, Huang J, Watkins PA, Moser AB, Desimone C, Song XY, Diehl AM. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology 2003; 37(2): 343–350

[58] Senn JJ, Klover PJ, Nowak IA, Zimmers TA, Koniaris LG, Furlanetto RW, Mooney RA. Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. J Biol Chem 2003; 278(16): 13740–13746

[59] Rahman K, Desai C, Iyer SS, Thorn NE, Kumar P, Liu Y, Smith T, Neish AS, Li H, Tan S, Wu P, Liu X, Yu Y, Farris AB, Nusrat A, Parkos CA, Anania FA. Loss of junctional adhesion molecule A promotes severe steatohepatitis in mice on a diet high in saturated fat, fructose, and cholesterol. Gastroenterology 2016; 151(4):733–746

[60] Corbin KD, Zeisel SH. Choline metabolism provides novel insights into nonalcoholic fatty liver disease and its progression. Curr Opin Gastroenterol 2012; 28(2): 159–165

[61] Zeisel SH. Choline: critical role during fetal development and dietary requirements in adults. Annu Rev Nutr 2006; 26(1): 229–250

[62] Zeisel SH, Wishnok JS, Blusztajn JK. Formation of methylamines from ingested choline and lecithin. J Pharmacol Exp Ther 1983; 225(2): 320–324

[63] al-Waiz M, Mikov M, Mitchell SC, Smith RL. The exogenous origin of trimethylamine in the mouse. Metabolism 1992; 41(2): 135–136

[64] Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM, Wu Y, Schauer P, Smith JD, Allayee H, Tang WH, DiDonato JA, Lusis AJ, Hazen SL. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011; 472(7341): 57–63

[65] Martínez-del Campo A, Bodea S, Hamer HA, Marks JA, Haiser HJ, Turnbaugh PJ, Balskus EP. Characterization and detection of a widely distributed gene cluster that predicts anaerobic choline utilization by human gut bacteria. MBio 2015; 6(2): e00042-15

[66] Sherriff JL, O’Sullivan TA, Properzi C, Oddo JL, Adams LA. Choline, its potential role in nonalcoholic fatty liver disease, and the case for human and bacterial genes. Adv Nutr 2016; 7(1): 5–13

[67] Spencer MD, Hamp TJ, Reid RW, Fischer LM, Zeisel SH, Fodor AA. Association between composition of the human gastrointestinal microbiome and development of fatty liver with choline deficiency. Gastroenterology 2011; 140(3): 976–986

[68] Betrapally NS, Gillevet PM, Bajaj JS. Changes in the intestinal microbiome and alcoholic and nonalcoholic liver diseases: causes or effects? Gastroenterology 2016; 150(8):1745–1755

[69] Matsubara T, Li F, Gonzalez FJ. FXR signaling in the enterohepatic system. Mol Cell Endocrinol 2013; 368(1-2): 17–29

[70] Brighton CA, Rievaj J, Kuhre RE, Glass LL, Schoonjans K, Holst JJ, Gribble FM, Reimann F. Bile acids trigger GLP-1 release predominantly by accessing basolaterally located g protein-coupled bile acid receptors. Endocrinology 2015; 156(11): 3961–3970

[71] 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(10): 2020–2030

[72] Polyzos SA, Kountouras J, Mantzoros CS. Adipose tissue, obesity and non-alcoholic fatty liver disease. Minerva Endocrinol 2017; 42(2): 92–108

[73] Houten SM, Watanabe M, Auwerx J. Endocrine functions of bile acids. EMBO J 2006; 25(7): 1419–1425

[74] Hylemon PB, Zhou H, Pandak WM, Ren S, Gil G, Dent P. Bile acids as regulatory molecules. J Lipid Res 2009; 50(8): 1509–1520

[75] Kim I, Ahn SH, Inagaki T, Choi M, Ito S, Guo GL, Kliewer SA, Gonzalez FJ. Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine. J Lipid Res 2007; 48(12): 2664–2672

[76] Chávez-Talavera O, Tailleux A, Lefebvre P, Staels B. Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease. Gastroenterology 2017; 152(7):1679–1694

[77] Russell DW. The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem 2003; 72(1): 137–174

