Precision medicine in alcoholic and nonalcoholic fatty liver disease via modulating the gut microbiota

American Journal of Physiology - Gastrointestinal and Liver Physiology

Volumn 311, Issue 6, 2016, Pages G1018-G1036

  Bluemel, Sena ^a   Williams, Brandon ^a   Knight, Rob ^b   Schnabl, Bernd ^a,c  

^a UNIVERSITY OF CALIFORNIA SAN DIEGO   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c VA SAN DIEGO HEALTHCARE SYSTEM   (United States)

Author keywords

Alcoholic liver disease; Intestinal microbiome; Nonalcoholic fatty liver disease; Precision medicine; Probiotics

Indexed keywords

ANTIBIOTIC AGENT; ANTIOXIDANT; FATTY ACID; PROBIOTIC AGENT;

ALCOHOL LIVER DISEASE; DYSBIOSIS; ENDOTOXEMIA; ENDOTOXIN-INDUCED LIVER INJURY; HUMAN; INTESTINE FLORA; LIPID DIET; MICROBIOME; NONALCOHOLIC FATTY LIVER; NONHUMAN; PERSONALIZED MEDICINE; PRIORITY JOURNAL; REVIEW; ANIMAL; FATTY LIVER, ALCOHOLIC; METABOLISM; MICROBIOLOGY; NON-ALCOHOLIC FATTY LIVER DISEASE; PROCEDURES;

ANIMALS; FATTY LIVER, ALCOHOLIC; GASTROINTESTINAL MICROBIOME; HUMANS; NON-ALCOHOLIC FATTY LIVER DISEASE; PRECISION MEDICINE; PROBIOTICS;

EID: 85006046067     PISSN: 01931857     EISSN: 15221547     Source Type: Journal    
DOI: 10.1152/ajpgi.00245.2016     Document Type: Review

References (233)

1. Abdelmegeed MA, Banerjee A, Jang S, Yoo SH, Yun JW, Gonzalez FJ, Keshavarzian A, Song BJ. CYP2E1 potentiates binge alcoholinduced gut leakiness, steatohepatitis, and apoptosis. Free Radic Biol Med 65: 1238-1245, 2013.
2. Abdou RM, Zhu L, Baker RD, Baker SS. Gut microbiota of nonalcoholic fatty liver disease. Dig Dis Sci 61: 1268-1281, 2016.
3. Adachi Y, Bradford BU, Gao W, Bojes HK, Thurman RG. Inactivation of Kupffer cells prevents early alcohol-induced liver injury. Hepatology 20: 453-460, 1994.
4. Adachi Y, Enomoto M, Adachi M, Suwa M, Nagamine Y, Nanno T, Hashimoto T, Inoue H, Yamamoto T. Enteric coated polymyxin B in the treatment of hyperammonemia and endotoxemia in liver cirrhosis. Gastroenterol Jpn 17: 550-557, 1982.
5. Adachi Y, Moore LE, Bradford BU, Gao W, Thurman RG. Antibiotics prevent liver injury in rats following long-term exposure to ethanol. Gastroenterology 108: 218-224, 1995.
6. al-Waiz M, Mikov M, Mitchell SC, Smith RL. The exogenous origin of trimethylamine in the mouse. Metab Clin Exp 41: 135-136, 1992.
7. 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 39: 1276-1285, 2014.
8. 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 50: 645-649, 2010.
9. Aller R, De Luis DA, Izaola O, Conde R, Gonzalez Sagrado M, Primo D, De La Fuente B, Gonzalez J. Effect of a probiotic on liver aminotransferases in nonalcoholic fatty liver disease patients: a double blind randomized clinical trial. Eur Rev Med Pharmacol Sci 15: 1090-1095, 2011.
10. Anonymous. Raising standards in microbiome research. Nat Microbiol 1: 16112, 2016.
11. Backhed 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 101: 15718-15723, 2004.
12. Backhed F, Manchester JK, Semenkovich CF, Gordon JI. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci USA 104: 979-984, 2007.
13. Bajaj JS, Heuman DM, Hylemon PB, Sanyal AJ, Puri P, Sterling RK, Luketic V, Stravitz RT, Siddiqui MS, Fuchs M, Thacker LR, Wade JB, Daita K, Sistrun S, White MB, Noble NA, Thorpe C, Kakiyama G, Pandak WM, Sikaroodi M, Gillevet PM. Randomised clinical trial: Lactobacillus GG modulates gut microbiome, metabolome and endotoxemia in patients with cirrhosis. Aliment Pharmacol Ther 39: 1113-1125, 2014.
14. Bajaj JS, Saeian K, Christensen KM, Hafeezullah M, Varma RR, Franco J, Pleuss JA, Krakower G, Hoffmann RG, Binion DG. Probiotic yogurt for the treatment of minimal hepatic encephalopathy. Am J Gastroenterol 103: 1707-1715, 2008.
15. Bala S, Marcos M, Gattu A, Catalano D, Szabo G. Acute binge drinking increases serum endotoxin and bacterial DNA levels in healthy individuals. PLos One 9: e96864, 2014.
16. Balmer ML, Slack E, de Gottardi A, Lawson MA, Hapfelmeier S, Miele L, Grieco A, Van Vlierberghe H, Fahrner R, Patuto N, Bernsmeier C, Ronchi F, Wyss M, Stroka D, Dickgreber N, Heim MH, McCoy KD, Macpherson AJ. The liver may act as a firewall mediating mutualism between the host and its gut commensal microbiota. Sci Transl Med 6: 237ra266, 2014.
17. Bang CS, Hong SH, Suk KT, Kim JB, Han SH, Sung H, Kim EJ, Kim MJ, Kim MY, Baik SK, Kim DJ. Effects of Korean red ginseng (Panax ginseng), urushiol (Rhus vernicifera Stokes), and probiotics (Lactobacillus rhamnosus R0011 and Lactobacillus acidophilus R0052) on the gut-liver axis of alcoholic liver disease. J Ginseng Res 38: 167-172, 2014.
18. Bauer TM, Schwacha H, Steinbruckner B, Brinkmann FE, Ditzen AK, Aponte JJ, Pelz K, Berger D, Kist M, Blum HE. Small intestinal bacterial overgrowth in human cirrhosis is associated with systemic endotoxemia. Am J Gastroenterol 97: 2364-2370, 2002.
19. Bech-Nielsen GV, Hansen CH, Hufeldt MR, Nielsen DS, Aasted B, Vogensen FK, Midtvedt T, Hansen AK. Manipulation of the gut microbiota in C57BL/6 mice changes glucose tolerance without affecting weight development and gut mucosal immunity. Res Vet Sci 92: 501-508, 2012.
20. Becker S, Oelschlaeger TA, Wullaert A, Vlantis K, Pasparakis M, Wehkamp J, Stange EF, Gersemann M. Bacteria regulate intestinal epithelial cell differentiation factors both in vitro and in vivo. PLos One 8: e55620, 2013.
21. Bender KO, Garland M, Ferreyra JA, Hryckowian AJ, Child MA, Puri AW, Solow-Cordero DE, Higginbottom SK, Segal E, Banaei N, Shen A, Sonnenburg JL, Bogyo M. A small-molecule antivirulence agent for treating Clostridium difficile infection. Sci Transl Med 7: 306ra148, 2015.
22. Bennett BJ, de Aguiar Vallim TQ, Wang Z, Shih DM, Meng Y, Gregory J, Allayee H, Lee R, Graham M, Crooke R, Edwards PA, Hazen SL, Lusis AJ. Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab 17: 49-60, 2013.
