Targeting the gut microbiota for the treatment of non-alcoholic fatty liver disease

Current Drug Targets

Volumn 16, Issue 12, 2015, Pages 1324-1331

  Mouzaki, Marialena ^a   Bandsma, Robert ^a  

^a HOSPITAL FOR SICK CHILDREN   (Canada)

Author keywords

Bile acids; Dysbiosis; Fatty liver; Microbiota; NAFLD; NASH

Indexed keywords

BILE ACID; FARNESOID X RECEPTOR; GLUCAGON LIKE PEPTIDE 1; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; PREBIOTIC AGENT; PROBIOTIC AGENT; SHORT CHAIN FATTY ACID; SYNBIOTIC AGENT; TRANSFORMING GROWTH FACTOR BETA; ANTIINFECTIVE AGENT; VOLATILE FATTY ACID;

ARTICLE; DIETARY INTAKE; ENDOTOXEMIA; FATTY LIVER; HUMAN; INTESTINE FLORA; LIPID METABOLISM; LIPOGENESIS; LIPOLYSIS; LIVER FIBROSIS; NONALCOHOLIC FATTY LIVER; NONHUMAN; PROTEIN EXPRESSION; SIGNAL TRANSDUCTION; ANIMAL; DRUG EFFECTS; MICROBIOLOGY; NON-ALCOHOLIC FATTY LIVER DISEASE; PATHOPHYSIOLOGY; PHYSIOLOGY;

ANIMALS; ANTI-BACTERIAL AGENTS; BILE ACIDS AND SALTS; FATTY ACIDS, VOLATILE; GASTROINTESTINAL MICROBIOME; HUMANS; LIPID METABOLISM; NON-ALCOHOLIC FATTY LIVER DISEASE; PROBIOTICS;

EID: 84946746574     PISSN: 13894501     EISSN: 18735592     Source Type: Journal    
DOI: 10.2174/1389450116666150416120351     Document Type: Article

References (112)