[78] Stacey M, Webb M. Studies on the antibacterial properties of the bile acids and some compounds derived from cholanic acid. Proc R Soc Med 1947; 134(877): 523–537

[79] Lorenzo-Zúñiga V, Bartolí R, Planas R, Hofmann AF, Viñado B, Hagey LR, Hernández JM, Mañé J, Alvarez MA, Ausina V, Gassull MA. Oral bile acids reduce bacterial overgrowth, bacterial translocation, and endotoxemia in cirrhotic rats. Hepatology 2003; 37(3): 551–557

[80] Ogata Y, Nishi M, Nakayama H, Kuwahara T, Ohnishi Y, Tashiro S. Role of bile in intestinal barrier function and its inhibitory effect on bacterial translocation in obstructive jaundice in rats. J Surg Res 2003; 115(1): 18–23

[81] Jamar G, Estadella D, Pisani LP. Contribution of anthocyanin-rich foods in obesity control through gut microbiota interactions. Biofactors 2017; 43(4): 507–516

[82] Zhu Y, Li F, Guo GL. Tissue-specific function of farnesoid X receptor in liver and intestine. Pharmacol Res 2011; 63(4): 259–265

[83] Hirokane H, Nakahara M, Tachibana S, Shimizu M, Sato R. Bile acid reduces the secretion of very low density lipoprotein by repressing microsomal triglyceride transfer protein gene expression mediated by hepatocyte nuclear factor-4. J Biol Chem 2004; 279(44): 45685–45692

[84] Ma J, Zhou Q, Li H. Gut microbiota and nonalcoholic fatty liver disease: insights on mechanisms and therapy. Nutrients 2017; 9(10): 1124

[85] Yoo JY, Kim SS. Probiotics and prebiotics: present status and future perspectives on metabolic disorders. Nutrients 2016; 8(3): 173

[86] Sanders ME. Probiotics: definition, sources, selection, and uses. Clin Infect Dis 2008; 46(Suppl 2):S58–61

[87] Ferolla SM, Armiliato GN, Couto CA, Ferrari TC. Probiotics as a complementary therapeutic approach in nonalcoholic fatty liver disease. World J Hepatol 2015; 7(3): 559–565

[88] Qamar AA. Probiotics in nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and cirrhosis. J Clin Gastroenterol 2015; 49(Suppl 1): S28–S32

[89] Fukushima M, Yamada A, Endo T, Nakano M. Effects of a mixture of organisms, Lactobacillus acidophilus or Streptococcus faecalis on delta6-desaturase activity in the livers of rats fed a fat- and cholesterol-enriched diet. Nutrition 1999; 15(5): 373–378

[90] Nguyen TD, Kang JH, Lee MS. Characterization of Lactobacillus plantarum PH04, a potential probiotic bacterium with cholesterol-lowering effects. Int J Food Microbiol 2007; 113(3): 358–361

[91] Okubo H, Sakoda H, Kushiyama A, Fujishiro M, Nakatsu Y, Fukushima T, Matsunaga Y, Kamata H, Asahara T, Yoshida Y, Chonan O, Iwashita M, Nishimura F, Asano T. Lactobacillus casei strain Shirota protects against nonalcoholic steatohepatitis development in a rodent model. Am J Physiol Gastrointest Liver Physiol 2013; 305(12): G911–G918

[92] Wagnerberger S, Spruss A, Kanuri G, Stahl C, Schröder M, Vetter W, Bischoff SC, Bergheim I. Lactobacillus casei Shirota protects from fructose-induced liver steatosis: a mouse model. J Nutr Biochem 2013; 24(3): 531–538

[93] Kawano M, Miyoshi M, Ogawa A, Sakai F, Kadooka Y. Lactobacillus gasseri SBT2055 inhibits adipose tissue inflammation and intestinal permeability in mice fed a high-fat diet. J Nutr Sci 2016; 5: e23

[94] Fazeli H, Moshtaghian J, Mirlohi M, Shirzadi M. Reduction in serum lipid parameters by incorporation of a native strain of Lactobacillus plantarum A7 in mice. Iranian J Diabetes Lipid Disord 2010; 9: 1–7