23. Bergheim I, Weber S, Vos M, Kramer S, Volynets V, Kaserouni S, McClain CJ, Bischoff SC. Antibiotics protect against fructose-induced hepatic lipid accumulation in mice: role of endotoxin. J Hepatol 48: 983-992, 2008.
24. Bergstrom A, Kristensen MB, Bahl MI, Metzdorff SB, Fink LN, Frokiaer H, Licht TR. Nature of bacterial colonization influences transcription of mucin genes in mice during the first week of life. BMC Res Notes 5: 402, 2012.
25. Bernet MF, Brassart D, Neeser JR, Servin AL. Lactobacillus acidophilus LA 1 binds to cultured human intestinal cell lines and inhibits cell attachment and cell invasion by enterovirulent bacteria. Gut 35: 483-489, 1994.
26. Binder HJ. Role of colonic short-chain fatty acid transport in diarrhea. Annu Rev Physiol 72: 297-313, 2010.
27. Bjarnason I, Peters TJ, Wise RJ. The leaky gut of alcoholism: possible route of entry for toxic compounds. Lancet 1: 179-182, 1984.
28. Bode C, Kugler V, Bode JC. Endotoxemia in patients with alcoholic and non-alcoholic cirrhosis and in subjects with no evidence of chronic liver disease following acute alcohol excess. J Hepatol 4: 8-14, 1987.
29. Bode C, Schafer C, Fukui H, Bode JC. Effect of treatment with paromomycin on endotoxemia in patients with alcoholic liver disease—a double-blind, placebo-controlled trial. Alcohol Clin Exp Res 21: 1367-1373, 1997.
30. Borthakur A, Anbazhagan AN, Kumar A, Raheja G, Singh V, Ramaswamy K, Dudeja PK. The probiotic Lactobacillus plantarum counteracts TNF-α-induced downregulation of SMCT1 expression and function. Am J Physiol Gastrointest Liver Physiol 299: G928-G934, 2010.
31. Boursier J, Mueller O, Barret M, Machado M, Fizanne L, Araujo-Perez F, Guy CD, Seed PC, Rawls JF, David LA, Hunault G, Oberti F, Cales P, Diehl AM. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology 63: 764-775, 2016.
32. Brun P, Castagliuolo I, Di Leo V, Buda A, Pinzani M, Palu G, Martines D. Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol 292: G518-G525, 2007.
33. Bull-Otterson L, Feng W, Kirpich I, Wang Y, Qin X, Liu Y, Gobejishvili L, Joshi-Barve S, Ayvaz T, Petrosino J, Kong M, Barker D, McClain C, Barve S. Metagenomic analyses of alcohol induced pathogenic alterations in the intestinal microbiome and the effect of Lactobacillus rhamnosus GG treatment. PLos One 8: e53028, 2013.
34. Caballero-Franco C, Keller K, De Simone C, Chadee K. The VSL#3 probiotic formula induces mucin gene expression and secretion in colonic epithelial cells. Am J Physiol Gastrointest Liver Physiol 292: G315-G322, 2007.
35. Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE. Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB. Nat Med 11: 183-190, 2005.
36. Candela M, Perna F, Carnevali P, Vitali B, Ciati R, Gionchetti P, Rizzello F, Campieri M, Brigidi P. Interaction of probiotic Lactobacillus and Bifidobacterium strains with human intestinal epithelial cells: adhesion properties, competition against enteropathogens and modulation of IL-8 production. Int J Food Microbiol 125: 286-292, 2008.
37. Canfora EE, Jocken JW, Blaak EE. Short-chain fatty acids in control of body weight and insulin sensitivity. Nat Rev Endocrinol 11: 577-591, 2015.
38. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmee E, Cousin B, Sulpice T, Chamontin B, Ferrieres J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56: 1761-1772, 2007.
39. Carvalho BM, Guadagnini D, Tsukumo DM, Schenka AA, Latuf-Filho P, Vassallo J, Dias JC, Kubota LT, Carvalheira JB, Saad MJ. Modulation of gut microbiota by antibiotics improves insulin signalling in high-fat fed mice. Diabetologia 55: 2823-2834, 2012.
40. Carvalho BM, Saad MJ. Influence of gut microbiota on subclinical inflammation and insulin resistance. Mediat Inflamm 2013: 986734, 2013.
41. Cash HL, Whitham CV, Behrendt CL, Hooper LV. Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313: 1126-1130, 2006.
42. Chang B, Sang L, Wang Y, Tong J, Zhang D, Wang B. The protective effect of VSL#3 on intestinal permeability in a rat model of alcoholic intestinal injury. BMC Gastroenterol 13: 151, 2013.
43. Charlton M, Krishnan A, Viker K, Sanderson S, Cazanave S, McConico A, Masuoko H, Gores G. Fast food diet mouse: novel small animal model of NASH with ballooning, progressive fibrosis, and high physiological fidelity to the human condition. Am J Physiol Gastrointest Liver Physiol 301: G825-G834, 2011.
44. Chen P, Miyamoto Y, Mazagova M, Lee KC, Eckmann L, Schnabl B. Microbiota protects mice against acute alcohol-induced liver injury. Alcohol Clin Exp Res 39: 2313-2323, 2015.
45. Chen P, Starkel P, Turner JR, Ho SB, Schnabl B. Dysbiosis-induced intestinal inflammation activates tumor necrosis factor receptor I and mediates alcoholic liver disease in mice. Hepatology 61: 883-894, 2015.
46. Chen P, Torralba M, Tan J, Embree M, Zengler K, Starkel P, van Pijkeren JP, DePew J, Loomba R, Ho SB, Bajaj JS, Mutlu EA, Keshavarzian A, Tsukamoto H, Nelson KE, Fouts DE, Schnabl B. Supplementation of saturated long-chain fatty acids maintains intestinal eubiosis and reduces ethanol-induced liver injury in mice. Gastroenterology 148: 203-214 e216, 2015.
47. Chen Y, Yang F, Lu H, Wang B, Chen Y, Lei D, Wang Y, Zhu B, Li L. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 54: 562-572, 2011.
48. Chen YM, Liu Y, Zhou RF, Chen XL, Wang C, Tan XY, Wang LJ, Zheng RD, Zhang HW, Ling WH, Zhu HL. Associations of gut-floradependent metabolite trimethylamine-N-oxide, betaine and choline with non-alcoholic fatty liver disease in adults. Sci Rep 6: 19076, 2016.
49. Chiu WC, Huang YL, Chen YL, Peng HC, Liao WH, Chuang HL, Chen JR, Yang SC. Synbiotics reduce ethanol-induced hepatic steatosis and inflammation by improving intestinal permeability and microbiota in rats. Food Function 6: 1692-1700, 2015.
50. Chou CJ, Membrez M, Blancher F. Gut decontamination with norfloxacin and ampicillin enhances insulin sensitivity in mice. Nestle Nutr Workshop Ser Paediatr Programme 62: 127-140, 2008.
51. Chumbler NM, Farrow MA, Lapierre LA, Franklin JL, Haslam DB, Goldenring JR, Lacy DB. Clostridium difficile toxin B causes epithelial cell necrosis through an autoprocessing-independent mechanism. PLoS Pathog 8: e1003072, 2012.
52. Cope K, Risby T, Diehl AM. Increased gastrointestinal ethanol production in obese mice: implications for fatty liver disease pathogenesis. Gastroenterology 119: 1340-1347, 2000.
53. Cresci GA, Bush K, Nagy LE. Tributyrin supplementation protects mice from acute ethanol-induced gut injury. Alcohol Clin Exp Res 38: 1489-1501, 2014.
