Semin Liver Dis 2016; 36(01): 037-047
DOI: 10.1055/s-0035-1571276
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Targeting Dysbiosis for the Treatment of Liver Disease

Gobind Anand
1   Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, California
,
Amir Zarrinpar
1   Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, California
,
Rohit Loomba
1   Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, California
2   NAFLD Translational Research Unit, Department of Medicine, University of California at San Diego, La Jolla, California
› Author Affiliations
Further Information

Publication History

Publication Date:
12 February 2016 (online)

Abstract

The gut microbiome is composed of a vast number of microbes in the gastrointestinal tract, which benefit host metabolism, aid in digestion, and contribute to normal immune function. Alterations in microbial composition can result in intestinal dysbiosis, which has been implicated in several diseases including obesity, inflammatory bowel disease, and liver diseases. Over the past several years, significant interactions between the intestinal microbiota and liver have been discovered, with possible mechanisms for the development as well as progression of liver disease and promising therapeutic targets to either prevent or halt the progression of liver disease. In this review the authors examine mechanisms of dysbiosis-induced liver disease; highlight current knowledge regarding the role of dysbiosis in nonalcoholic liver disease, alcoholic liver disease, and cirrhosis; and discuss potential therapeutic targets.

 
  • References

  • 1 Wang FS, Fan JG, Zhang Z, Gao B, Wang HY. The global burden of liver disease: the major impact of China. Hepatology 2014; 60 (6) 2099-2108
  • 2 Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol 2013; 10 (11) 686-690
  • 3 Farrell GC, Wong VW, Chitturi S. NAFLD in Asia—as common and important as in the West. Nat Rev Gastroenterol Hepatol 2013; 10 (5) 307-318
  • 4 Rinella ME, Loomba R, Caldwell SH , et al. Controversies in the Diagnosis and Management of NAFLD and NASH. Gastroenterol Hepatol (N Y) 2014; 10 (4) 219-227
  • 5 Younossi ZM, Stepanova M, Afendy M , et al. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol 2011; 9 (6) 524-530.e1 , quiz e60
  • 6 Bazick J, Donithan M, Neuschwander-Tetri BA , et al. Clinical model for NASH and advanced fibrosis in adult patients with diabetes and NAFLD: guidelines for referral in NAFLD. Diabetes Care 2015; 38 (7) 1347-1355
  • 7 Tremaroli V, Bäckhed F. Functional interactions between the gut microbiota and host metabolism. Nature 2012; 489 (7415) 242-249
  • 8 Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R. Diversity, stability and resilience of the human gut microbiota. Nature 2012; 489 (7415) 220-230
  • 9 Minemura M, Shimizu Y. Gut microbiota and liver diseases. World J Gastroenterol 2015; 21 (6) 1691-1702
  • 10 Schwabe RF, Jobin C. The microbiome and cancer. Nat Rev Cancer 2013; 13 (11) 800-812
  • 11 Seo YS, Shah VH. The role of gut-liver axis in the pathogenesis of liver cirrhosis and portal hypertension. Clin Mol Hepatol 2012; 18 (4) 337-346
  • 12 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) 1877-1887
  • 13 Rao R. Endotoxemia and gut barrier dysfunction in alcoholic liver disease. Hepatology 2009; 50 (2) 638-644
  • 14 Giorgio V, Miele L, Principessa L , et al. Intestinal permeability is increased in children with non-alcoholic fatty liver disease, and correlates with liver disease severity. Dig Liver Dis 2014; 46 (6) 556-560
  • 15 Bellot P, Francés R, Such J. Pathological bacterial translocation in cirrhosis: pathophysiology, diagnosis and clinical implications. Liver Int 2013; 33 (1) 31-39
  • 16 Arslan N. Obesity, fatty liver disease and intestinal microbiota. World J Gastroenterol 2014; 20 (44) 16452-16463
  • 17 Szabo G, Dolganiuc A, Mandrekar P. Pattern recognition receptors: a contemporary view on liver diseases. Hepatology 2006; 44 (2) 287-298