[95] Wang Y, Xu N, Xi A, Ahmed Z, Zhang B, Bai X. Effects of Lactobacillus plantarum MA2 isolated from Tibet kefir on lipid metabolism and intestinal microflora of rats fed on high-cholesterol diet. Appl Microbiol Biotechnol 2009; 84(2): 341–347

[96] Li C, Nie SP, Zhu KX, Ding Q, Li C, Xiong T, Xie MY. Lactobacillus plantarum NCU116 improves liver function, oxidative stress and lipid metabolism in rats with high fat diet induced non-alcoholic fatty liver disease. Food Funct 2014; 5(12): 3216–3223

[97] Aoki R, Kamikado K, Suda W, Takii H, Mikami Y, Suganuma N, Hattori M, Koga Y. A proliferative probiotic Bifidobacterium strain in the gut ameliorates progression of metabolic disorders via microbiota modulation and acetate elevation. Sci Rep 2017; 7: 43522

[98] Ren T, Huang C, Cheng M. Dietary blueberry and bifidobacteria attenuate nonalcoholic fatty liver disease in rats by affecting SIRT1-mediated signaling pathway. Oxid Med Cell Longev 2014; 2014:469059

[99] Plaza-Díaz J, Ruiz-Ojeda FJ, Vilchez-Padial LM, Gil A. Evidence of the anti-inflammatory effects of probiotics and synbiotics in intestinal chronic diseases. Nutrients 2017; 9(6): E555

[100] Chen J, Wang R, Li XF, Wang RL. Bifidobacterium adolescentis supplementation ameliorates visceral fat accumulation and insulin sensitivity in an experimental model of the metabolic syndrome. Br J Nutr 2012; 107(10): 1429–1434

[101] Cano PG, Santacruz A, Trejo FM, Sanz Y. Bifidobacterium CECT 7765 improves metabolic and immunological alterations associated with obesity in high-fat diet-fed mice. Obesity (Silver Spring) 2013; 21(11): 2310–2321

[102] Xu RY, Wan YP, Fang QY, Lu W, Cai W. Supplementation with probiotics modifies gut flora and attenuates liver fat accumulation in rat nonalcoholic fatty liver disease model. J Clin Biochem Nutr 2012; 50(1): 72–77

[103] Fedorak RN, Feagan BG, Hotte N, Leddin D, Dieleman LA, Petrunia DM, Enns R, Bitton A, Chiba N, Paré P, Rostom A, Marshall J, Depew W, Bernstein CN, Panaccione R, Aumais G, Steinhart AH, Cockeram A, Bailey RJ, Gionchetti P, Wong C, Madsen K. The probiotic VSL#3 has anti-inflammatory effects and could reduce endoscopic recurrence after surgery for Crohn’s disease. Clin Gastroenterol Hepatol 2015; 13(5):928–935

[104] Dhiman RK, Rana B, Agrawal S, Garg A, Chopra M, Thumburu KK, Khattri A, Malhotra S, Duseja A, Chawla YK. Probiotic VSL#3 reduces liver disease severity and hospitalization in patients with cirrhosis: a randomized, controlled trial. Gastroenterology 2014; 147(6):1327–37

[105] Wong RK, Yang C, Song GH, Wong J, Ho KY. Melatonin regulation as a possible mechanism for probiotic (VSL#3) in irritable bowel syndrome: a randomized double-blinded placebo study. Dig Dis Sci 2015; 60(1): 186–194

[106] Mencarelli A, Cipriani S, Renga B, Bruno A, D’Amore C, Distrutti E, Fiorucci S. VSL#3 resets insulin signaling and protects against NASH and atherosclerosis in a model of genetic dyslipidemia and intestinal inflammation. PLoS One 2012; 7(9): e45425

[107] Ma X, Hua J, Li Z. Probiotics improve high fat diet-induced hepatic steatosis and insulin resistance by increasing hepatic NKT cells. J Hepatol 2008; 49(5): 821–830

[108] Mei L, Tang Y, Li M, Yang P, Liu Z, Yuan J, Zheng P. Co-administration of cholesterol-lowering probiotics and anthraquinone from Cassia obtusifolia L. Ameliorate non-alcoholic fatty liver. PLoS One 2015; 10(9): e0138078

