Download PDF
Semin Liver Dis 2021; 41(01): 087-102
DOI: 10.1055/s-0040-1719174
Review Article

New Developments in Microbiome in Alcohol-Associated and Nonalcoholic Fatty Liver Disease

Phillipp Hartmann
1   Department of Pediatrics, University of California San Diego, La Jolla, California
2   Department of Medicine, University of California San Diego, La Jolla, California
,
Bernd Schnabl
2   Department of Medicine, University of California San Diego, La Jolla, California
3   Department of Medicine, VA San Diego Healthcare System, San Diego, California
› Author Affiliations Funding This work was supported by National Institutes of Health grants K12 HD85036 (to P.H.), R01 AA020703, R01 AA24726, U01 AA026939, and by Award Number BX004594 from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development (to B.S.) and services provided by P30 DK120515 and P50 AA011999.
› Further Information
    Permissions and Reprints

Abstract

Alcohol-associated liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are important causes of morbidity and mortality worldwide. The intestinal microbiota is involved in the development and progression of both ALD and NAFLD. Here we describe associated changes in the intestinal microbiota, and we detail randomized clinical trials in ALD and NAFLD which evaluate treatments modulating the intestinal microbiome including fecal microbiota transplantation, probiotics, prebiotics, synbiotics, and antibiotics. Finally, we discuss precision medicine approaches targeting the intestinal microbiome to ameliorate ALD and NAFLD.

Keywords

microbiome - alcohol-associated liver disease - nonalcoholic fatty liver disease - new developments - precision medicine


Publication History

Article published online:
14 January 2021

© 2021. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Rehm J, Samokhvalov AV, Shield KD. Global burden of alcoholic liver diseases. J Hepatol 2013; 59 (01) 160-168
    CrossrefPubMedGoogle Scholar
  • 2 Cotter TG, Rinella M. Nonalcoholic fatty liver disease 2020: the state of the disease. Gastroenterology 2020; 158 (07) 1851-1864
    CrossrefPubMedGoogle Scholar
  • 3 Cholankeril G, Ahmed A. Alcoholic liver disease replaces hepatitis c virus infection as the leading indication for liver transplantation in the United States. Clin Gastroenterol Hepatol 2018; 16 (08) 1356-1358
    CrossrefPubMedGoogle Scholar
  • 4 Lee BP, Vittinghoff E, Dodge JL, Cullaro G, Terrault NA. National trends and long-term outcomes of liver transplant for alcohol-associated liver disease in the United States. JAMA Intern Med 2019; 179 (03) 340-348
    CrossrefPubMedGoogle Scholar
  • 5 Sender R, Fuchs S, Milo R. Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell 2016; 164 (03) 337-340
    CrossrefPubMedGoogle Scholar
  • 6 Sender R, Fuchs S, Milo R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol 2016; 14 (08) e1002533
    CrossrefPubMedGoogle Scholar
  • 7 Schroeder BO, Bäckhed F. Signals from the gut microbiota to distant organs in physiology and disease. Nat Med 2016; 22 (10) 1079-1089
    CrossrefPubMedGoogle Scholar
  • 8 Eckburg PB, Bik EM, Bernstein CN. et al. Diversity of the human intestinal microbial flora. Science 2005; 308 (5728): 1635-1638
    CrossrefPubMedGoogle Scholar
  • 9 Hartmann P, Chen WC, Schnabl B. The intestinal microbiome and the leaky gut as therapeutic targets in alcoholic liver disease. Front Physiol 2012; 3: 402
    CrossrefPubMedGoogle Scholar
  • 10 Hartmann P, Schnabl B. Risk factors for progression of and treatment options for NAFLD in children. Clin Liver Dis (Hoboken) 2018; 11 (01) 11-15
    CrossrefPubMedGoogle Scholar
  • 11 Hartmann P, Chu H, Duan Y, Schnabl B. Gut microbiota in liver disease: too much is harmful, nothing at all is not helpful either. Am J Physiol Gastrointest Liver Physiol 2019; 316 (05) G563-G573