1. [1] Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol 2013; 10(11): 686-90.
2. [2] Charlton MR, Burns JM, Pedersen RA, Watt KD, Heimbach JK, Dierkhising RA. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology 2011; 141(4): 1249-53.
3. [3] Oh S, Tanaka K, Tsujimoto T, So R, Shida T, Shoda J. Regular exercise coupled to diet regimen accelerates reduction of hepatic steatosis and associated pathological conditions in nonalcoholic fatty liver disease. Metab Syndr Relat Disord 2014; 12(5): 290-8.
4. [4] Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 2010; 52(5): 1836-46.
5. [5] Barbieri M, Esposito A, Angellotti E, Rizzo MR, Marfella R, Paolisso G. Association of genetic variation in adaptor protein APPL1/APPL2 loci with non-alcoholic fatty liver disease. PLoS One 2013; 8(8): e71391.
6. [6] Rinella ME, Sanyal AJ. NAFLD in 2014: Genetics, diagnostics and therapeutic advances in NAFLD. Nat Rev Gastroenterol Hepatol 2015; 12(2): 65-6.
7. [7] Zain SM, Mohamed R, Mahadeva S, et al. A multi-ethnic study of a PNPLA3 gene variant and its association with disease severity in non-alcoholic fatty liver disease. Hum Genet 2012; 131(7): 1145-52.
8. [8] Birkenfeld AL, Shulman GI. Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes. Hepatology 2014; 59(2): 713-23.
9. [9] Sutti S, Jindal A, Locatelli I, et al. Adaptive immune responses triggered by oxidative stress contribute to hepatic inflammation in NASH. Hepatology 2014; 59(3): 886-97.
10. [10] Alkhouri N, Dixon LJ, Feldstein AE. Lipotoxicity in nonalcoholic fatty liver disease: not all lipids are created equal. Expert Rev Gastroenterol Hepatol 2009; 3(4): 445-51.
11. [11] Lim JS, Mietus-Snyder M, Valente A, Schwarz JM, Lustig RH. The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol 2010; 7(5): 251-64.
12. [12] Turnbaugh PJ, Ridaura VK, Faith JJ, Rey FE, Knight R, Gordon JI. The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci Transl Med 2009; 1(6): 6ra14.
13. [13] Hollister EB, Gao C, Versalovic J. Compositional and functional features of the gastrointestinal microbiome and their effects on human health. Gastroenterology 2014; 146(6): 1449-58.
14. [14] Biedermann L, Rogler G. The intestinal microbiota: its role in health and disease. Eur J Pediatr 2015; 174(2): 151-67.
15. [15] Dethlefsen L, McFall-Ngai M, Relman DA. An ecological and evolutionary perspective on human-microbe mutualism and disease. Nature 2007; 449(7164): 811-8.
16. [16] Duncan SH, Lobley GE, Holtrop G, et al. Human colonic microbiota associated with diet, obesity and weight loss. Int J Obes (Lond) 2008; 32(11): 1720-4.
17. [17] Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature 2006; 444(7122): 1022-3.
18. [18] Turnbaugh PJ, Hamady M, Yatsunenko T, et al. A core gut microbiome in obese and lean twins. Nature 2009; 457(7228): 480-4.
19. [19] Wu X, Ma C, Han L, et al. Molecular characterisation of the faecal microbiota in patients with type II diabetes. Curr Microbiol 2010; 61(1): 69-78.
20. [20] Furet JP, Kong LC, Tap J, et al. Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: links with metabolic and low-grade inflammation markers. Diabetes 2010; 59(12): 3049-57.
21. [21] Mouzaki M, Comelli EM, Arendt BM, et al. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology 2013; 58(1): 120-7.
22. [22] Zhu L, Baker SS, Gill C, et al. Characterization of the gut microbiome in non-alcoholic steatohepatitis (NASH) patients: A connection between endogenous alcohol and NASH. Hepatology 2012; 9(12): 687.
23. [23] Sajjad A, Mottershead M, Syn WK, Jones R, Smith S, Nwokolo CU. , 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(2): 206-11.
24. [24] Cani PD, Dewever C, Delzenne NM. Inulin-type fructans modulate gastrointestinal peptides involved in appetite regulation (glucagonlike peptide-1 and ghrelin) in rats. Br J Nutr 2004; 92(3): 521-6.
25. [25] Parnell JA, Reimer RA. Prebiotic fibres dose-dependently increase satiety hormones and alter Bacteroidetes and Firmicutes in lean and obese JCR: LA-cp rats. Br J Nutr 2012; 107(4): 601-13.
26. [26] Bjerg AT, Kristensen M, Ritz C, et al. Lactobacillus paracasei subsp paracasei L. casei W8 suppresses energy intake acutely. Appetite 2014; 82: 111-8.
27. [27] Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006; 444(7122): 1027-31.
28. [28] Jumpertz R, Le DS, Turnbaugh PJ, et al. Energy-balance studies reveal associations between gut microbes, caloric load, and nutrient absorption in humans. Am J Clin Nutr 2011; 94(1): 58-65.
29. [29] Backhed F, Manchester JK, Semenkovich CF, Gordon JI. Mechanisms underlying the resistance to diet-induced obesity in germfree mice. Proc Natl Acad Sci USA 2007; 104(3): 979-84.
30. [30] Membrez M, Blancher F, Jaquet M, et al. Gut microbiota modulation with norfloxacin and ampicillin enhances glucose tolerance in mice. FASEB J 2008; 22(7): 2416-26.
31. [31] 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. Gut 2009; 58(8): 1091-103.
32. [32] Mehta NN, McGillicuddy FC, Anderson PD, et al. Experimental endotoxemia induces adipose inflammation and insulin resistance in humans. Diabetes 2010; 59(1): 172-81.
33. [33] Miele L, Valenza V, La Torre G, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 2009; 49(6): 1877-87.
34. [34] Cani PD, Neyrinck AM, Fava F, et al. Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia. Diabetologia 2007; 50(11): 2374-83.
35. [35] 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(2): 206-11.
36. [36] Thuy S, Ladurner R, Volynets V, et al. Nonalcoholic fatty liver disease in humans is associated with increased plasma endotoxin and plasminogen activator inhibitor 1 concentrations and with fructose intake. J Nutr 2008; 138(8): 1452-5.
37. [37] Ruiz AG, Casafont F, Crespo J, et al. Lipopolysaccharide-binding protein plasma levels and liver TNF-alpha gene expression in obese patients: evidence for the potential role of endotoxin in the pathogenesis of non-alcoholic steatohepatitis. Obes Surg 2007; 17(10): 1374-80.
38. [38] 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): 645-9.
39. [39] Jin R, Willment A, Patel SS, et al. Fructose induced endotoxemia in pediatric nonalcoholic Fatty liver disease. Int J Hepatol 2014; 2014: 560620.
40. [40] Rivera CA, Adegboyega P, van Rooijen N, Tagalicud A, Allman M, Wallace M. Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. J Hepatol 2007; 47(4): 571-9.
41. [41] Miura K, Kodama Y, Inokuchi S, et al. Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice. Gastroenterology 2010; 139(1): 323-34
42. [42] Wagnerberger S, Spruss A, Kanuri G, et al. Toll-like receptors 1-9 are elevated in livers with fructose-induced hepatic steatosis. Br J Nutr 2012; 107(12): 1727-38.
43. [43] Sonnenburg ED, Zheng H, Joglekar P, et al. Specificity of polysaccharide use in intestinal bacteroides species determines dietinduced microbiota alterations. Cell 2010; 141(7): 1241-52.
44. [44] Karczewski J, Troost FJ, Konings I, et al. Regulation of human epithelial tight junction proteins by Lactobacillus plantarum in vivo and protective effects on the epithelial barrier. Am J Physiol Gastrointest Liver Physiol 2010; 298(6): G851-9.
45. [45] Seki E, Schnabl B. Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut. J Physiol 2012; 590(3): 447-58.
46. [46] Paik YH, Schwabe RF, Bataller R, Russo MP, Jobin C, Brenner DA. Toll-like receptor 4 mediates inflammatory signaling by bacterial bacteriallipopolysaccharide in human hepatic stellate cells. Hepatology 2003; 37(5): 1043-55.
47. [47] 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(7): 1932-41.
48. [48] You M, Crabb DW. Molecular mechanisms of alcoholic fatty liver: role of sterol regulatory element-binding proteins. Alcohol 2004; 34(1): 39-43.
49. [49] Garcia-Villafranca J, Guillen A, Castro J. Ethanol consumption impairs regulation of fatty acid metabolism by decreasing the activity of AMP-activated protein kinase in rat liver. Biochimie 2008; n90(3): 460-6.
50. [50] Nanji AA, Dannenberg AJ, Jokelainen K, Bass NM. Alcoholic liver injury in the rat is associated with reduced expression of peroxisome proliferator-alpha (PPARalpha)-regulated genes and is ameliorated by PPARalpha activation. J Pharmacol Exp Ther 2004; 310(1): 417-24.
51. [51] Rao RK, Seth A, Sheth P. Recent advances in alcoholic liver disease i. role of intestinal permeability and endotoxemia in alcoholic liver disease. Am J Physiol Gastrointest Liver Physiol 2004; 286(6): G881-4.
52. [52] McNeil NI. The contribution of the large intestine to energy supplies in man. Am J Clin Nutr 1984; 39(2): 338-42.
53. [53] Kimura I, Ozawa K, Inoue D, et al. The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat Commun 2013; 4: 1829.
54. [54] Schwiertz A, Taras D, Schafer K, et al. Microbiota and SCFA in lean and overweight healthy subjects. Obesity (Silver Spring) 2010; 18(1): 190-5.
55. [55] Puddu A, Sanguineti R, Montecucco F, Viviani GL. Evidence for the gut microbiota short-chain fatty acids as key pathophysiological molecules improving diabetes. Mediat Inflamm 2014; 2014: 162021.