54. Crespo J, Cayon A, Fernandez-Gil P, Hernandez-Guerra M, Mayorga M, Dominguez-Diez A, Fernandez-Escalante JC, Pons-Romero F. Gene expression of tumor necrosis factor-α and TNF receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology 34: 1158-1163, 2001.
55. den Besten G, Bleeker A, Gerding A, van Eunen K, Havinga R, van Dijk TH, Oosterveer MH, Jonker JW, Groen AK, Reijngoud DJ, Bakker BM. Short-chain fatty acids protect against high-fat diet-induced obesity via a PPAR-dependent switch from lipogenesis to fat oxidation. Diabetes 64: 2398-2408, 2015.
56. 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 147: 1327-1337 e1323, 2014.
57. Di Sabatino A, Morera R, Ciccocioppo R, Cazzola P, Gotti S, Tinozzi FP, Tinozzi S, Corazza GR. Oral butyrate for mildly to moderately active Crohn’s disease. Aliment Pharmacol Ther 22: 789-794, 2005.
58. Donohoe DR, Garge N, Zhang X, Sun W, O’Connell TM, Bunger MK, Bultman SJ. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab 13: 517-526, 2011.
59. Douhara A, Moriya K, Yoshiji H, Noguchi R, Namisaki T, Kitade M, Kaji K, Aihara Y, Nishimura N, Takeda K, Okura Y, Kawaratani H, Fukui H. Reduction of endotoxin attenuates liver fibrosis through suppression of hepatic stellate cell activation and remission of intestinal permeability in a rat non-alcoholic steatohepatitis model. Mol Med Rep 11: 1693-1700, 2015.
60. Du Plessis J, Vanheel H, Janssen CE, Roos L, Slavik T, Stivaktas PI, Nieuwoudt M, van Wyk SG, Vieira W, Pretorius E, Beukes M, Farre R, Tack J, Laleman W, Fevery J, Nevens F, Roskams T, Van der Merwe SW. Activated intestinal macrophages in patients with cirrhosis release NO and IL-6 that may disrupt intestinal barrier function. J Hepatol 58: 1125-1132, 2013.
61. 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 103: 12511-12516, 2006.
62. Eckel-Mahan KL, Patel VR, de Mateo S, Orozco-Solis R, Ceglia NJ, Sahar S, Dilag-Penilla SA, Dyar KA, Baldi P, Sassone-Corsi P. Reprogramming of the circadian clock by nutritional challenge. Cell 155: 1464-1478, 2013.
63. Ellul MA, Gholkar SA, Cross TJ. Hepatic encephalopathy due to liver cirrhosis. BMJ 351: h4187, 2015.
64. Endo H, Niioka M, Kobayashi N, Tanaka M, Watanabe T. Butyrateproducing probiotics reduce nonalcoholic fatty liver disease progression in rats: new insight into the probiotics for the gut-liver axis. PLos One 8: e63388, 2013.
65. Erridge C, Attina T, Spickett CM, Webb DJ. A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of postprandial inflammation. Am J Clin Nutr 86: 1286-1292, 2007.
66. Esposito E, Iacono A, Bianco G, Autore G, Cuzzocrea S, Vajro P, Canani RB, Calignano A, Raso GM, Meli R. Probiotics reduce the inflammatory response induced by a high-fat diet in the liver of young rats. J Nutr 139: 905-911, 2009.
67. Everard A, Geurts L, Caesar R, Van Hul M, Matamoros S, Duparc T, Denis RG, Cochez P, Pierard F, Castel J, Bindels LB, Plovier H, Robine S, Muccioli GG, Renauld JC, Dumoutier L, Delzenne NM, Luquet S, Backhed F, Cani PD. Intestinal epithelial MyD88 is a sensor switching host metabolism towards obesity according to nutritional status. Nat Commun 5: 5648, 2014.
68. Everard A, Lazarevic V, Gaia N, Johansson M, Stahlman M, Backhed F, Delzenne NM, Schrenzel J, Francois P, Cani PD. Microbiome of prebiotic-treated mice reveals novel targets involved in host response during obesity. ISME J 8: 2116-2130, 2014.
69. Fernandes CF, Shahani KM, Amer MA. Therapeutic role of dietary lactobacilli and lactobacillic fermented dairy products. FEMS Microbiol Lett 46: 343-356, 1987.
70. Fleet T, Stashi E, Zhu B, Rajapakshe K, Marcelo KL, Kettner NM, Gorman BK, Coarfa C, Fu L, O’Malley BW, York B. Genetic and environmental models of circadian disruption link SRC-2 function to hepatic pathology. J Biol Rhythms 31: 443-460, 2016.
71. Forsyth CB, Farhadi A, Jakate SM, Tang Y, Shaikh M, Keshavarzian A. Lactobacillus GG treatment ameliorates alcohol-induced intestinal oxidative stress, gut leakiness, and liver injury in a rat model of alcoholic steatohepatitis. Alcohol 43: 163-172, 2009.
72. Forsyth CB, Voigt RM, Shaikh M, Tang Y, Cederbaum AI, Turek FW, Keshavarzian A. Role for intestinal CYP2E1 in alcohol-induced circadian gene-mediated intestinal hyperpermeability. Am J Physiol Gastrointest Liver Physiol 305: G185-G195, 2013.
73. Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, Nakanishi Y, Uetake C, Kato K, Kato T, Takahashi M, Fukuda NN, Murakami S, Miyauchi E, Hino S, Atarashi K, Onawa S, Fujimura Y, Lockett T, Clarke JM, Topping DL, Tomita M, Hori S, Ohara O, Morita T, Koseki H, Kikuchi J, Honda K, Hase K, Ohno H. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504: 446-450, 2013.
74. Gaeta GB, Perna P, Adinolfi LE, Utili R, Ruggiero G. Endotoxemia in a series of 104 patients with chronic liver diseases: prevalence and significance. Digestion 23: 239-244, 1982.
75. Gangarapu V, Ince AT, Baysal B, Kayar Y, Kilic U, Gok O, Uysal O, Senturk H. Efficacy of rifaximin on circulating endotoxins and cytokines in patients with nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol 27: 840-845, 2015.
76. Gao B, Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology 141: 1572-1585, 2011.
77. Gao Z, Yin J, Zhang J, Ward RE, Martin RJ, Lefevre M, Cefalu WT, Ye J. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes 58: 1509-1517, 2009.
78. Gerding DN, Meyer T, Lee C, Cohen SH, Murthy UK, Poirier A, Van Schooneveld TC, Pardi DS, Ramos A, Barron MA, Chen H, Villano S. Administration of spores of nontoxigenic Clostridium difficile strain M3 for prevention of recurrent C. difficile infection: a randomized clinical trial. JAMA 313: 1719-1727, 2015.
79. Giorgio V, Miele L, Principessa L, Ferretti F, Villa MP, Negro V, Grieco A, Alisi A, Nobili V. Intestinal permeability is increased in children with non-alcoholic fatty liver disease and correlates with liver disease severity. Dig Liver Dis 46: 556-560, 2014.
80. Guo JH, Han DW, Li XQ, Zhang Y, Zhao YC. The impact of small doses of LPS on NASH in high sucrose and high fat diet induced rats. Eur Rev Med Pharmacol Sci 18: 2742-2747, 2014.
81. Gupta A, Dhiman RK, Kumari S, Rana S, Agarwal R, Duseja A, Chawla Y. Role of small intestinal bacterial overgrowth and delayed gastrointestinal transit time in cirrhotic patients with minimal hepatic encephalopathy. J Hepatol 53: 849-855, 2010.