    CrossrefPubMedGoogle Scholar
  • 12 Hartmann P, Seebauer CT, Schnabl B. Alcoholic liver disease: the gut microbiome and liver cross talk. Alcohol Clin Exp Res 2015; 39 (05) 763-775
    CrossrefPubMedGoogle Scholar
  • 13 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 (08) 675-682
    CrossrefPubMedGoogle Scholar
  • 14 Leclercq S, Matamoros S, Cani PD. et al. Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity. Proc Natl Acad Sci U S A 2014; 111 (42) E4485-E4493
    CrossrefPubMedGoogle Scholar
  • 15 Mutlu EA, Gillevet PM, Rangwala H. et al. Colonic microbiome is altered in alcoholism. Am J Physiol Gastrointest Liver Physiol 2012; 302 (09) G966-G978
    CrossrefPubMedGoogle Scholar
  • 16 Chen Y, Yang F, Lu H. et al. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 2011; 54 (02) 562-572
    CrossrefPubMedGoogle Scholar
  • 17 Quigley EM, Quera R. Small intestinal bacterial overgrowth: roles of antibiotics, prebiotics, and probiotics. Gastroenterology 2006; 130 (02) (Suppl. 01) S78-S90
    CrossrefPubMedGoogle Scholar
  • 18 Zhong C, Qu C, Wang B, Liang S, Zeng B. Probiotics for preventing and treating small intestinal bacterial overgrowth: a meta-analysis and systematic review of current evidence. J Clin Gastroenterol 2017; 51 (04) 300-311
    CrossrefPubMedGoogle Scholar
  • 19 Lichtman SN, Sartor RB, Keku J, Schwab JH. Hepatic inflammation in rats with experimental small intestinal bacterial overgrowth. Gastroenterology 1990; 98 (02) 414-423
    CrossrefPubMedGoogle Scholar
  • 20 Lichtman SN, Keku J, Schwab JH, Sartor RB. Hepatic injury associated with small bowel bacterial overgrowth in rats is prevented by metronidazole and tetracycline. Gastroenterology 1991; 100 (02) 513-519
    CrossrefPubMedGoogle Scholar
  • 21 Wegener M, Schaffstein J, Dilger U, Coenen C, Wedmann B, Schmidt G. Gastrointestinal transit of solid-liquid meal in chronic alcoholics. Dig Dis Sci 1991; 36 (07) 917-923
    CrossrefPubMedGoogle Scholar
  • 22 Bode C, Bode JC. Alcohol's role in gastrointestinal tract disorders. Alcohol Health Res World 1997; 21 (01) 76-83
    PubMedGoogle Scholar
  • 23 Hartmann P, Chen P, Wang HJ. et al. Deficiency of intestinal mucin-2 ameliorates experimental alcoholic liver disease in mice. Hepatology 2013; 58 (01) 108-119
    CrossrefPubMedGoogle Scholar
  • 24 Yan AW, Fouts DE, Brandl J. et al. Enteric dysbiosis associated with a mouse model of alcoholic liver disease. Hepatology 2011; 53 (01) 96-105
    CrossrefPubMedGoogle Scholar
  • 25 Wang L, Fouts DE, Stärkel P. et al. Intestinal REG3 lectins protect against alcoholic steatohepatitis by reducing mucosa-associated microbiota and preventing bacterial translocation. Cell Host Microbe 2016; 19 (02) 227-239
    CrossrefPubMedGoogle Scholar
  • 26 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 (05) 742-747
    CrossrefPubMedGoogle Scholar
  • 27 Hanck C, Rossol S, Böcker U, Tokus M, Singer MV. Presence of plasma endotoxin is correlated with tumour necrosis factor receptor levels and disease activity in alcoholic cirrhosis. Alcohol Alcohol 1998; 33 (06) 606-608
    CrossrefPubMedGoogle Scholar
  • 28 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 (01) 218-224
    CrossrefPubMedGoogle Scholar
  • 29 Ferrier L, Bérard F, Debrauwer L. et al. Impairment of the intestinal barrier by ethanol involves enteric microflora and mast cell activation in rodents. Am J Pathol 2006; 168 (04) 1148-1154
    CrossrefPubMedGoogle Scholar
  • 30 Uesugi T, Froh M, Arteel GE, Bradford BU, Thurman RG. Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice. Hepatology 2001; 34 (01) 101-108
    CrossrefPubMedGoogle Scholar
  • 31 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 (02) 601-609
    CrossrefPubMedGoogle Scholar