[109] Xue L, He J, Gao N, Lu X, Li M, Wu X, Liu Z, Jin Y, Liu J, Xu J, Geng Y. Probiotics may delay the progression of nonalcoholic fatty liver disease by restoring the gut microbiota structure and improving intestinal endotoxemia. Sci Rep 2017; 7: 45176

[110] Kim DH, Kim H, Jeong D, Kang IB, Chon JW, Kim HS, Song KY, Seo KH. Kefir alleviates obesity and hepatic steatosis in high-fat diet-fed mice by modulation of gut microbiota and mycobiota: targeted and untargeted community analysis with correlation of biomarkers. J Nutr Biochem 2017; 44: 35–43

[111] Karahan N, Işler M, Koyu A, Karahan AG, Başyığıt Kiliç G, Cırış IM, Sütçü R, Onaran I, Cam H, Keskın M. Effects of probiotics on methionine choline deficient diet-induced steatohepatitis in rats. Turk J Gastroenterol 2012; 23(2): 110–121

[112] Ji YS, Kim HN, Park HJ, Lee JE, Yeo SY, Yang JS, Park SY, Yoon HS, Cho GS, Franz CM, Bomba A, Shin HK, Holzapfel WH. Modulation of the murine microbiome with a concomitant anti-obesity effect by Lactobacillus rhamnosus GG and Lactobacillus sakei NR28. Benef Microbes 2012; 3(1): 13–22

[113] Kobyliak N, Falalyeyeva T, Bodnar P, Beregova T. Probiotics supplemented with omega-3 fatty acids are more effective for hepatic steatosis reduction in an animal model of obesity. Probiotics Antimicrob Proteins 2017; 9(2): 123–130

[114] Alisi A, Bedogni G, Baviera G, Giorgio V, Porro E, Paris C, Giammaria P, Reali L, Anania F, Nobili V. Randomised clinical trial: The beneficial effects of VSL#3 in obese children with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2014; 39(11): 1276–1285

[115] Famouri F, Shariat Z, Hashemipour M, Keikha M, Kelishadi R. Effects of probiotics on non-alcoholic fatty liver disease in obese children and adolescents: a randomized clinical trial. J Pediatr Gastroenterol Nutr 2017; 64(3):413– 417

[116] Vajro P, Mandato C, Licenziati MR, Franzese A, Vitale DF, Lenta S, Caropreso M, Vallone G, Meli R. Effects of Lactobacillus rhamnosus strain GG in pediatric obesity-related liver disease. J Pediatr Gastroenterol Nutr 2011; 52(6): 740–743

[117] Roberfroid M. Prebiotics: the concept revisited. J Nutr 2007; 137(3 Suppl 2): 830S–837S

[118] Parnell JA, Raman M, Rioux KP, Reimer RA. The potential role of prebiotic fibre for treatment and management of non-alcoholic fatty liver disease and associated obesity and insulin resistance. Liver Int 2012; 32(5): 701–711

[119] Daubioul CA, Horsmans Y, Lambert P, Danse E, Delzenne NM. Effects of oligofructose on glucose and lipid metabolism in patients with nonalcoholic steatohepatitis: results of a pilot study. Eur J Clin Nutr 2005; 59(5): 723–726

[120] Fan JG, Xu ZJ, Wang GL. Effect of lactulose on establishment of a rat non-alcoholic steatohepatitis model. World J Gastroenterol 2005; 11(32): 5053–5056

[121] Salminen S, Salminen E. Lactulose, lactic acid bacteria, intestinal microecology and mucosal protection. Scand J Gastroenterol Suppl 1997; 32(sup222): 45–48

[122] Cani PD, Possemiers S, Van de Wiele T, Guiot Y, Everard A, Rottier O, Geurts L, Naslain D, Neyrinck A, Lambert DM, Muccioli GG, Delzenne NM. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 2009; 58(8): 1091–1103

[123] Matsumoto K, Ichimura M, Tsuneyama K, Moritoki Y, Tsunashima H, Omagari K, Hara M, Yasuda I, Miyakawa H, Kikuchi K. Fructo-oligosaccharides and intestinal barrier function in a methionine-choline-deficient mouse model of nonalcoholic steatohepatitis. PLoS One 2017; 12(6): e0175406