  • 18 Nakamoto N, Kanai T. Role of toll-like receptors in immune activation and tolerance in the liver. Front Immunol 2014; 5: 221
  • 19 Miura K, Ohnishi H. Role of gut microbiota and Toll-like receptors in nonalcoholic fatty liver disease. World J Gastroenterol 2014; 20 (23) 7381-7391
  • 20 Hritz I, Mandrekar P, Velayudham A , et al. The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88. Hepatology 2008; 48 (4) 1224-1231
  • 21 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) 571-579
  • 22 Henao-Mejia J, Elinav E, Thaiss CA, Licona-Limon P, Flavell RA. Role of the intestinal microbiome in liver disease. J Autoimmun 2013; 46: 66-73
  • 23 Chalasani N, Younossi Z, Lavine JE , et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012; 55 (6) 2005-2023
  • 24 Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol 2015; 13 (4) 643-54.e1 , 9, quiz e39–e40
  • 25 Loomba R, Abraham M, Unalp A , et al; Nonalcoholic Steatohepatitis Clinical Research Network. Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. Hepatology 2012; 56 (3) 943-951
  • 26 Bäckhed F, Ding H, Wang T , et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A 2004; 101 (44) 15718-15723
  • 27 Festi D, Schiumerini R, Eusebi LH, Marasco G, Taddia M, Colecchia A. Gut microbiota and metabolic syndrome. World J Gastroenterol 2014; 20 (43) 16079-16094
  • 28 Malhi H, Gores GJ. Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease. Semin Liver Dis 2008; 28 (4) 360-369
  • 29 Day CP, James OF. Steatohepatitis: a tale of two “hits”?. Gastroenterology 1998; 114 (4) 842-845
  • 30 Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology 2006; 43 (2) (Suppl. 01) S99-S112
  • 31 Loomba R, Quehenberger O, Armando A, Dennis EA. Polyunsaturated fatty acid metabolites as novel lipidomic biomarkers for noninvasive diagnosis of nonalcoholic steatohepatitis. J Lipid Res 2015; 56 (1) 185-192
  • 32 Feldstein AE, Werneburg NW, Canbay A , et al. Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway. Hepatology 2004; 40 (1) 185-194
  • 33 Le Roy T, Llopis M, Lepage P , et al. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut 2013; 62 (12) 1787-1794
  • 34 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) 1027-1031
  • 35 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) 601-609
  • 36 Cope K, Risby T, Diehl AM. Increased gastrointestinal ethanol production in obese mice: implications for fatty liver disease pathogenesis. Gastroenterology 2000; 119 (5) 1340-1347
  • 37 Dumas ME, Barton RH, Toye A , et al. Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proc Natl Acad Sci U S A 2006; 103 (33) 12511-12516
  • 38 Swann JR, Want EJ, Geier FM , et al. Systemic gut microbial modulation of bile acid metabolism in host tissue compartments. Proc Natl Acad Sci U S A 2011; 108 (Suppl. 01) 4523-4530
  • 39 Henao-Mejia J, Elinav E, Jin C , et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 2012; 482 (7384) 179-185
  • 40 Mouzaki M, Comelli EM, Arendt BM , et al. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology 2013; 58 (1) 120-127
  • 41 Raman M, Ahmed I, Gillevet PM , et al. Fecal microbiome and volatile organic compound metabolome in obese humans with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2013; 11 (7) 868-75.e1 , 3
  • 42 Jiang W, Wu N, Wang X , et al. Dysbiosis gut microbiota associated with inflammation and impaired mucosal immune function in intestine of humans with non-alcoholic fatty liver disease. Sci Rep 2015; 5: 8096
  • 43 David LA, Maurice CF, Carmody RN , et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 2014; 505 (7484) 559-563
  • 44 Nardone G, Compare D, Liguori E , et al. Protective effects of Lactobacillus paracasei F19 in a rat model of oxidative and metabolic hepatic injury. Am J Physiol Gastrointest Liver Physiol 2010; 299 (3) G669-G676
  • 45 Joyce SA, MacSharry J, Casey PG , et al. Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut. Proc Natl Acad Sci U S A 2014; 111 (20) 7421-7426