82. Gupta N, Kumar A, Sharma P, Garg V, Sharma BC, Sarin SK. Effects of the adjunctive probiotic VSL#3 on portal haemodynamics in patients with cirrhosis and large varices: a randomized trial. Liver Int 33: 1148-1157, 2013.
83. Han SH, Suk KT, Kim DJ, Kim MY, Baik SK, Kim YD, Cheon GJ, Choi DH, Ham YL, Shin DH, Kim EJ. Effects of probiotics (cultured Lactobacillus subtilis/Streptococcus faecium) in the treatment of alcoholic hepatitis: randomized-controlled multicenter study. Eur J Gastroenterol Hepatol 27: 1300-1306, 2015.
84. Hartmann P, Chen P, Wang HJ, Wang L, McCole DF, Brandl K, Starkel P, Belzer C, Hellerbrand C, Tsukamoto H, Ho SB, Schnabl B. Deficiency of intestinal mucin-2 ameliorates experimental alcoholic liver disease in mice. Hepatology 58: 108-119, 2013.
85. Hartmann P, Chen WC, Schnabl B. The intestinal microbiome and the leaky gut as therapeutic targets in alcoholic liver disease. Front Physiol 3: 402, 2012.
86. Hartmann P, Seebauer CT, Mazagova M, Horvath A, Wang L, Llorente C, Varki NM, Brandl K, Ho SB, Schnabl B. Deficiency of intestinal mucin-2 protects mice from diet-induced fatty liver disease and obesity. Am J Physiol Gastrointest Liver Physiol 310: G310-G322, 2016.
87. Hartmann P, Seebauer CT, Schnabl B. Alcoholic liver disease: the gut microbiome and liver cross talk. Alcohol Clin Exp Res 39: 763-775, 2015.
88. Hatayama H, Iwashita J, Kuwajima A, Abe T. The short chain fatty acid, butyrate, stimulates MUC2 mucin production in the human colon cancer cell line, LS174T. Biochem Biophys Res Commun 356: 599-603, 2007.
89. Haub S, Kanuri G, Volynets V, Brune T, Bischoff SC, Bergheim I. Serotonin reuptake transporter (SERT) plays a critical role in the onset of fructose-induced hepatic steatosis in mice. Am J Physiol Gastrointest Liver Physiol 298: G335-G344, 2010.
90. Hobara N, Watanabe A, Kobayashi M, Tsuji T, Gomita Y, Araki Y. Quinone derivatives lower blood and liver acetaldehyde but not ethanol concentrations following ethanol loading to rats. Pharmacology 37: 264-267, 1988.
91. Hong M, Kim SW, Han SH, Kim DJ, Suk KT, Kim YS, Kim MJ, Kim MY, Baik SK, Ham YL. Probiotics (Lactobacillus rhamnosus R0011 and acidophilus R0052) reduce the expression of toll-like receptor 4 in mice with alcoholic liver disease. PLos One 10: e0117451, 2015.
92. Hoogerwerf WA. Role of biological rhythms in gastrointestinal health and disease. Rev Endocr Metab Disord 10: 293-300, 2009.
93. 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 29: 2397-2411, 2015.
94. Ianiro G, Tilg H, Gasbarrini A. Antibiotics as deep modulators of gut microbiota: between good and evil. Gut. In press.
95. Jayakumar S, Carbonneau M, Hotte N, Befus AD, St Laurent C, Owen R, McCarthy M, Madsen K, Bailey RJ, Ma M, Bain V, Rioux K, Tandon P. VSL#3 probiotic therapy does not reduce portal pressures in patients with decompensated cirrhosis. Liver Int 33: 1470-1477, 2013.
96. Jiang C, Xie C, Li F, Zhang L, Nichols RG, Krausz KW, Cai J, Qi Y, Fang ZZ, Takahashi S, Tanaka N, Desai D, Amin SG, Albert I, Patterson AD, Gonzalez FJ. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J Clin Invest 125: 386-402, 2015.
97. Jiang W, Wu N, Wang X, Chi Y, Zhang Y, Qiu X, Hu Y, Li J, Liu Y. Dysbiosis gut microbiota associated with inflammation and impaired mucosal immune function in intestine of humans with non-alcoholic fatty liver disease. Sci Rep 5: 8096, 2015.
98. Jin CJ, Sellmann C, Engstler AJ, Ziegenhardt D, Bergheim I. Supplementation of sodium butyrate protects mice from the development of non-alcoholic steatohepatitis (NASH). Br J Nutr 114: 1745-1755, 2015.
99. Jin P, Chen Y, Lv L, Yang J, Lu H, Li L. Lactobacillus fermentum ZYL0401 attenuates lipopolysaccharide-induced hepatic TNF-α expression and liver injury via an IL-10-and PGE2-EP4-dependent mechanism. PLos One 10: e0126520, 2015.
100. Jin R, Willment A, Patel SS, Sun X, Song M, Mannery YO, Kosters A, McClain CJ, Vos MB. Fructose induced endotoxemia in pediatric nonalcoholic fatty liver disease. Int J Hepatol 2014: 560620, 2014.
101. Kanuri G, Ladurner R, Skibovskaya J, Spruss A, Konigsrainer A, Bischoff SC, Bergheim I. Expression of toll-like receptors 1-5 but not TLR 6-10 is elevated in livers of patients with non-alcoholic fatty liver disease. Liver Int 35: 562-568, 2015.
102. Kersten S, Mandard S, Tan NS, Escher P, Metzger D, Chambon P, Gonzalez FJ, Desvergne B, Wahli W. Characterization of the fastinginduced adipose factor FIAF, a novel peroxisome proliferator-activated receptor target gene. J Biol Chem 275: 28488-28493, 2000.
103. Keshavarzian A, Fields JZ, Vaeth J, Holmes EW. The differing effects of acute and chronic alcohol on gastric and intestinal permeability. Am J Gastroenterol 89: 2205-2211, 1994.
104. Kiczka W. [Role of bacterial endotoxins in liver pathology]. Pol Arch Med Wewn 62: 179-185, 1979.
105. Kim D, Kim WR. Non-obese fatty liver disease. Clin Gastroenterol Hepatol. In press.
106. Kirpich IA, Solovieva NV, Leikhter SN, Shidakova NA, Lebedeva OV, Sidorov PI, Bazhukova TA, Soloviev AG, Barve SS, McClain CJ, Cave M. Probiotics restore bowel flora and improve liver enzymes in human alcohol-induced liver injury: a pilot study. Alcohol 42: 675-682, 2008.
107. Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L, Smith JD, DiDonato JA, Chen J, Li H, Wu GD, Lewis JD, Warrier M, Brown JM, Krauss RM, Tang WH, Bushman FD, Lusis AJ, Hazen SL. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 19: 576-585, 2013.
108. Kudo T, Tamagawa T, Shibata S. Effect of chronic ethanol exposure on the liver of Clock-mutant mice. J Circadian Rhythms 7: 4, 2009.
109. Kumar A, Alrefai WA, Borthakur A, Dudeja PK. Lactobacillus acidophilus counteracts enteropathogenic E. coli-induced inhibition of butyrate uptake in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 309: G602-G607, 2015.
110. Kwak DS, Jun DW, Seo JG, Chung WS, Park SE, Lee KN, Khalid-Saeed W, Lee HL, Lee OY, Yoon BC, Choi HS. Short-term probiotic therapy alleviates small intestinal bacterial overgrowth, but does not improve intestinal permeability in chronic liver disease. Eur J Gastroenterol Hepatol 26: 1353-1359, 2014.
111. Land MH, Rouster-Stevens K, Woods CR, Cannon ML, Cnota J, Shetty AK. Lactobacillus sepsis associated with probiotic therapy. Pediatrics 115: 178-181, 2005.