[124] Neyrinck AM, Possemiers S, Verstraete W, De Backer F, Cani PD, Delzenne NM. Dietary modulation of clostridial cluster XIVa gut bacteria (Roseburia spp.) by chitin-glucan fiber improves host metabolic alterations induced by high-fat diet in mice. J Nutr Biochem 2012; 23(1): 51–59

[125] Dewulf EM, Cani PD, Claus SP, Fuentes S, Puylaert PG, Neyrinck AM, Bindels LB, de Vos WM, Gibson GR, Thissen JP, Delzenne NM. Insight into the prebiotic concept: lessons from an exploratory, double blind intervention study with inulin-type fructans in obese women. Gut 2013; 62(8): 1112–1121

[126] Micka A, Siepelmeyer A, Holz A, Theis S, Schön C. Effect of consumption of chicory inulin on bowel function in healthy subjects with constipation: a randomized, double-blind, placebo-controlled trial. Int J Food Sci Nutr 2017; 68(1): 82–89

[127] Poesen R, Evenepoel P, de Loor H, Delcour JA, Courtin CM, Kuypers D, Augustijns P, Verbeke K, Meijers B. The influence of prebiotic arabinoxylan oligosaccharides on microbiota derived uremic retention solutes in patients with chronic kidney disease: a randomized controlled trial. PLoS One 2016; 11(4): e0153893

[128] Tarantino G, Finelli C. Systematic review on intervention with prebiotics/probiotics in patients with obesity-related nonalcoholic fatty liver disease. Future Microbiol 2015; 10(5): 889–902

[129] de Vrese M, Schrezenmeir J. Probiotics, prebiotics, and synbiotics. Adv Biochem Eng Biotechnol 2008; 111: 1–66

[130] Sáez-Lara MJ, Robles-Sanchez C, Ruiz-Ojeda FJ, Plaza-Diaz J, Gil A. Effects of probiotics and synbiotics on obesity, insulin resistance syndrome, type 2 diabetes and non-alcoholic fatty liver disease: a review of human clinical trials. Int J Mol Sci 2016; 17(6): E928

[131] Furrie E, Macfarlane S, Kennedy A, Cummings JH, Walsh SV, O’neil DA, Macfarlane GT. Synbiotic therapy (Bifidobacterium longum/Synergy 1) initiates resolution of inflammation in patients with active ulcerative colitis: a randomised controlled pilot trial. Gut 2005; 54(2): 242–249

[132] Cortez-Pinto H, Borralho P, Machado J, Lopes MT, Gato IV, Santos AM, Guerreiro AS. Microbiota modulation with synbiotic decreases liver fibrosis in a high fat choline deficient diet mice model of non-alcoholic steatohepatitis (NASH). GE Port J Gastroenterol 2016; 23(3): 132–141

[133] Mofidi F, Poustchi H, Yari Z, Nourinayyer B, Merat S, Sharafkhah M, Malekzadeh R, Hekmatdoost A. Synbiotic supplementation in lean patients with non-alcoholic fatty liver disease: a pilot, randomised, double-blind, placebo-controlled, clinical trial. Br J Nutr 2017; 117(5): 662–668

[134] Ferolla SM, Couto CA, Costa-Silva L, Armiliato GN, Pereira CA, Martins FS, Ferrari ML, Vilela EG, Torres HO, Cunha AS, Ferrari TC. Beneficial effect of synbiotic supplementation on hepatic steatosis and anthropometric parameters, but not on gut permeability in a population with nonalcoholic steatohepatitis. Nutrients 2016; 8(7): E397

[135] Hwang I, Park YJ, Kim YR, Kim YN, Ka S, Lee HY, Seong JK, Seok YJ, Kim JB. Alteration of gut microbiota by vancomycin and bacitracin improves insulin resistance via glucagon-like peptide 1 in diet-induced obesity. FASEB J 2015; 29(6): 2397–2411

[136] Gangarapu V, Ince AT, Baysal B, Kayar Y, Kılıç U, Gök Ö, Uysal Ö, Şenturk H. Efficacy of rifaximin on circulating endotoxins and cytokines in patients with nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol 2015; 27(7): 840–845