56. [56] Tolhurst G, Heffron H, Lam YS, et al. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-proteincoupled receptor FFAR2. Diabetes 2012; 61(2): 364-71.
57. [57] Donohoe DR, Garge N, Zhang X, et al. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab 2011; 13(5): 517-26.
58. [58] Nicholson JK, Holmes E, Kinross J, et al. Host-gut microbiota metabolic interactions. Science 2012; 336(6086): 1262-7.
59. [59] Maslowski KM, Vieira AT, Ng A, et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 2009; 461(7268): 1282-6.
60. [60] Roelofsen H, Priebe MG, Vonk RJ. The interaction of short-chain fatty acids with adipose tissue: relevance for prevention of type 2 diabetes. Beneficial Microbes 2010; 1(4): 433-7.
61. [61] Saemann MD, Bohmig GA, Osterreicher CH, et al. Antiinflammatory effects of sodium butyrate on human monocytes: potent inhibition of IL-12 and up-regulation of IL-10 production. FASEB J 2000 ; 14(15): 2380-2.
62. [62] Vinolo MA, Rodrigues HG, Nachbar RT, Curi R. Regulation of inflammation by short chain fatty acids. Nutrients 2011; 3(10): 858-76.
63. [63] Dawson PA, Karpen SJ. Intestinal transport and metabolism of bile acids. J Lipid Res 2015; 56(6): 1085-99.
64. [64] Fuchs C, Claudel T, Trauner M. Bile acid-mediated control of liver triglycerides. Semin Liver Dis 2013; 33(4): 330-42.
65. [65] Watanabe M, Houten SM, Wang L, et al. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest 2004; 113(10): 1408-18.
66. [66] Torra PI, Claudel T, Duval C, Kosykh V, Fruchart JC, Staels B. Bile acids induce the expression of the human peroxisome proliferator- activated receptor alpha gene via activation of the farnesoid X receptor. Mol Endocrinol 2003; 17(2): 259-72.
67. [67] 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): 45685-92.
68. [68] Kast HR, Nguyen CM, Sinal CJ, et al. Farnesoid X-activated receptor induces apolipoprotein C-II transcription: a molecular mechanism linking plasma triglyceride levels to bile acids. Mol Endocrinol 2001; 15(10): 1720-8.
69. [69] Watanabe M, Houten SM, Mataki C, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 2006; 439(7075): 484-9.
70. [70] Wang YD, Chen WD, Wang M, Yu D, Forman BM, Huang W. Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology 2008; 48(5): 1632-43.
71. [71] 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(1): 78-84.
72. [72] Fiorucci S, Antonelli E, Rizzo G, et al. The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology 2004; 127(5): 1497-512.
73. [73] Schreuder TC, Marsman HA, Lenicek M, et al. The hepatic response to FGF19 is impaired in patients with nonalcoholic fatty liver disease and insulin resistance. Am J Physiol Gastrointest Liver Physiol 2010; 298(3): G440-5.
74. [74] Wojcik M, Janus D, Dolezal-Oltarzewska K, et al. A decrease in fasting FGF19 levels is associated with the development of nonalcoholic fatty liver disease in obese adolescents. J Pediatr Endocrinol Metab 2012; 25(11-12): 1089-93.
75. [75] 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(2): 601-9.
76. [76] Sayin SI, Wahlstrom A, Felin J, et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab 2013; 17(2): 225-35.
77. [77] Tanaka H, Doesburg K, Iwasaki T, Mierau I. Screening of lactic acid bacteria for bile salt hydrolase activity. J Dairy Sci 1999; 82(12): 2530-5.
78. [78] Choi SB, Lew LC, Yeo SK, Parvathy NS, Liong MT. Probiotics and the BSH-related cholesterol lowering mechanism: a Jekyll and Hyde scenario. Crit Rev Biotechnol 2015; 35(3): 392-401.
79. [79] Jiang C, Xie C, Li F, et al. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J Clin Invest 2015; 125(1): 386-402.
80. [80] Wells JE, Berr F, Thomas LA, Dowling RH, Hylemon PB. Isolation and characterization of cholic acid 7alpha-dehydroxylating fecal bacteria from cholesterol gallstone patients. J Hepatol 2000; 32(1): 4-10.
81. [81] Vrieze A, Out C, Fuentes S, et al. Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity. J Hepatol 2014; 60(4): 824-31.
82. [82] Begley M, Gahan CG, Hill C. The interaction between bacteria and bile. FEMS Microbiol Rev 2005; 29(4): 625-51.
83. [83] Inagaki T, Moschetta A, Lee YK, et al. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci USA 2006; 103(10): 3920-5.
84. [84] Vijay-Kumar M, Aitken JD, Carvalho FA, et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 2010; 328(5975): 228-31.
85. [85] Adachi Y, Moore LE, Bradford BU, Gao W, Thurman RG. Antibiotics prevent liver injury in rats following long-term exposure to ethanol. Gastroenterology 1995; 108(1): 218-24.
86. [86] Nanji AA, Khettry U, Sadrzadeh SM. Lactobacillus feeding reduces endotoxemia and severity of experimental alcoholic liver (disease). Proc Soc Exp Biol Med 1994; 205(3): 243-7.