  • 46 Zarrinpar A, Chaix A, Yooseph S, Panda S. Diet and feeding pattern affect the diurnal dynamics of the gut microbiome. Cell Metab 2014; 20 (6) 1006-1017
  • 47 Sayin SI, Wahlström 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) 225-235
  • 48 Li F, Jiang C, Krausz KW , et al. Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nat Commun 2013; 4: 2384
  • 49 Matsubara T, Li F, Gonzalez FJ. FXR signaling in the enterohepatic system. Mol Cell Endocrinol 2013; 368 (1–2) 17-29
  • 50 Pols TW, Noriega LG, Nomura M, Auwerx J, Schoonjans K. The bile acid membrane receptor TGR5 as an emerging target in metabolism and inflammation. J Hepatol 2011; 54 (6) 1263-1272
  • 51 Mudaliar S, Henry RR, Sanyal AJ , et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 2013; 145 (3) 574-82.e1
  • 52 Zarrinpar A, Loomba R. Review article: the emerging interplay among the gastrointestinal tract, bile acids and incretins in the pathogenesis of diabetes and non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2012; 36 (10) 909-921
  • 53 O'Shea RS, Dasarathy S, McCullough AJ. Practice Guideline Committee of the American Association for the Study of Liver Diseases; Practice Parameters Committee of the American College of Gastroenterology. Alcoholic liver disease. Hepatology 2010; 51 (1) 307-328
  • 54 Addolorato G, Montalto M, Capristo E , et al. Influence of alcohol on gastrointestinal motility: lactulose breath hydrogen testing in orocecal transit time in chronic alcoholics, social drinkers and teetotaler subjects. Hepatogastroenterology 1997; 44 (16) 1076-1081
  • 55 Bull-Otterson L, Feng W, Kirpich I , et al. Metagenomic analyses of alcohol induced pathogenic alterations in the intestinal microbiome and the effect of Lactobacillus rhamnosus GG treatment. PLoS ONE 2013; 8 (1) e53028
  • 56 Mutlu EA, Gillevet PM, Rangwala H , et al. Colonic microbiome is altered in alcoholism. Am J Physiol Gastrointest Liver Physiol 2012; 302 (9) G966-G978
  • 57 Rao RK. Acetaldehyde-induced barrier disruption and paracellular permeability in Caco-2 cell monolayer. Methods Mol Biol 2008; 447: 171-183
  • 58 Seth A, Basuroy S, Sheth P, Rao RK. L-Glutamine ameliorates acetaldehyde-induced increase in paracellular permeability in Caco-2 cell monolayer. Am J Physiol Gastrointest Liver Physiol 2004; 287 (3) G510-G517
  • 59 Sheth P, Seth A, Atkinson KJ , et al. Acetaldehyde dissociates the PTP1B-E-cadherin-beta-catenin complex in Caco-2 cell monolayers by a phosphorylation-dependent mechanism. Biochem J 2007; 402 (2) 291-300
  • 60 Sheth P, Seth A, Thangavel M, Basuroy S, Rao RK. Epidermal growth factor prevents acetaldehyde-induced paracellular permeability in Caco-2 cell monolayer. Alcohol Clin Exp Res 2004; 28 (5) 797-804
  • 61 Fleming S, Toratani S, Shea-Donohue T, Kashiwabara Y, Vogel SN, Metcalf ES. Pro- and anti-inflammatory gene expression in the murine small intestine and liver after chronic exposure to alcohol. Alcohol Clin Exp Res 2001; 25 (4) 579-589
  • 62 Chen P, Stärkel 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 2015; 61 (3) 883-894
  • 63 Bajaj JS, Heuman DM, Hylemon PB , et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J Hepatol 2014; 60 (5) 940-947
  • 64 Parlesak A, Schäfer C, Schütz T, Bode JC, Bode C. Increased intestinal permeability to macromolecules and endotoxemia in patients with chronic alcohol abuse in different stages of alcohol-induced liver disease. J Hepatol 2000; 32 (5) 742-747
  • 65 Chen Y, Yang F, Lu H , et al. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 2011; 54 (2) 562-572
  • 66 Qin N, Yang F, Li A , et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 2014; 513 (7516) 59-64
  • 67 Guarner C, Runyon BA, Young S, Heck M, Sheikh MY. Intestinal bacterial overgrowth and bacterial translocation in cirrhotic rats with ascites. J Hepatol 1997; 26 (6) 1372-1378
  • 68 Bauer TM, Schwacha H, Steinbrückner B , et al. Small intestinal bacterial overgrowth in human cirrhosis is associated with systemic endotoxemia. Am J Gastroenterol 2002; 97 (9) 2364-2370
  • 69 Bauer TM, Steinbrückner B, Brinkmann FE , et al. Small intestinal bacterial overgrowth in patients with cirrhosis: prevalence and relation with spontaneous bacterial peritonitis. Am J Gastroenterol 2001; 96 (10) 2962-2967
  • 70 Gupta A, Dhiman RK, Kumari S , et al. Role of small intestinal bacterial overgrowth and delayed gastrointestinal transit time in cirrhotic patients with minimal hepatic encephalopathy. J Hepatol 2010; 53 (5) 849-855
  • 71 Pande C, Kumar A, Sarin SK. Small-intestinal bacterial overgrowth in cirrhosis is related to the severity of liver disease. Aliment Pharmacol Ther 2009; 29 (12) 1273-1281
  • 72 Dukowicz AC, Lacy BE, Levine GM. Small intestinal bacterial overgrowth: a comprehensive review. Gastroenterol Hepatol (N Y) 2007; 3 (2) 112-122
  • 73 Cirera I, Bauer TM, Navasa M , et al. Bacterial translocation of enteric organisms in patients with cirrhosis. J Hepatol 2001; 34 (1) 32-37
  • 74 Such J, Francés R, Muñoz C , et al. Detection and identification of bacterial DNA in patients with cirrhosis and culture-negative, nonneutrocytic ascites. Hepatology 2002; 36 (1) 135-141
  • 75 Bellot P, García-Pagán JC, Francés R , et al. Bacterial DNA translocation is associated with systemic circulatory abnormalities and intrahepatic endothelial dysfunction in patients with cirrhosis. Hepatology 2010; 52 (6) 2044-2052
  • 76 Patel R, DuPont HL. New approaches for bacteriotherapy: prebiotics, new-generation probiotics, and synbiotics. Clin Infect Dis 2015; 60 (Suppl. 02) S108-S121
  • 77 Frei R, Akdis M, O'Mahony L. Prebiotics, probiotics, synbiotics, and the immune system: experimental data and clinical evidence. Curr Opin Gastroenterol 2015; 31 (2) 153-158
  • 78 Cummings JH, Macfarlane GT. Gastrointestinal effects of prebiotics. Br J Nutr 2002; 87 (Suppl. 02) S145-S151
  • 79 Bouhnik Y, Flourié B, D'Agay-Abensour L , et al. Administration of transgalacto-oligosaccharides increases fecal bifidobacteria and modifies colonic fermentation metabolism in healthy humans. J Nutr 1997; 127 (3) 444-448
  • 80 Riggio O, Varriale M, Testore GP , et al. Effect of lactitol and lactulose administration on the fecal flora in cirrhotic patients. J Clin Gastroenterol 1990; 12 (4) 433-436
  • 81 Chen P, Torralba M, Tan J , et al. Supplementation of saturated long-chain fatty acids maintains intestinal eubiosis and reduces ethanol-induced liver injury in mice. Gastroenterology 2015; 148 (1) 203-214.e16
  • 82 Kailasapathy K, Chin J. Survival and therapeutic potential of probiotic organisms with reference to Lactobacillus acidophilus and Bifidobacterium spp. Immunol Cell Biol 2000; 78 (1) 80-88
  • 83 Lewis K, Lutgendorff F, Phan V, Söderholm JD, Sherman PM, McKay DM. Enhanced translocation of bacteria across metabolically stressed epithelia is reduced by butyrate. Inflamm Bowel Dis 2010; 16 (7) 1138-1148
  • 84 Yan F, Polk DB. Probiotic bacterium prevents cytokine-induced apoptosis in intestinal epithelial cells. J Biol Chem 2002; 277 (52) 50959-50965
  • 85 Loguercio C, De Simone T, Federico A , et al. Gut-liver axis: a new point of attack to treat chronic liver damage?. Am J Gastroenterol 2002; 97 (8) 2144-2146
  • 86 Loguercio C, Federico A, Tuccillo C , et al. Beneficial effects of a probiotic VSL#3 on parameters of liver dysfunction in chronic liver diseases. J Clin Gastroenterol 2005; 39 (6) 540-543
  • 87 Solga SF, Buckley G, Clark JM, Horska A, Diehl AM. The effect of a probiotic on hepatic steatosis. J Clin Gastroenterol 2008; 42 (10) 1117-1119
  • 88 Aller R, De Luis DA, Izaola O , et al. Effect of a probiotic on liver aminotransferases in nonalcoholic fatty liver disease patients: a double blind randomized clinical trial. Eur Rev Med Pharmacol Sci 2011; 15 (9) 1090-1095
  • 89 Wong VW, Won GL, Chim AM , et al. Treatment of nonalcoholic steatohepatitis with probiotics. A proof-of-concept study. Ann Hepatol 2013; 12 (2) 256-262