  • 32 Cope K, Risby T, Diehl AM. Increased gastrointestinal ethanol production in obese mice: implications for fatty liver disease pathogenesis. Gastroenterology 2000; 119 (05) 1340-1347
    CrossrefPubMedGoogle Scholar
  • 33 Elamin EE, Masclee AA, Dekker J, Jonkers DM. Ethanol metabolism and its effects on the intestinal epithelial barrier. Nutr Rev 2013; 71 (07) 483-499
    CrossrefPubMedGoogle Scholar
  • 34 Zakhari S. Overview: how is alcohol metabolized by the body?. Alcohol Res Health 2006; 29 (04) 245-254
    PubMedGoogle Scholar
  • 35 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 (06) G881-G884
    CrossrefPubMedGoogle Scholar
  • 36 Wang Y, Kirpich I, Liu Y. et al. Lactobacillus rhamnosus GG treatment potentiates intestinal hypoxia-inducible factor, promotes intestinal integrity and ameliorates alcohol-induced liver injury. Am J Pathol 2011; 179 (06) 2866-2875
    CrossrefPubMedGoogle Scholar
  • 37 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 (01) 203-214.e16
    CrossrefPubMedGoogle Scholar
  • 38 Xie G, Zhong W, Zheng X. et al. Chronic ethanol consumption alters mammalian gastrointestinal content metabolites. J Proteome Res 2013; 12 (07) 3297-3306
    CrossrefPubMedGoogle Scholar
  • 39 Cresci GA, Glueck B, McMullen MR, Xin W, Allende D, Nagy LE. Prophylactic tributyrin treatment mitigates chronic-binge ethanol-induced intestinal barrier and liver injury. J Gastroenterol Hepatol 2017; 32 (09) 1587-1597
    CrossrefPubMedGoogle Scholar
  • 40 Duan Y, Llorente C, Lang S. et al. Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease. Nature 2019; 575 (7783): 505-511
    CrossrefPubMedGoogle Scholar
  • 41 Lang S, Demir M, Duan Y, Martin A, Schnabl B. Cytolysin-positive Enterococcus faecalis is not increased in patients with non-alcoholic steatohepatitis. Liver Int 2020; 40 (04) 860-865
    CrossrefPubMedGoogle Scholar
  • 42 Wu GD, Chen J, Hoffmann C. et al. Linking long-term dietary patterns with gut microbial enterotypes. Science 2011; 334 (6052): 105-108
    CrossrefPubMedGoogle Scholar
  • 43 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 (07) 868-75.e1 , 3
    CrossrefPubMedGoogle Scholar
  • 44 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
    CrossrefPubMedGoogle Scholar
  • 45 Da Silva HE, Teterina A, Comelli EM. et al. Nonalcoholic fatty liver disease is associated with dysbiosis independent of body mass index and insulin resistance. Sci Rep 2018; 8 (01) 1466
    CrossrefPubMedGoogle Scholar
  • 46 Mouzaki M, Comelli EM, Arendt BM. et al. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology 2013; 58 (01) 120-127
    CrossrefPubMedGoogle Scholar
  • 47 Wong VW, Tse CH, Lam TT. et al. Molecular characterization of the fecal microbiota in patients with nonalcoholic steatohepatitis--a longitudinal study. PLoS One 2013; 8 (04) e62885
    CrossrefPubMedGoogle Scholar
  • 48 Schwimmer JB, Johnson JS, Angeles JE. et al. Microbiome signatures associated with steatohepatitis and moderate to severe fibrosis in children with nonalcoholic fatty liver disease. Gastroenterology 2019; 157 (04) 1109-1122
    CrossrefPubMedGoogle Scholar
  • 49 Loomba R, Seguritan V, Li W. et al. Gut microbiome-based metagenomic signature for non-invasive detection of advanced fibrosis in human nonalcoholic fatty liver disease. Cell Metab 2017; 25 (05) 1054-1062.e5
    CrossrefPubMedGoogle Scholar
  • 50 Boursier J, Mueller O, Barret M. et al. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology 2016; 63 (03) 764-775
    Google Scholar
  • 51 Miele L, Valenza V, La Torre G. et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 2009; 49 (06) 1877-1887
    Google Scholar
  • 52 Sabaté JM, Jouët P, Harnois F. et al. High prevalence of small intestinal bacterial overgrowth in patients with morbid obesity: a contributor to severe hepatic steatosis. Obes Surg 2008; 18 (04) 371-377
    CrossrefPubMedGoogle Scholar
  • 53 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 (02) 206-211
    CrossrefPubMedGoogle Scholar
  • 54 Luther J, Garber JJ, Khalili H. et al. Hepatic injury in nonalcoholic steatohepatitis contributes to altered intestinal permeability. Cell Mol Gastroenterol Hepatol 2015; 1 (02) 222-232
    CrossrefPubMedGoogle Scholar
  • 55 Alisi A, Manco M, Devito R, Piemonte F, Nobili V. Endotoxin and plasminogen activator inhibitor-1 serum levels associated with nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr 2010; 50 (06) 645-649
    CrossrefPubMedGoogle Scholar
  • 56 Farhadi A, Gundlapalli S, Shaikh M. et al. Susceptibility to gut leakiness: a possible mechanism for endotoxaemia in non-alcoholic steatohepatitis. Liver Int 2008; 28 (07) 1026-1033
    CrossrefPubMedGoogle Scholar
  • 57 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) 1374-1380
    CrossrefPubMedGoogle Scholar
  • 58 Henao-Mejia J, Elinav E, Jin C. et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 2012; 482 (7384): 179-185
    CrossrefPubMedGoogle Scholar
  • 59 Yuan J, Chen C, Cui J. et al. Fatty liver disease caused by high-alcohol-producing Klebsiella pneumoniae. Cell Metab 2019; 30 (04) 675-688.e7
    CrossrefPubMedGoogle Scholar
  • 60 Painter K, Cordell BJ, Sticco KL. Auto-Brewery Syndrome (Gut Fermentation). Treasure Island, FL: StatPearls; 2020
    Google Scholar
  • 61 Malik F, Wickremesinghe P, Saverimuttu J. Case report and literature review of auto-brewery syndrome: probably an underdiagnosed medical condition. BMJ Open Gastroenterol 2019; 6 (01) e000325
    CrossrefPubMedGoogle Scholar
  • 62 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
    CrossrefPubMedGoogle Scholar
  • 63 Yu D, Shu XO, Xiang YB. et al. Higher dietary choline intake is associated with lower risk of nonalcoholic fatty liver in normal-weight Chinese women. J Nutr 2014; 144 (12) 2034-2040
    CrossrefPubMedGoogle Scholar
  • 64 Guerrerio AL, Colvin RM, Schwartz AK. et al. Choline intake in a large cohort of patients with nonalcoholic fatty liver disease. Am J Clin Nutr 2012; 95 (04) 892-900
    CrossrefPubMedGoogle Scholar
  • 65 Ferrere G, Wrzosek L, Cailleux F. et al. Fecal microbiota manipulation prevents dysbiosis and alcohol-induced liver injury in mice. J Hepatol 2017; 66 (04) 806-815
    CrossrefPubMedGoogle Scholar
  • 66 Llopis M, Cassard AM, Wrzosek L. et al. Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease. Gut 2016; 65 (05) 830-839
    CrossrefPubMedGoogle Scholar
  • 67 Philips CA, Pande A, Shasthry SM. et al. Healthy donor fecal microbiota transplantation in steroid-ineligible severe alcoholic hepatitis: a pilot study. Clin Gastroenterol Hepatol 2017; 15 (04) 600-602
    CrossrefPubMedGoogle Scholar
  • 68 Philips CA, Phadke N, Ganesan K, Ranade S, Augustine P. Corticosteroids, nutrition, pentoxifylline, or fecal microbiota transplantation for severe alcoholic hepatitis. Indian J Gastroenterol 2018; 37 (03) 215-225
    CrossrefPubMedGoogle Scholar
  • 69 Bajaj JS, Kassam Z, Fagan A. et al. Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: a randomized clinical trial. Hepatology 2017; 66 (06) 1727-1738
    CrossrefPubMedGoogle Scholar
  • 70 Mehta R, Kabrawala M, Nandwani S. et al. Preliminary experience with single fecal microbiota transplant for treatment of recurrent overt hepatic encephalopathy-a case series. Indian J Gastroenterol 2018; 37 (06) 559-562
    CrossrefPubMedGoogle Scholar
  • 71 Bajaj JS, Salzman NH, Acharya C. et al. Fecal microbial transplant capsules are safe in hepatic encephalopathy: a phase 1, randomized, placebo-controlled trial. Hepatology 2019; 70 (05) 1690-1703
    CrossrefPubMedGoogle Scholar
  • 72 Bajaj JS, Salzman N, Acharya C. et al. Microbial functional change is linked with clinical outcomes after capsular fecal transplant in cirrhosis. JCI Insight 2019; 4 (24) 4
    Google Scholar
  • 73 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 (04) 913-6.e7
    CrossrefPubMedGoogle Scholar
  • 74 Kootte RS, Levin E, Salojärvi J. et al. Improvement of insulin sensitivity after lean donor feces in metabolic syndrome is driven by baseline intestinal microbiota composition. Cell Metab 2017; 26 (04) 611-619.e6
    CrossrefPubMedGoogle Scholar
  • 75 de Groot P, Scheithauer T, Bakker GJ. et al. Donor metabolic characteristics drive effects of faecal microbiota transplantation on recipient insulin sensitivity, energy expenditure and intestinal transit time. Gut 2020; 69 (03) 502-512
    CrossrefPubMedGoogle Scholar
  • 76 Yu EW, Gao L, Stastka P. et al. Fecal microbiota transplantation for the improvement of metabolism in obesity: the FMT-TRIM double-blind placebo-controlled pilot trial. PLoS Med 2020; 17 (03) e1003051
    CrossrefPubMedGoogle Scholar
  • 77 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 (02) 163-172
    CrossrefPubMedGoogle Scholar
  • 78 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 (01) e53028
    Google Scholar
  • 79 Nanji AA, Khettry U, Sadrzadeh SM. Lactobacillus feeding reduces endotoxemia and severity of experimental alcoholic liver (disease). Proc Soc Exp Biol Med 1994; 205 (03) 243-247
    CrossrefPubMedGoogle Scholar
  • 80 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 2012; 303 (01) G32-G41
    CrossrefPubMedGoogle Scholar
  • 81 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 2013; 13: 151
    CrossrefPubMedGoogle Scholar
  • 82 Grander C, Adolph TE, Wieser V. et al. Recovery of ethanol-induced Akkermansia muciniphila depletion ameliorates alcoholic liver disease. Gut 2018; 67 (05) 891-901
    CrossrefPubMedGoogle Scholar
  • 83 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 (06) 540-543
    CrossrefPubMedGoogle Scholar
  • 84 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 (06) 1327-37.e3
    CrossrefPubMedGoogle Scholar
  • 85 Dalal R, McGee RG, Riordan SM, Webster AC. Probiotics for people with hepatic encephalopathy. Cochrane Database Syst Rev 2017; 2: CD008716
    PubMedGoogle Scholar
  • 86 Xiao MW, Lin SX, Shen ZH, Luo WW, Wang XY. Systematic review with meta-analysis: the effects of probiotics in nonalcoholic fatty liver disease. Gastroenterol Res Pract 2019; 2019: 1484598
    PubMedGoogle Scholar
  • 87 Tang Y, Huang J, Zhang WY. et al. Effects of probiotics on nonalcoholic fatty liver disease: a systematic review and meta-analysis. Therap Adv Gastroenterol 2019; 12: 1756284819878046
    CrossrefPubMedGoogle Scholar
  • 88 Javadi L, Ghavami M, Khoshbaten M. et al. The effect of probiotic and/or prebiotic on liver function tests in patients with nonalcoholic fatty liver disease: a double blind randomized clinical trial. Iran Red Crescent Med J 2017; 19 (04) e46017
    CrossrefPubMedGoogle Scholar
  • 89 Daubioul CA, Horsmans Y, Lambert P, Danse E, Delzenne NM. Effects of oligofructose on glucose and lipid metabolism in patients with nonalcoholic steatohepatitis: results of a pilot study. Eur J Clin Nutr 2005; 59 (05) 723-726
    CrossrefPubMedGoogle Scholar
  • 90 Behrouz V, Jazayeri S, Aryaeian N, Zahedi MJ, Hosseini F. Effects of probiotic and prebiotic supplementation on leptin, adiponectin, and glycemic parameters in non-alcoholic fatty liver disease: a randomized clinical trial. Middle East J Dig Dis 2017; 9 (03) 150-157
    CrossrefPubMedGoogle Scholar
  • 91 Bomhof MR, Parnell JA, Ramay HR. et al. Histological improvement of non-alcoholic steatohepatitis with a prebiotic: a pilot clinical trial. Eur J Nutr 2019; 58 (04) 1735-1745
    CrossrefPubMedGoogle Scholar
  • 92 Shukla S, Shukla A, Mehboob S, Guha S. Meta-analysis: the effects of gut flora modulation using prebiotics, probiotics and synbiotics on minimal hepatic encephalopathy. Aliment Pharmacol Ther 2011; 33 (06) 662-671
    CrossrefPubMedGoogle Scholar
  • 93 Riordan SM, Skinner NA, McIver CJ. et al. Synbiotic-associated improvement in liver function in cirrhotic patients: Relation to changes in circulating cytokine messenger RNA and protein levels. Microb Ecol Health Dis 2007; 19: 7-16
    CrossrefPubMedGoogle Scholar
  • 94 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 (08) 2144-2146
    CrossrefPubMedGoogle Scholar
  • 95 Asgharian A, Askari G, Esmailzade A, Feizi A, Mohammadi V. The effect of symbiotic supplementation on liver enzymes, C-reactive protein and ultrasound findings in patients with non-alcoholic fatty liver disease: a clinical trial. Int J Prev Med 2016; 7: 59
    CrossrefPubMedGoogle Scholar
  • 96 Liu L, Li P, Liu Y, Zhang Y. Efficacy of probiotics and synbiotics in patients with nonalcoholic fatty liver disease: a meta-analysis. Dig Dis Sci 2019; 64 (12) 3402-3412
    CrossrefPubMedGoogle Scholar
  • 97 Scorletti E, Afolabi PR, Miles EA. et al. Synbiotics alter fecal microbiomes, but not liver fat or fibrosis, in a randomized trial of patients with nonalcoholic fatty liver disease. Gastroenterology 2020; 158 (06) 1597-1610.e7
    CrossrefPubMedGoogle Scholar
  • 98 Leber B, Spindelboeck W, Stadlbauer V. Infectious complications of acute and chronic liver disease. Semin Respir Crit Care Med 2012; 33 (01) 80-95
    Article in Thieme ConnectPubMedGoogle Scholar
  • 99 Terg R, Fassio E, Guevara M. et al. Ciprofloxacin in primary prophylaxis of spontaneous bacterial peritonitis: a randomized, placebo-controlled study. J Hepatol 2008; 48 (05) 774-779
    CrossrefPubMedGoogle Scholar
  • 100 Ginés P, Rimola A, Planas R. et al. Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial. Hepatology 1990; 12 (4 Pt 1): 716-724
    Google Scholar
  • 101 Madrid AM, Hurtado C, Venegas M, Cumsille F, Defilippi C. Long-term treatment with cisapride and antibiotics in liver cirrhosis: effect on small intestinal motility, bacterial overgrowth, and liver function. Am J Gastroenterol 2001; 96 (04) 1251-1255
    CrossrefPubMedGoogle Scholar
  • 102 Casafont Morencos F, de las Heras Castaño G, Martín Ramos L, López Arias MJ, Ledesma F, Pons Romero F. Small bowel bacterial overgrowth in patients with alcoholic cirrhosis. Dig Dis Sci 1996; 41 (03) 552-556
    CrossrefPubMedGoogle Scholar
  • 103 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
    CrossrefPubMedGoogle Scholar
  • 104 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
    CrossrefPubMedGoogle Scholar
  • 105 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 (03) 883-894
    CrossrefPubMedGoogle Scholar
  • 106 Bode C, Schäfer 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 1997; 21 (08) 1367-1373
    PubMedGoogle Scholar
  • 107 Ponziani FR, Zocco MA, D'Aversa F, Pompili M, Gasbarrini A. Eubiotic properties of rifaximin: Disruption of the traditional concepts in gut microbiota modulation. World J Gastroenterol 2017; 23 (25) 4491-4499
    CrossrefPubMedGoogle Scholar
  • 108 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 (04) e60042
    CrossrefPubMedGoogle Scholar
  • 109 Bergheim I, Weber S, Vos M. et al. Antibiotics protect against fructose-induced hepatic lipid accumulation in mice: role of endotoxin. J Hepatol 2008; 48 (06) 983-992
    CrossrefPubMedGoogle Scholar
  • 110 Wu WC, Zhao W, Li S. Small intestinal bacteria overgrowth decreases small intestinal motility in the NASH rats. World J Gastroenterol 2008; 14 (02) 313-317
    CrossrefPubMedGoogle Scholar
  • 111 Gangarapu V, Ince AT, Baysal B. et al. Efficacy of rifaximin on circulating endotoxins and cytokines in patients with nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol 2015; 27 (07) 840-845
    CrossrefPubMedGoogle Scholar
  • 112 Abdel-Razik A, Mousa N, Shabana W. et al. Rifaximin in nonalcoholic fatty liver disease: hit multiple targets with a single shot. Eur J Gastroenterol Hepatol 2018; 30 (10) 1237-1246
    CrossrefPubMedGoogle Scholar
  • 113 Hartmann P, Hochrath K, Horvath A. et al. Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice. Hepatology 2018; 67 (06) 2150-2166
    CrossrefPubMedGoogle Scholar
  • 114 Fang S, Suh JM, Reilly SM. et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med 2015; 21 (02) 159-165
    CrossrefPubMedGoogle Scholar
  • 115 Zhou M, Learned RM, Rossi SJ, DePaoli AM, Tian H, Ling L. Engineered FGF19 eliminates bile acid toxicity and lipotoxicity leading to resolution of steatohepatitis and fibrosis in mice. Hepatol Commun 2017; 1 (10) 1024-1042
    CrossrefPubMedGoogle Scholar
  • 116 Wojcik M, Janus D, Dolezal-Oltarzewska K. et al. A decrease in fasting FGF19 levels is associated with the development of non-alcoholic fatty liver disease in obese adolescents. J Pediatr Endocrinol Metab 2012; 25 (11-12): 1089-1093
    CrossrefPubMedGoogle Scholar
  • 117 Eren F, Kurt R, Ermis F, Atug O, Imeryuz N, Yilmaz Y. Preliminary evidence of a reduced serum level of fibroblast growth factor 19 in patients with biopsy-proven nonalcoholic fatty liver disease. Clin Biochem 2012; 45 (09) 655-658
    CrossrefPubMedGoogle Scholar
  • 118 Alisi A, Ceccarelli S, Panera N. et al. Association between serum atypical fibroblast growth factors 21 and 19 and pediatric nonalcoholic fatty liver disease. PLoS One 2013; 8 (06) e67160
    CrossrefPubMedGoogle Scholar
  • 119 Harrison SA, Rinella ME, Abdelmalek MF. et al. NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2018; 391 (10126): 1174-1185
    CrossrefPubMedGoogle Scholar
  • 120 Harrison SA, Rossi SJ, Paredes AH. et al. NGM282 improves liver fibrosis and histology in 12 weeks in patients with nonalcoholic steatohepatitis. Hepatology 2020; 71 (04) 1198-1212
    CrossrefPubMedGoogle Scholar
  • 121 Neuschwander-Tetri BA, Loomba R, Sanyal AJ. NASH Clinical Research Network. et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015; 385 (9972): 956-965
    CrossrefPubMedGoogle Scholar
  • 122 Hendrikx T, Duan Y, Wang Y. et al. Bacteria engineered to produce IL-22 in intestine induce expression of REG3G to reduce ethanol-induced liver disease in mice. Gut 2019; 68 (08) 1504-1515
    CrossrefPubMedGoogle Scholar
  • 123 Kurtz CB, Millet YA, Puurunen MK. et al. An engineered E. coli Nissle improves hyperammonemia and survival in mice and shows dose-dependent exposure in healthy humans. Sci Transl Med 2019; 11 (475) 11
    Google Scholar
  • 124 Synlogic. 2019 Available at: https://investor.synlogictx.com/news-releases/news-release-details/synlogic-discontinues-development-synb1020-treat-hyperammonemia. Accessed July 24, 2020
  • 125 Auchtung TA, Fofanova TY, Stewart CJ. et al. Investigating colonization of the healthy adult gastrointestinal tract by fungi. MSphere 2018; 3 (02) 3
    CrossrefPubMedGoogle Scholar
  • 126 Yang AM, Inamine T, Hochrath K. et al. Intestinal fungi contribute to development of alcoholic liver disease. J Clin Invest 2017; 127 (07) 2829-2841
    CrossrefPubMedGoogle Scholar
  • 127 Lang S, Duan Y, Liu J. et al. Intestinal fungal dysbiosis and systemic immune response to fungi in patients with alcoholic hepatitis. Hepatology 2020; 71 (02) 522-538
    CrossrefPubMedGoogle Scholar
  • 128 Chu H, Duan Y, Lang S. et al. The Candida albicans exotoxin candidalysin promotes alcohol-associated liver disease. J Hepatol 2020; 72 (03) 391-400
    CrossrefPubMedGoogle Scholar