87. [87] Li Z, Yang S, Lin H, et al. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology 2003; 37(2): 343-50.
88. [88] 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): 701-11.
89. [89] Imajo K, Yoneda M, Ogawa Y, Wada K, Nakajima A. Microbiota and nonalcoholic steatohepatitis. Semin Immunopathol 2014; 36(1): 115-32.
90. [90] 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): 72-7.
91. [91] Gao Z, Yin J, Zhang J, et al. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes 2009; 58(7): 1509-17.
92. [92] Raso MG, Simeoli R, Russo R, et al. Effects of sodium butyrate and its synthetic amide derivative on liver inflammation and glucose tolerance in an animal model of steatosis induced by high fat diet. PLoS One 2013; 8(7): e68626.
93. [93] Endo H, Niioka M, Kobayashi N, Tanaka M, Watanabe T. Butyrate- producing probiotics reduce nonalcoholic fatty liver disease progression in rats: new insight into the probiotics for the gut-liver axis. PLoS One 2013; 8(5): e63388.
94. [94] Cho EJ, Yoon JH, Kwak MS, et al. Tauroursodeoxycholic acid attenuates progression of steatohepatitis in mice fed a methioninecholine- deficient diet. Dig Dis Sci 2014; 59(7): 1461-74.
95. [95] Cipriani S, Mencarelli A, Palladino G, Fiorucci S. FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats. J Lipid Res 2010; 51(4): 771-84.
96. [96] Gabbi C, Bertolotti M, Anzivino C, et al. Effects of bile duct ligation and cholic acid treatment on fatty liver in two rat models of non-alcoholic fatty liver disease. Dig Liver Dis 2012; 44(12): 1018-26.
97. [97] Pathil A, Mueller J, Warth A, Chamulitrat W, Stremmel W. Ursodeoxycholyl lysophosphatidylethanolamide improves steatosis and inflammation in murine models of nonalcoholic fatty liver disease. Hepatology 2012; 55(5): 1369-78.
98. [98] Quintero P, Pizarro M, Solis N, et al. Bile acid supplementation improves established liver steatosis in obese mice independently of glucagon-like peptide-1 secretion. J Physiol Biochem 2014; 70(3): 667-74.
99. [99] Wu W, Liu X, Peng X, et al. Bile acids override steatosis in farnesoid X receptor deficient mice in a model of non-alcoholic steatohepatitis. Biochem Biophys Res Commun 2014; 448(1): 50-5.
100. [100] 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(40): 6911-8.
101. [101] Alisi A, Bedogni G, Baviera G, et al. Randomised clinical trial: The beneficial effects of VSL#3 in obese children with nonalcoholic steatohepatitis. Aliment Pharmacol Ther 2014; 39(11): 1276-85.
102. [102] Eslamparast T, Poustchi H, Zamani F, Sharafkhah M, Malekzadeh R, Hekmatdoost A. Synbiotic supplementation in nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled pilot study. Am J Clin Nutr 2014 ; 99(3): 535-42.
103. [103] 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(4): 913-6 .
104. [104] Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, nonalcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo- controlled trial. Lancet 2015; 385(9972): 956-65.
105. [105] 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(1): 81-90.
106. [106] Wagnerberger S, Spruss A, Kanuri G, et al. Lactobacillus casei Shirota protects from fructose-induced liver steatosis: a mouse model. J Nutr Biochem 2013; 24(3): 531-8.
107. [107] Okubo H, Sakoda H, Kushiyama A, et al. Lactobacillus casei strain Shirota protects against nonalcoholic steatohepatitis development in a rodent model. Am J Physiol Gastrointest Liver Physiol 2013; 305(12): G911-8.
108. [108] Ritze Y, Bardos G, Claus A, et al. Lactobacillus rhamnosus GG protects against non-alcoholic fatty liver disease in mice. PLoS One 2014; 9(1): e80169.
109. [109] Pachikian BD, Essaghir A, Demoulin JB, Catry E, Neyrinck AM, Dewulf EM, et al. Prebiotic approach alleviates hepatic steatosis: implication of fatty acid oxidative and cholesterol synthesis pathways. Mol Nutr Food Res 2013; 57(2): 347-59.
110. [110] Seo M, Inoue I, Tanaka M, et al. Clostridium butyricum MIYAIRI 588 improves high-fat diet-induced non-alcoholic fatty liver disease in rats. Dig Dis Sci 2013; 58(12): 3534-44.
111. [111] Karahan N, Isler M, Koyu A, et al. Effects of probiotics on methionine choline deficient diet-induced steatohepatitis in rats. Turkish J Gastroenterol 2012; 23(2): 110-21.
112. [112] Velayudham A, Dolganiuc A, Ellis M, et al. VSL#3 probiotic treatment attenuates fibrosis without changes in steatohepatitis in a diet-induced nonalcoholic steatohepatitis model in mice. Hepatology 2009; 49(3): 989-97.