  • 90 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) 6911-6918
  • 91 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) 243-247
  • 92 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 2009; 43 (2) 163-172
  • 93 Mutlu E, Keshavarzian A, Engen P, Forsyth CB, Sikaroodi M, Gillevet P. Intestinal dysbiosis: a possible mechanism of alcohol-induced endotoxemia and alcoholic steatohepatitis in rats. Alcohol Clin Exp Res 2009; 33 (10) 1836-1846
  • 94 Kirpich IA, Solovieva NV, Leikhter SN , et al. Probiotics restore bowel flora and improve liver enzymes in human alcohol-induced liver injury: a pilot study. Alcohol 2008; 42 (8) 675-682
  • 95 Rincón D, Vaquero J, Hernando A , et al. Oral probiotic VSL#3 attenuates the circulatory disturbances of patients with cirrhosis and ascites. Liver Int 2014; 34 (10) 1504-1512
  • 96 Lata J, Novotný I, Príbramská V , et al. The effect of probiotics on gut flora, level of endotoxin and Child-Pugh score in cirrhotic patients: results of a double-blind randomized study. Eur J Gastroenterol Hepatol 2007; 19 (12) 1111-1113
  • 97 Dhiman RK, Rana B, Agrawal S , et al. Probiotic VSL#3 reduces liver disease severity and hospitalization in patients with cirrhosis: a randomized, controlled trial. Gastroenterology 2014; 147 (6) 1327-37.e3
  • 98 MacBeth WA, Kass EH, McDermott Jr WV. Treatment of hepatic encephalopathy by alteration of intestinal flora with lactobacillus acidophilus. Lancet 1965; 1 (7382) 399-403
  • 99 Read AE, McCarthy CF, Heaton KW, Laidlaw J. Lactobacillus acidophilus (enpac) in treatment of hepatic encephalopathy. BMJ 1966; 1 (5498) 1267-1269
  • 100 McGee RG, Bakens A, Wiley K, Riordan SM, Webster AC. Probiotics for patients with hepatic encephalopathy. Cochrane Database Syst Rev 2011; (11) CD008716
  • 101 Lunia MK, Sharma BC, Sharma P, Sachdeva S, Srivastava S. Probiotics prevent hepatic encephalopathy in patients with cirrhosis: a randomized controlled trial. Clin Gastroenterol Hepatol 2014; 12 (6) 1003-8.e1
  • 102 Bajaj JS, Heuman DM, Hylemon PB , et al. Randomised clinical trial: Lactobacillus GG modulates gut microbiome, metabolome and endotoxemia in patients with cirrhosis. Aliment Pharmacol Ther 2014; 39 (10) 1113-1125
  • 103 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) 535-542
  • 104 Malaguarnera M, Vacante M, Antic T , et al. Bifidobacterium longum with fructo-oligosaccharides in patients with non alcoholic steatohepatitis. Dig Dis Sci 2012; 57 (2) 545-553
  • 105 Malaguarnera M, Gargante MP, Malaguarnera G , et al. Bifidobacterium combined with fructo-oligosaccharide versus lactulose in the treatment of patients with hepatic encephalopathy. Eur J Gastroenterol Hepatol 2010; 22 (2) 199-206
  • 106 Liu Q, Duan ZP, Ha DK, Bengmark S, Kurtovic J, Riordan SM. Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology 2004; 39 (5) 1441-1449
  • 107 Pérez-Cobas AE, Artacho A, Knecht H , et al. Differential effects of antibiotic therapy on the structure and function of human gut microbiota. PLoS ONE 2013; 8 (11) e80201
  • 108 Macfarlane S. Antibiotic treatments and microbes in the gut. Environ Microbiol 2014; 16 (4) 919-924
  • 109 Bajaj JS, Heuman DM, Sanyal AJ , et al. Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy. PLoS ONE 2013; 8 (4) e60042
  • 110 Runyon BA . AASLD Practice Guidelines Committee. Management of adult patients with ascites due to cirrhosis: an update. Hepatology 2009; 49 (6) 2087-2107
  • 111 Bass NM, Mullen KD, Sanyal A , et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med 2010; 362 (12) 1071-1081
  • 112 van Nood E, Vrieze A, Nieuwdorp M , et al. Duodenal infusion of donor feces for recurrent Clostridium difficile . N Engl J Med 2013; 368 (5) 407-415
  • 113 Seekatz AM, Aas J, Gessert CE , et al. Recovery of the gut microbiome following fecal microbiota transplantation. MBio 2014; 5 (3) e00893-e14
  • 114 Shen TC, Albenberg L, Bittinger K , et al. Engineering the gut microbiota to treat hyperammonemia. J Clin Invest 2015; 125 (7) 2841-2850