112. Lee K, Paek K, Lee HY, Park JH, Lee Y. Antiobesity effect of trans-10,cis-12-conjugated linoleic acid-producing Lactobacillus plantarum PL62 on diet-induced obese mice. J Appl Microbiol 103: 1140-1146, 2007.
113. Lessa FC, Mu Y, Bamberg WM, Beldavs ZG, Dumyati GK, Dunn JR, Farley MM, Holzbauer SM, Meek JI, Phipps EC, Wilson LE, Winston LG, Cohen JA, Limbago BM, Fridkin SK, Gerding DN, McDonald LC. Burden of Clostridium difficile infection in the United States. N Engl J Med 372: 825-834, 2015.
114. 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 Function 5: 3216-3223, 2014.
115. Li S, Wu WC, He CY, Han Z, Jin DY, Wang L. Change of intestinal mucosa barrier function in the progress of non-alcoholic steatohepatitis in rats. World J Gastroenterol 14: 3254-3258, 2008.
116. Li X, Wang C, Nie J, Lv D, Wang T, Xu Y. Toll-like receptor 4 increases intestinal permeability through up-regulation of membrane PKC activity in alcoholic steatohepatitis. Alcohol 47: 459-465, 2013.
117. 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 37: 343-350, 2003.
118. Liang S, Webb T, Li Z. Probiotic antigens stimulate hepatic natural killer T cells. Immunology 141: 203-210, 2014.
119. Lieber CS. Role of oxidative stress and antioxidant therapy in alcoholic and nonalcoholic liver diseases. Adv Pharmacol 38: 601-628, 1997.
120. Lin YC, Hsieh IC, Chen PC. Long-term day-and-night rotating shift work poses a barrier to the normalization of alanine transaminase. Chronobiol Int 31: 487-495, 2014.
121. Llopis M, Cassard AM, Wrzosek L, Boschat L, Bruneau A, Ferrere G, Puchois V, Martin JC, Lepage P, Le Roy T, Lefevre L, Langelier B, Cailleux F, Gonzalez-Castro AM, Rabot S, Gaudin F, Agostini H, Prevot S, Berrebi D, Ciocan D, Jousse C, Naveau S, Gerard P, Perlemuter G. Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease. Gut 65: 830-839, 2016.
122. Llorente C, Schnabl B. The gut microbiota and liver disease. Cell Mol Gastroenterol Hepatol 1: 275-284, 2015.
123. Loguercio C, De Simone T, Federico A, Terracciano F, Tuccillo C, Di Chicco M, Carteni M. Gut-liver axis: a new point of attack to treat chronic liver damage? Am J Gastroenterol 97: 2144-2146, 2002.
124. Loguercio C, Federico A, Tuccillo C, Terracciano F, D’Auria MV, De Simone C, Del Vecchio Blanco C. Beneficial effects of a probiotic VSL#3 on parameters of liver dysfunction in chronic liver diseases. J Clin Gastroenterol 39: 540-543, 2005.
125. Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol 10: 686-690, 2013.
126. Lowy I, Molrine DC, Leav BA, Blair BM, Baxter R, Gerding DN, Nichol G, Thomas WD Jr, Leney M, Sloan S, Hay CA, Ambrosino DM. Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med 362: 197-205, 2010.
127. Lozupone CA, Stombaugh J, Gonzalez A, Ackermann G, Wendel D, Vazquez-Baeza Y, Jansson JK, Gordon JI, Knight R. Meta-analyses of studies of the human microbiota. Genome Res 23: 1704-1714, 2013.
128. Luther J, Garber JJ, Khalili H, Dave M, Bale SS, Jindal R, Motola DL, Luther S, Bohr S, Jeoung SW, Deshpande V, Singh G, Turner JR, Yarmush ML, Chung RT, Patel SJ. Hepatic injury in nonalcoholic steatohepatitis contributes to altered intestinal permeability. Cell Mol Gastroenterol Hepatol 1: 222-232, 2015.
129. Lv LX, Hu XJ, Qian GR, Zhang H, Lu HF, Zheng BW, Jiang L, Li LJ. Administration of Lactobacillus salivarius LI01 or Pediococcus pentosaceus LI05 improves acute liver injury induced by D-galactosamine in rats. Appl Microbiol Biotechnol 98: 5619-5632, 2014.
130. Ma X, Hua J, Li Z. Probiotics improve high fat diet-induced hepatic steatosis and insulin resistance by increasing hepatic NKT cells. J Hepatol 49: 821-830, 2008.
131. Maassen CB, van Holten-Neelen C, Balk F, den Bak-Glashouwer MJ, Leer RJ, Laman JD, Boersma WJ, Claassen E. Strain-dependent induction of cytokine profiles in the gut by orally administered Lactobacillus strains. Vaccine 18: 2613-2623, 2000.
132. Malaguarnera M, Vacante M, Antic T, Giordano M, Chisari G, Acquaviva R, Mastrojeni S, Malaguarnera G, Mistretta A, Li Volti G, Galvano F. Bifidobacterium longum with fructo-oligosaccharides in patients with non alcoholic steatohepatitis. Dig Dis Sci 57: 545-553, 2012.
133. Mariadason JM, Barkla DH, Gibson PR. Effect of short-chain fatty acids on paracellular permeability in Caco-2 intestinal epithelium model. Am J Physiol Gastrointest Liver Physiol 272: G705-G712, 1997.
134. Matsushita K, Arents JC, Bader R, Yamada M, Adachi O, Postma PW. Escherichia coli is unable to produce pyrroloquinoline quinone (PQQ). Microbiology 143: 3149-3156, 1997.
135. Mattace Raso G, Simeoli R, Russo R, Iacono A, Santoro A, Paciello O, Ferrante MC, Canani RB, Calignano A, Meli R. 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 8: e68626, 2013.
136. Mazagova M, Wang L, Anfora AT, Wissmueller M, Lesley SA, Miyamoto Y, Eckmann L, Dhungana S, Pathmasiri W, Sumner S, Westwater C, Brenner DA, Schnabl B. Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice. FASEB J 29: 1043-1055, 2015.
137. Membrez M, Blancher F, Jaquet M, Bibiloni R, Cani PD, Burcelin RG, Corthesy I, Mace K, Chou CJ. Gut microbiota modulation with norfloxacin and ampicillin enhances glucose tolerance in mice. FASEB J 22: 2416-2426, 2008.
138. Mencin A, Kluwe J, Schwabe RF. Toll-like receptors as targets in chronic liver diseases. Gut 58: 704-720, 2009.
139. Miele L, Valenza V, La Torre G, Montalto M, Cammarota G, Ricci R, Masciana R, Forgione A, Gabrieli ML, Perotti G, Vecchio FM, Rapaccini G, Gasbarrini G, Day CP, Grieco A. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 49: 1877-1887, 2009.
140. Miura K, Seki E, Ohnishi H, Brenner DA. Role of toll-like receptors and their downstream molecules in the development of nonalcoholic fatty liver disease. Gastroenterol Res Pract 2010: 362847, 2010.
141. Moro-Sibilot L, Blanc P, Taillardet M, Bardel E, Couillault C, Boschetti G, Traverse-Glehen A, Defrance T, Kaiserlian D, Dubois B. Mouse and human liver contain immunoglobulin A-secreting cells originating from Peyer’s patches and directed against intestinal antigens. Gastroenterology 151: 311-323, 2016.
142. Mouralidarane A, Soeda J, Sugden D, Bocianowska A, Carter R, Ray S, Saraswati R, Cordero P, Novelli M, Fusai G, Vinciguerra M, Poston L, Taylor PD, Oben JA. Maternal obesity programs offspring non-alcoholic fatty liver disease through disruption of 24-h rhythms in mice. Int J Obes 39: 1339-1348, 2015.
143. Mouzaki M, Comelli EM, Arendt BM, Bonengel J, Fung SK, Fischer SE, McGilvray ID, Allard JP. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology 58: 120-127, 2013.
144. Mukherji A, Kobiita A, Ye T, Chambon P. Homeostasis in intestinal epithelium is orchestrated by the circadian clock and microbiota cues transduced by TLRs. Cell 153: 812-827, 2013.
145. Murakami M, Tognini P, Liu Y, Eckel-Mahan KL, Baldi P, Sassone-Corsi P. Gut microbiota directs PPARγ-driven reprogramming of the liver circadian clock by nutritional challenge. EMBO Rep 17: 1292-1303, 2016.
146. Murphy EF, Cotter PD, Hogan A, O’Sullivan O, Joyce A, Fouhy F, Clarke SF, Marques TM, O’Toole PW, Stanton C, Quigley EM, Daly C, Ross PR, O’Doherty RM, Shanahan F. Divergent metabolic outcomes arising from targeted manipulation of the gut microbiota in diet-induced obesity. Gut 62: 220-226, 2013.
147. Mykhal’chyshyn HP, Bodnar PM, Kobyliak NM. [Effect of probiotics on proinflammatory cytokines level in patients with type 2 diabetes and nonalcoholic fatty liver disease] (Abstract). Lik Sprava Mar: 56-62, 2013.
148. Nabavi S, Rafraf M, Somi MH, Homayouni-Rad A, Asghari-Jafarabadi M. Effects of probiotic yogurt consumption on metabolic factors in individuals with nonalcoholic fatty liver disease. J Dairy Sci 97: 7386-7393, 2014.
149. Nanji AA, Khettry U, Sadrzadeh SM. Lactobacillus feeding reduces endotoxemia and severity of experimental alcoholic liver (disease). Proc Soc Exp Biol Med 205: 243-247, 1994.
150. Okin D, Medzhitov R. The effect of sustained inflammation on hepatic mevalonate pathway results in hyperglycemia. Cell 165: 343-356, 2016.
151. 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 305: G911-G918, 2013.
152. Ouyang X, Cirillo P, Sautin Y, McCall S, Bruchette JL, Diehl AM, Johnson RJ, Abdelmalek MF. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol 48: 993-999, 2008.
153. Park Y, Storkson JM, Albright KJ, Liu W, Pariza MW. Evidence that the trans-10,cis-12 isomer of conjugated linoleic acid induces body composition changes in mice. Lipids 34: 235-241, 1999.
154. Parvez S, Malik KA, Ah Kang S, Kim HY. Probiotics and their fermented food products are beneficial for health. J Appl Microbiol 100: 1171-1185, 2006.
155. Petrasek J, Iracheta-Vellve A, Csak T, Satishchandran A, Kodys K, Kurt-Jones EA, Fitzgerald KA, Szabo G. STING-IRF3 pathway links endoplasmic reticulum stress with hepatocyte apoptosis in early alcoholic liver disease. Proc Natl Acad Sci USA 110: 16544-16549, 2013.
156. 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 151: 733-746, 2016.
157. Raman M, Ahmed I, Gillevet PM, Probert CS, Ratcliffe NM, Smith S, Greenwood R, Sikaroodi M, Lam V, Crotty P, Bailey J, Myers RP, Rioux KP. Fecal microbiome and volatile organic compound metabolome in obese humans with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 11: 868-875 e861-863, 2013.
158. Rao RK. Acetaldehyde-induced barrier disruption and paracellular permeability in Caco-2 cell monolayer. Methods Mol Biol 447: 171-183, 2008.
159. Raso GM, Simeoli R, Iacono A, Santoro A, Amero P, Paciello O, Russo R, D’Agostino G, Di Costanzo M, Canani RB, Calignano A, Meli R. 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 25: 81-90, 2014.
160. Rehm J, Mathers C, Popova S, Thavorncharoensap M, Teerawattananon Y, Patra J. Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders. Lancet 373: 2223-2233, 2009.
161. Reichold A, Brenner SA, Spruss A, Forster-Fromme K, Bergheim I, Bischoff SC. Bifidobacterium adolescentis protects from the development of nonalcoholic steatohepatitis in a mouse model. J Nutr Biochem 25: 118-125, 2014.
162. Riquelme AJ, Calvo MA, Guzman AM, Depix MS, Garcia P, Perez C, Arrese M, Labarca JA. Saccharomyces cerevisiae fungemia after Saccharomyces boulardii treatment in immunocompromised patients. J Clin Gastroenterol 36: 41-43, 2003.
163. Ritze Y, Bardos G, Claus A, Ehrmann V, Bergheim I, Schwiertz A, Bischoff SC. Lactobacillus rhamnosus GG protects against non-alcoholic fatty liver disease in mice. PLos One 9: e80169, 2014.
164. Robinson GM, Orrego H, Israel Y, Devenyi P, Kapur BM. Lowmolecular-weight polyethylene glycol as a probe of gastrointestinal permeability after alcohol ingestion. Dig Dis Sci 26: 971-977, 1981.
165. Romano KA, Vivas EI, Amador-Noguez D, Rey FE. Intestinal microbiota composition modulates choline bioavailability from diet and accumulation of the proatherogenic metabolite trimethylamine-N-oxide. mBio 6: e02481, 2015.
166. Rosenbaum M, Knight R, Leibel RL. The gut microbiota in human energy homeostasis and obesity. Trends Endocrinol Metab 26: 493-501, 2015.
167. Ruiz AG, Casafont F, Crespo J, Cayon A, Mayorga M, Estebanez A, Fernadez-Escalante JC, Pons-Romero F. Lipopolysaccharide-binding protein plasma levels and liver TNF-α gene expression in obese patients: evidence for the potential role of endotoxin in the pathogenesis of non-alcoholic steatohepatitis. Obes Surg 17: 1374-1380, 2007
168. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA, Lavine JE, Tonascia J, Unalp A, Van Natta M, Clark J, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR, Nash CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 362: 1675-1685, 2010.
169. Satapathy SK, Garg S, Chauhan R, Sakhuja P, Malhotra V, Sharma BC, Sarin SK. Beneficial effects of tumor necrosis factor-α inhibition by pentoxifylline on clinical, biochemical, and metabolic parameters of patients with nonalcoholic steatohepatitis. Am J Gastroenterol 99: 1946-1952, 2004
170. Sautter T, Liehr H, Grun M, Brunswig D. [Polymyxin B treatment of endotoxinemia in liver cirrhosis]. Verh Dtsch Ges Inn Med 83: 1148-1151, 1977.
171. Sayin SI, Wahlstrom A, Felin J, Jantti S, Marschall HU, Bamberg K, Angelin B, Hyotylainen T, Oresic M, Backhed F. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-β-muricholic acid, a naturally occurring FXR antagonist. Cell Metab 17: 225-235, 2013.
172. Segawa S, Wakita Y, Hirata H, Watari J. Oral administration of heat-killed Lactobacillus brevis SBC8803 ameliorates alcoholic liver disease in ethanol-containing diet-fed C57BL/6N mice. Int J Food Microbiol 128: 371-377, 2008.
173. Seki E, De Minicis S, Osterreicher CH, Kluwe J, Osawa Y, Brenner DA, Schwabe RF. TLR4 enhances TGF-β signaling and hepatic fibrosis. Nat Med 13: 1324-1332, 2007.
174. Seo M, Inoue I, Tanaka M, Matsuda N, Nakano T, Awata T, Katayama S, Alpers DH, Komoda T. Clostridium butyricum MIYAIRI 588 improves high-fat diet-induced non-alcoholic fatty liver disease in rats. Dig Dis Sci 58: 3534-3544, 2013.
175. Sepideh A, Karim P, Hossein A, Leila R, Hamdollah M, Mohammad EG, Mojtaba S, Mohammad S, Ghader G, Seyed Moayed A. Effects of multistrain probiotic supplementation on glycemic and inflammatory indices in patients with nonalcoholic fatty liver disease: a double-blind randomized clinical trial. J Am Coll Nutr 35: 1-6, 2015.
176. Seth A, Yan F, Polk DB, Rao RK. Probiotics ameliorate the hydrogen peroxide-induced epithelial barrier disruption by a PKC-and MAP kinase-dependent mechanism. Am J Physiol Gastrointest Liver Physiol 294: G1060-G1069, 2008.
177. Sharifnia T, Antoun J, Verriere TG, Suarez G, Wattacheril J, Wilson KT, Peek RM Jr, Abumrad NN, Flynn CR. Hepatic TLR4 signaling in obese NAFLD. Am J Physiol Gastrointest Liver Physiol 309: G270-G278, 2015.
178. Shavakhi A, Minakari M, Firouzian H, Assali R, Hekmatdoost A, Ferns G. Effect of a probiotic and metformin on liver aminotransferases in non-alcoholic steatohepatitis: a double blind randomized clinical trial. Int J Prev Med 4: 531-537, 2013.
179. Shen TC, Albenberg L, Bittinger K, Chehoud C, Chen YY, Judge CA, Chau L, Ni J, Sheng M, Lin A, Wilkins BJ, Buza EL, Lewis JD, Daikhin Y, Nissim I, Yudkoff M, Bushman FD, Wu GD. Engineering the gut microbiota to treat hyperammonemia. J Clin Invest 125: 2841-2850, 2015.
180. Sheth RU, Cabral V, Chen SP, Wang HH. Manipulating bacterial communities by in situ microbiome engineering. Trends Genet 32: 189-200, 2016.
181. Shimizu M, Lasker JM, Tsutsumi M, Lieber CS. Immunohistochemical localization of ethanol-inducible P450IIE1 in the rat alimentary tract. Gastroenterology 99: 1044-1053, 1990.
182. Shin NR, Whon TW, Bae JW. Proteobacteria: microbial signature of dysbiosis in gut microbiota. Trends Biotechnol 33: 496-503, 2015.
183. Singh AK, Pandey SK, Naresh Kumar G. Pyrroloquinoline quinonesecreting probiotic Escherichia coli Nissle 1917 ameliorates ethanol-induced oxidative damage and hyperlipidemia in rats. Alcohol Clin Exp Res 38: 2127-2137, 2014.
184. Sookoian S, Castano G, Gemma C, Gianotti TF, Pirola CJ. Common genetic variations in CLOCK transcription factor are associated with nonalcoholic fatty liver disease. World J Gastroenterol 13: 4242-4248, 2007.
185. Spadoni I, Zagato E, Bertocchi A, Paolinelli R, Hot E, Di Sabatino A, Caprioli F, Bottiglieri L, Oldani A, Viale G, Penna G, Dejana E, Rescigno M. A gut-vascular barrier controls the systemic dissemination of bacteria. Science 350: 830-834, 2015.
186. Spruss A, Kanuri G, Wagnerberger S, Haub S, Bischoff SC, Bergheim I. Toll-like receptor 4 is involved in the development of fructoseinduced hepatic steatosis in mice. Hepatology 50: 1094-1104, 2009.
187. Stenman LK, Waget A, Garret C, Klopp P, Burcelin R, Lahtinen S. Potential probiotic Bifidobacterium animalis ssp. lactis 420 prevents weight gain and glucose intolerance in diet-induced obese mice. Benef Microbes 5: 437-445, 2014.
188. Summa KC, Voigt RM, Forsyth CB, Shaikh M, Cavanaugh K, Tang Y, Vitaterna MH, Song S, Turek FW, Keshavarzian A. Disruption of the circadian clock in mice increases intestinal permeability and promotes alcohol-induced hepatic pathology and inflammation. PLos One 8: e67102, 2013.
189. Swanson G, Forsyth CB, Tang Y, Shaikh M, Zhang L, Turek FW, Keshavarzian A. Role of intestinal circadian genes in alcohol-induced gut leakiness. Alcohol Clin Exp Res 35: 1305-1314, 2011.
190. Tandon P, Moncrief K, Madsen K, Arrieta MC, Owen RJ, Bain VG, Wong WW, Ma MM. Effects of probiotic therapy on portal pressure in patients with cirrhosis: a pilot study. Liver Int 29: 1110-1115, 2009.
191. Tang WH, Hazen SL. Microbiome, trimethylamine N-oxide, and cardiometabolic disease. Transl Res J Lab Clin Med. In press.
192. Tao Y, Drabik KA, Waypa TS, Musch MW, Alverdy JC, Schneewind O, Chang EB, Petrof EO. Soluble factors from Lactobacillus GG activate MAPKs and induce cytoprotective heat shock proteins in intestinal epithelial cells. Am J Physiol Cell Physiol 290: C1018-C1030, 2006.
193. Tarao K, Moroi T, Hirabayashi Y, Ikeuchi T, Endo O, Takamura Y. Effect of paromomycin sulfate on endotoxemia in patients with cirrhosis. J Clin Gastroenterol 4: 263-267, 1982.
194. Thaiss CA, Zeevi D, Levy M, Zilberman-Schapira G, Suez J, Tengeler AC, Abramson L, Katz MN, Korem T, Zmora N, Kuperman Y, Biton I, Gilad S, Harmelin A, Shapiro H, Halpern Z, Segal E, Elinav E. Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis. Cell 159: 514-529, 2014.
195. Thibault R, De Coppet P, Daly K, Bourreille A, Cuff M, Bonnet C, Mosnier JF, Galmiche JP, Shirazi-Beechey S, Segain JP. Downregulation of the monocarboxylate transporter 1 is involved in butyrate deficiency during intestinal inflammation. Gastroenterology 133: 1916-1927, 2007.
196. Tuomisto S, Pessi T, Collin P, Vuento R, Aittoniemi J, Karhunen PJ. Changes in gut bacterial populations and their translocation into liver and ascites in alcoholic liver cirrhotics. BMC Gastroenterol 14: 40, 2014.
197. 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 52: 740-743, 2011.
198. Van der Sluis M, De Koning BA, De Bruijn AC, Velcich A, Meijerink JP, Van Goudoever JB, Buller HA, Dekker J, Van Seuningen I, Renes IB, Einerhand AW. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 131: 117-129, 2006.
199. van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper EJ, Bartelsman JF, Tijssen JG, Speelman P, Dijkgraaf MG, Keller JJ. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 368: 407-415, 2013.
200. Vance JE, Vance DE. The role of phosphatidylcholine biosynthesis in the secretion of lipoproteins from hepatocytes. Can J Biochem Cell Biol 63: 870-881, 1985.
201. Velayudham A, Dolganiuc A, Ellis M, Petrasek J, Kodys K, Mandrekar P, Szabo G. VSL#3 probiotic treatment attenuates fibrosis without changes in steatohepatitis in a diet-induced nonalcoholic steatohepatitis model in mice. Hepatology 49: 989-997, 2009.
202. Velcich A, Yang W, Heyer J, Fragale A, Nicholas C, Viani S, Kucherlapati R, Lipkin M, Yang K, Augenlicht L. Colorectal cancer in mice genetically deficient in the mucin Muc2. Science 295: 1726-1729, 2002.
203. Vital M, Howe AC, Tiedje JM. Revealing the bacterial butyrate synthesis pathways by analyzing (meta)genomic data. mBio 5: e00889, 2014.
204. Vlachogiannakos J, Viazis N, Vasianopoulou P, Vafiadis I, Karamanolis DG, Ladas SD. Long-term administration of rifaximin improves the prognosis of patients with decompensated alcoholic cirrhosis. J Gastroenterol Hepatol 28: 450-455, 2013.
205. Volta U, Bonazzi C, Bianchi FB, Baldoni AM, Zoli M, Pisi E. IgA antibodies to dietary antigens in liver cirrhosis. Ric Clin Lab 17: 235-242, 1987.
206. Volynets V, Kuper MA, Strahl S, Maier IB, Spruss A, Wagnerberger S, Konigsrainer A, Bischoff SC, Bergheim I. Nutrition, intestinal permeability, and blood ethanol levels are altered in patients with nonalcoholic fatty liver disease (NAFLD). Dig Dis Sci 57: 1932-1941, 2012.
207. Wade S, Lemonnier D, Alexiu A, Bocquet L. Effect of early postnatal under-and overnutrition on the development of IgA plasma cells in mouse gut. J Nutr 112: 1047-1051, 1982.
208. Walters WA, Xu Z, Knight R. Meta-analyses of human gut microbes associated with obesity and IBD. FEBS Lett 588: 4223-4233, 2014.
209. Wang L, Fouts DE, Starkel P, Hartmann P, Chen P, Llorente C, DePew J, Moncera K, Ho SB, Brenner DA, Hooper LV, Schnabl B. Intestinal REG3 lectins protect against alcoholic steatohepatitis by reducing mucosa-associated microbiota and preventing bacterial translocation. Cell Host Microbe 19: 227-239, 2016.
210. Wang Y, Kirpich I, Liu Y, Ma Z, Barve S, McClain CJ, Feng W. Lactobacillus rhamnosus GG treatment potentiates intestinal hypoxiainducible factor, promotes intestinal integrity and ameliorates alcoholinduced liver injury. Am J Pathol 179: 2866-2875, 2011.
211. Wang Y, Liu Y, Kirpich I, Ma Z, Wang C, Zhang M, Suttles J, McClain C, Feng W. Lactobacillus rhamnosus GG reduces hepatic TNFα production and inflammation in chronic alcohol-induced liver injury. J Nutr Biochem 24: 1609-1615, 2013.
212. Wang Y, Liu Y, Sidhu A, Ma Z, McClain C, Feng W. Lactobacillus rhamnosus GG culture supernatant ameliorates acute alcohol-induced intestinal permeability and liver injury. Am J Physiol Gastrointest Liver Physiol 303: G32-G41, 2012.
213. Weingarden A, Gonzalez A, Vazquez-Baeza Y, Weiss S, Humphry G, Berg-Lyons D, Knights D, Unno T, Bobr A, Kang J, Khoruts A, Knight R, Sadowsky MJ. Dynamic changes in short-and long-term bacterial composition following fecal microbiota transplantation for recurrent Clostridium difficile infection. Microbiome 3: 10, 2015.
214. Weng H, Endo K, Li J, Kito N, Iwai N. Induction of peroxisomes by butyrate-producing probiotics. PLos One 10: e0117851, 2015.
215. Wieland A, Frank DN, Harnke B, Bambha K. Systematic review: microbial dysbiosis and nonalcoholic fatty liver disease. Aliment Pharmacol Ther 42: 1051-1063, 2015.
216. Wong VW, Won GL, Chim AM, Chu WC, Yeung DK, Li KC, Chan HL. Treatment of nonalcoholic steatohepatitis with probiotics. A proofof-concept study. Ann Hepatol 12: 256-262, 2013.
217. Wong VW, Wong GL, Chan HY, Yeung DK, Chan RS, Chim AM, Chan CK, Tse YK, Woo J, Chu WC, Chan HL. Bacterial endotoxin and non-alcoholic fatty liver disease in the general population: a prospective cohort study. Aliment Pharmacol Ther 42: 731-740, 2015.
218. Xie G, Zhong W, Zheng X, Li Q, Qiu Y, Li H, Chen H, Zhou Z, Jia W. Chronic ethanol consumption alters mammalian gastrointestinal content metabolites. J Proteome Res 12: 3297-3306, 2013.
219. Xin J, Zeng D, Wang H, Ni X, Yi D, Pan K, Jing B. Preventing non-alcoholic fatty liver disease through Lactobacillus johnsonii BS15 by attenuating inflammation and mitochondrial injury and improving gut environment in obese mice. Appl Microbiol Biotechnol 98: 6817-6829, 2014.
220. 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 50: 72-77, 2012.
221. Yamanaka M, Nomura T, Kametaka M. Influence of intestinal microbes on heat production in germ-free, gnotobiotic and conventional mice. J Nutr Sci Vitaminol 23: 221-226, 1977.
222. Yan AW, Fouts DE, Brandl J, Starkel P, Torralba M, Schott E, Tsukamoto H, Nelson KE, Brenner DA, Schnabl B. Enteric dysbiosis associated with a mouse model of alcoholic liver disease. Hepatology 53: 96-105, 2011.
223. Yan AW, Schnabl B. Bacterial translocation and changes in the intestinal microbiome associated with alcoholic liver disease. World J Hepatol 4: 110-118, 2012.
224. Yan F, Cao H, Cover TL, Whitehead R, Washington MK, Polk DB. Soluble proteins produced by probiotic bacteria regulate intestinal epithelial cell survival and growth. Gastroenterology 132: 562-575, 2007.
225. Yan F, Polk DB. Probiotic bacterium prevents cytokine-induced apoptosis in intestinal epithelial cells. J Biol Chem 277: 50959-50965, 2002.
226. Ye D, Guo S, Al-Sadi R, Ma TY. MicroRNA regulation of intestinal epithelial tight junction permeability. Gastroenterology 141: 1323-1333, 2011.
227. Yuan J, Baker SS, Liu W, Alkhouri R, Baker RD, Xie J, Ji G, Zhu L. Endotoxemia unrequired in the pathogenesis of pediatric nonalcoholic steatohepatitis. J Gastroenterol Hepatol 29: 1292-1298, 2014.
228. Zarrinpar A, Chaix A, Yooseph S, Panda S. Diet and feeding pattern affect the diurnal dynamics of the gut microbiome. Cell Metab 20: 1006-1017, 2014.
229. Zein CO, Yerian LM, Gogate P, Lopez R, Kirwan JP, Feldstein AE, McCullough AJ. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology 54: 1610-1619, 2011.
230. Zeng H, Liu J, Jackson MI, Zhao FQ, Yan L, Combs GF Jr. Fatty liver accompanies an increase in Lactobacillus species in the hind gut of C57BL/6 mice fed a high-fat diet. J Nutr 143: 627-631, 2013.
231. Zhao H, Zhao C, Dong Y, Zhang M, Wang Y, Li F, Li X, McClain C, Yang S, Feng W. Inhibition of miR122a by Lactobacillus rhamnosus GG culture supernatant increases intestinal occludin expression and protects mice from alcoholic liver disease. Toxicol Lett 234: 194-200, 2015.
232. Zhou C, Zhao J, Li J, Wang H, Tang C. Acute ethanol administration inhibits Toll-like receptor 4 signaling pathway in rat intestinal epithelia. Alcohol 47: 231-239, 2013.
233. Zhu L, Baker SS, Gill C, Liu W, Alkhouri R, Baker RD, Gill SR. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 57: 601-609, 2013.