[137] Aroniadis OC, Brandt LJ. Fecal microbiota transplantation: past, present and future. Curr Opin Gastroenterol 2013; 29(1): 79–84

[138] Cohen NA, Maharshak N. Novel indications for fecal microbial transplantation: update and review of the literature. Dig Dis Sci 2017; 62(5): 1131–1145

[139] Jegatheesan P, Beutheu S, Ventura G, Sarfati G, Nubret E, Kapel N, Waligora-Dupriet AJ, Bergheim I, Cynober L, De-Bandt JP. Effect of specific amino acids on hepatic lipid metabolism in fructose-induced non-alcoholic fatty liver disease. Clin Nutr 2016; 35(1): 175–182

[140] Herman MA, Samuel VT. The sweet path to metabolic demise: fructose and lipid synthesis. Trends Endocrinol Metab 2016; 27(10): 719–730

[141] Clarke SF, Murphy EF, O’Sullivan O, Lucey AJ, Humphreys M, Hogan A, Hayes P, O’Reilly M, Jeffery IB, Wood-Martin R, Kerins DM, Quigley E, Ross RP, O’Toole PW, Molloy MG, Falvey E, Shanahan F, Cotter PD. Exercise and associated dietary extremes impact on gut microbial diversity. Gut 2014; 63(12): 1913–1920

[142] Denou E, Marcinko K, Surette MG, Steinberg GR, Schertzer JD. High-intensity exercise training increases the diversity and metabolic capacity of the mouse distal gut microbiota during diet-induced obesity. Am J Physiol Endocrinol Metab 2016; 310(11): E982–E993

[143] Matsumoto M, Inoue R, Tsukahara T, Ushida K, Chiji H, Matsubara N, Hara H. Voluntary running exercise alters microbiota composition and increases n-butyrate concentration in the rat cecum. Biosci Biotechnol Biochem 2008; 72(2): 572–576

[144] Hua W, Ding L, Chen Y, Gong B, He J, Xu G. Determination of berberine in human plasma by liquid chromatography-electrospray ionization-mass spectrometry. J Pharm Biomed Anal 2007; 44(4): 931–937

[145] Zhang X, Zhao Y, Zhang M, Pang X, Xu J, Kang C, Li M, Zhang C, Zhang Z, Zhang Y, Li X, Ning G, Zhao L. Structural changes of gut microbiota during berberine-mediated prevention of obesity and insulin resistance in high-fat diet-fed rats. PLoS One 2012; 7(8): e42529

[146] Li C, He JZ, Zhou XD, Xu X. Berberine regulates type 2 diabetes mellitus related with insulin resistance. China J Chin Materia Medica (Zhongguo Zhongyao Zazhi) 2017; 42: 2254–2260 (in Chinese)

[147] Xu JH, Liu XZ, Pan W, Zou DJ. Berberine protects against diet-induced obesity through regulating metabolic endotoxemia and gut hormone levels. Mol Med Rep 2017; 15(5): 2765–2787

[148] Lin P, Lu J, Wang Y, Gu W, Yu J, Zhao R. Naturally occurring stilbenoid TSG reverses non-alcoholic fatty liver diseases via gut-liver axis. PLoS One 2015; 10(10): e0140346

[149] Hussain A, Yadav MK, Bose S, Wang JH, Lim D, Song YK, Ko SG, Kim H. Daesiho-Tang is an effective herbal formulation in attenuation of obesity in mice through alteration of gene expression and modulation of intestinal microbiota. PLoS One 2016; 11(11): e0165483

[150] Yin X, Peng J, Zhao L, Yu Y, Zhang X, Liu P, Feng Q, Hu Y, Pang X. Structural changes of gut microbiota in a rat non-alcoholic fatty liver disease model treated with a Chinese herbal formula. Syst Appl Microbiol 2013; 36(3): 188–196

Acknowledgements

Houkai Li was funded by National Natural Science Foundation of China (No. 81673662), The Program for Professor of Special Appointment (Eastern Scholar), and Shuguang Scholar (No. 16SG36) at Shanghai Institutions of Higher Learning from Shanghai Municipal Education Commission.

Compliance with ethics guidelines

Ruiting Han, Junli Ma, and Houkai Li declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

RIGHTS & PERMISSIONS

2018 Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature