Download PDF
Semin Liver Dis 2023; 43(03): 311-322
DOI: 10.1055/a-2145-7331
Review Article

Gut Microbiome-Centered Therapies for Alcohol-Associated Liver Disease

Tannaz Ranjbarian
1   Department of Medicine, University of California San Diego, La Jolla, California
,
Bernd Schnabl
1   Department of Medicine, University of California San Diego, La Jolla, California
2   Department of Medicine, VA San Diego Healthcare System, San Diego, California
› Author Affiliations
› Further Information
    Permissions and Reprints


Abstract

Globally, liver disease caused by alcohol is becoming more prevalent each year. Misuse of alcohol causes a spectrum of liver diseases, such as liver steatosis, steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. The cornerstone of treatment is abstinence from alcohol. In spite of this, available treatment for alcohol-associated liver disease (ALD) shows limited effectiveness currently. There are numerous ways in which alcohol disrupts the gut–liver axis, including dysbiosis of the gut microbiome, disruption of mucus and epithelial cell barriers, impaired production of antimicrobial molecules, and dysfunction of the immune system, causing translocation of viable microbes and microbial products to the liver and systemic circulation. Microbial exposure results in not only inflammation and progression of liver disease but also infections in late-stage ALD. This led scientists to focus their therapeutic strategies and targets for ALD on the gut microbiome. Throughout this review, we address the role of gut microbiome–centered therapeutic approaches for ALD focusing predominantly on randomized controlled trials. We will summarize the latest clinical trials using probiotics, antibiotics, and fecal microbial transplants in modulating the gut–liver axis and for improvement of ALD.

Keywords

alcoholic liver disease - liver steatosis - hepatocellular carcinoma - microbiota


Publication History

Accepted Manuscript online:
01 August 2023

Article published online:
30 August 2023

© 2023. Thieme. All rights reserved.

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

 

  • References

  • 1 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
  • 2 Rehm J, Samokhvalov AV, Shield KD. Global burden of alcoholic liver diseases. J Hepatol 2013; 59 (01) 160-168
    CrossrefPubMedGoogle Scholar
  • 3 Rehm J, Dawson D, Frick U. et al. Burden of disease associated with alcohol use disorders in the United States. Alcohol Clin Exp Res 2014; 38 (04) 1068-1077
    CrossrefPubMedGoogle Scholar
  • 4 Arroyo V, Moreau R, Kamath PS. et al. Acute-on-chronic liver failure in cirrhosis. Nat Rev Dis Primers 2016; 2: 16041
    CrossrefPubMedGoogle Scholar
  • 5 Fuster D, Samet JH. Alcohol use in patients with chronic liver disease. N Engl J Med 2018; 379 (13) 1251-1261
    CrossrefPubMedGoogle Scholar
  • 6 Bataller R, Arab JP, Shah VH. Alcohol-associated hepatitis. N Engl J Med 2022; 387 (26) 2436-2448
    CrossrefPubMedGoogle Scholar
  • 7 Louvet A, Thursz MR, Kim DJ. et al. Corticosteroids reduce risk of death within 28 days for patients with severe alcoholic hepatitis, compared with pentoxifylline or placebo - a meta-analysis of individual data from controlled trials. Gastroenterology 2018; 155 (02) 458-468.e8
    CrossrefPubMedGoogle Scholar
  • 8 Cederbaum AI. Alcohol metabolism. Clin Liver Dis 2012; 16 (04) 667-685
    CrossrefPubMedGoogle Scholar
  • 9 Galicia-Moreno M, Rosique-Oramas D, Medina-Avila Z. et al. Behavior of oxidative stress markers in alcoholic liver cirrhosis patients. Oxid Med Cell Longev 2016; 9370565
    PubMedGoogle Scholar
  • 10 Sies H, Berndt C, Jones DP. Oxidative stress. Annu Rev Biochem 2017; 86: 715-748
    CrossrefPubMedGoogle Scholar
  • 11 Weiskirchen R, Weiskirchen S, Tacke F. Recent advances in understanding liver fibrosis: bridging basic science and individualized treatment concepts. F1000 Res 2018; 7: 7
    CrossrefPubMedGoogle Scholar
  • 12 Sugimoto K, Takei Y. Pathogenesis of alcoholic liver disease. Hepatol Res 2017; 47 (01) 70-79
    CrossrefPubMedGoogle Scholar
  • 13 Consortium HMP. Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 2012; 486 (7402) 207-214
    CrossrefPubMedGoogle Scholar
  • 14 Biedermann L, Rogler G. The intestinal microbiota: its role in health and disease. Eur J Pediatr 2015; 174 (02) 151-167
    CrossrefPubMedGoogle Scholar
  • 15 Konturek PC, Harsch IA, Konturek K. et al. Gut–liver axis: How do gut bacteria influence the liver?. Med Sci (Basel) 2018; 6 (03) 6
    PubMedGoogle Scholar
  • 16 Gao B, Duan Y, Lang S. et al. Functional microbiomics reveals alterations of the gut microbiome and host co-metabolism in patients with alcoholic hepatitis. Hepatol Commun 2020; 4 (08) 1168-1182
    CrossrefPubMedGoogle Scholar
  • 17 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
  • 18 Bode JC, Bode C, Heidelbach R, Dürr HK, Martini GA. Jejunal microflora in patients with chronic alcohol abuse. Hepatogastroenterology 1984; 31 (01) 30-34
    PubMedGoogle Scholar
  • 19 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 (09) 2364-2370
    CrossrefPubMedGoogle Scholar
  • 20 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
  • 21 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
  • 22 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
  • 23 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 (05) 940-947
    CrossrefPubMedGoogle Scholar
  • 24 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
  • 25 Hsu CL, Schnabl B. The gut-liver axis and gut microbiota in health and liver disease. Nat Rev Microbiol 2023; DOI: 10.1038/s41579-023-00904-3.
    CrossrefPubMedGoogle Scholar
  • 26 Lang S, Fairfied B, Gao B. et al. Changes in the fecal bacterial microbiota associated with disease severity in alcoholic hepatitis patients. Gut Microbes 2020; 12 (01) 1785251
    CrossrefPubMedGoogle Scholar
  • 27 Stärkel P, Schnabl B. Bidirectional communication between liver and gut during alcoholic liver disease. Semin Liver Dis 2016; 36 (04) 331-339
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Méndez-Sánchez N, Valencia-Rodriguez A, Vera-Barajas A. et al. The mechanism of dysbiosis in alcoholic liver disease leading to liver cancer. Hepatoma Res 2020; 6: 6
    PubMedGoogle Scholar
  • 29 Brandl K, Schnabl B. Is intestinal inflammation linking dysbiosis to gut barrier dysfunction during liver disease?. Expert Rev Gastroenterol Hepatol 2015; 9 (08) 1069-1076
    CrossrefPubMedGoogle Scholar
  • 30 Inokuchi S, Tsukamoto H, Park E, Liu ZX, Brenner DA, Seki E. Toll-like receptor 4 mediates alcohol-induced steatohepatitis through bone marrow-derived and endogenous liver cells in mice. Alcohol Clin Exp Res 2011; 35 (08) 1509-1518
    PubMedGoogle Scholar
  • 31 Seki E, De Minicis S, Osterreicher CH. et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med 2007; 13 (11) 1324-1332
    CrossrefPubMedGoogle Scholar
  • 32 Duan Y, Chu H, Brandl K. et al. CRIg on liver macrophages clears pathobionts and protects against alcoholic liver disease. Nat Commun 2021; 12 (01) 7172
    CrossrefPubMedGoogle Scholar
  • 33 Chang B, Xu MJ, Zhou Z. et al. Short- or long-term high-fat diet feeding plus acute ethanol binge synergistically induce acute liver injury in mice: an important role for CXCL1. Hepatology 2015; 62 (04) 1070-1085
    CrossrefPubMedGoogle Scholar
  • 34 Kouno T, Zeng S, Wang Y. et al. Engineered bacteria producing aryl-hydrocarbon receptor agonists protect against ethanol-induced liver disease in mice. Alcohol (Hanover) 2023; 47 (05) 856-867
    CrossrefPubMedGoogle Scholar
  • 35 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
  • 36 Neish AS. Microbes in gastrointestinal health and disease. Gastroenterology 2009; 136 (01) 65-80
    CrossrefPubMedGoogle Scholar
  • 37 Hsieh PS, Chen CW, Kuo YW, Ho HH. Lactobacillus spp. reduces ethanol-induced liver oxidative stress and inflammation in a mouse model of alcoholic steatohepatitis. Exp Ther Med 2021; 21 (03) 188
    CrossrefPubMedGoogle Scholar
  • 38 Lata J, Jurankova J, Kopacova M, Vitek P. Probiotics in hepatology. World J Gastroenterol 2011; 17 (24) 2890-2896
    CrossrefPubMedGoogle Scholar
  • 39 Gu Z, Liu Y, Hu S. et al. Probiotics for alleviating alcoholic liver injury. Gastroenterol Res Pract 2019; 9097276
    PubMedGoogle Scholar
  • 40 Li X, Liu Y, Guo X, Ma Y, Zhang H, Liang H. Effect of Lactobacillus casei on lipid metabolism and intestinal microflora in patients with alcoholic liver injury. Eur J Clin Nutr 2021; 75 (08) 1227-1236
    CrossrefPubMedGoogle Scholar
  • 41 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
  • 42 Han SH, Suk KT, Kim DJ. et al. Effects of probiotics (cultured Lactobacillus subtilis/Streptococcus faecium) in the treatment of alcoholic hepatitis: randomized-controlled multicenter study. Eur J Gastroenterol Hepatol 2015; 27 (11) 1300-1306
    CrossrefPubMedGoogle Scholar
  • 43 Vatsalya V, Feng W, Kong M, Hu H, Szabo G, McCullough A, Dasarathy S, Nagy LE, Radaeva S, Barton B, Mitchell M, McClain CJ. The beneficial effects of Lactobacillus GG therapy on liver and drinking assessments in patients with moderate alcohol-associated hepatitis. Am J Gastroenterol 2023; 118 (08) 1457-1460 DOI: 10.14309/ajg.0000000000002283. . PMID: 37040544
    CrossrefPubMedGoogle Scholar
  • 44 Wiest R, Lawson M, Geuking M. Pathological bacterial translocation in liver cirrhosis. J Hepatol 2014; 60 (01) 197-209
    CrossrefPubMedGoogle Scholar
  • 45 Wiest R, Garcia-Tsao G. Bacterial translocation (BT) in cirrhosis. Hepatology 2005; 41 (03) 422-433
    CrossrefPubMedGoogle Scholar
  • 46 Stadlbauer V, Mookerjee RP, Hodges S, Wright GA, Davies NA, Jalan R. Effect of probiotic treatment on deranged neutrophil function and cytokine responses in patients with compensated alcoholic cirrhosis. J Hepatol 2008; 48 (06) 945-951
    CrossrefPubMedGoogle Scholar
  • 47 Macnaughtan J, Figorilli F, García-López E. et al. A double-blind, randomized placebo-controlled trial of probiotic Lactobacillus casei Shirota in stable cirrhotic patients. Nutrients 2020; 12 (06) 12
    CrossrefPubMedGoogle Scholar
  • 48 Hou MC, Lin HC, Liu TT. et al. Antibiotic prophylaxis after endoscopic therapy prevents rebleeding in acute variceal hemorrhage: a randomized trial. Hepatology 2004; 39 (03) 746-753
    CrossrefPubMedGoogle Scholar
  • 49 Fernández J, Acevedo J, Castro M. et al. Prevalence and risk factors of infections by multiresistant bacteria in cirrhosis: a prospective study. Hepatology 2012; 55 (05) 1551-1561
    CrossrefPubMedGoogle Scholar
  • 50 Bass NM, Mullen KD, Sanyal A. et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med 2010; 362 (12) 1071-1081
    CrossrefPubMedGoogle Scholar
  • 51 Kimer N, Pedersen JS, Tavenier J. et al; Members of the CoRif Study Group. Rifaximin has minor effects on bacterial composition, inflammation, and bacterial translocation in cirrhosis: a randomized trial. J Gastroenterol Hepatol 2018; 33 (01) 307-314
    CrossrefPubMedGoogle Scholar
  • 52 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
  • 53 Kang DJ, Kakiyama G, Betrapally NS. et al. Rifaximin exerts beneficial effects independent of its ability to alter microbiota composition. Clin Transl Gastroenterol 2016; 7 (08) e187
    CrossrefPubMedGoogle Scholar
  • 54 Jiménez C, Ventura-Cots M, Sala M. et al. Effect of rifaximin on infections, acute-on-chronic liver failure and mortality in alcoholic hepatitis: a pilot study (RIFA-AH). Liver Int 2022; 42 (05) 1109-1120
    CrossrefPubMedGoogle Scholar
  • 55 Kimer N, Meldgaard M, Hamberg O. et al. The impact of rifaximin on inflammation and metabolism in alcoholic hepatitis: a randomized clinical trial. PLoS One 2022; 17 (03) e0264278
    CrossrefPubMedGoogle Scholar
  • 56 Louvet A, Labreuche J, Dao T. et al. Effect of prophylactic antibiotics on mortality in severe alcohol-related hepatitis: a randomized clinical trial. JAMA 2023; 329 (18) 1558-1566
    CrossrefPubMedGoogle Scholar
  • 57 Lucey MR. Alcohol-associated cirrhosis. Clin Liver Dis 2019; 23 (01) 115-126
    CrossrefPubMedGoogle Scholar
  • 58 Bajaj JS, Hassanein TI, Pyrsopoulos NT. et al. Dosing of rifaximin soluble solid dispersion tablets in adults with cirrhosis: 2 randomized, placebo-controlled trials. Clin Gastroenterol Hepatol 2023; 21 (03) 723-731.e9
    CrossrefPubMedGoogle Scholar
  • 59 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 2013; 28 (03) 450-455
    CrossrefPubMedGoogle Scholar
  • 60 Kalambokis GN, Mouzaki A, Rodi M. et al. Rifaximin improves systemic hemodynamics and renal function in patients with alcohol-related cirrhosis and ascites. Clin Gastroenterol Hepatol 2012; 10 (07) 815-818
    CrossrefPubMedGoogle Scholar
  • 61 Kalambokis GN, Mouzaki A, Rodi M, Tsianos EV. Rifaximin improves thrombocytopenia in patients with alcoholic cirrhosis in association with reduction of endotoxaemia. Liver Int 2012; 32 (03) 467-475
    CrossrefPubMedGoogle Scholar
  • 62 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
    CrossrefPubMedGoogle Scholar
  • 63 Sarin SK, Pande A, Schnabl B. Microbiome as a therapeutic target in alcohol-related liver disease. J Hepatol 2019; 70 (02) 260-272
    CrossrefPubMedGoogle Scholar
  • 64 Sharma A, Roy A, Premkumar M. et al. Fecal microbiota transplantation in alcohol-associated acute-on-chronic liver failure: an open-label clinical trial. Hepatol Int 2022; 16 (02) 433-446
    CrossrefPubMedGoogle Scholar
  • 65 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
  • 66 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
  • 67 Philips CA, Ahamed R, Rajesh S, Abduljaleel JKP, Augustine P. Long-term outcomes of stool transplant in alcohol-associated hepatitis-analysis of clinical outcomes, relapse, gut microbiota and comparisons with standard care. J Clin Exp Hepatol 2022; 12 (04) 1124-1132
    CrossrefPubMedGoogle Scholar
  • 68 Pande A, Sharma S, Khillan V. et al. Fecal microbiota transplantation compared with prednisolone in severe alcoholic hepatitis patients: a randomized trial. Hepatol Int 2023; 17 (01) 249-261
    CrossrefPubMedGoogle Scholar
  • 69 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
  • 70 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
  • 71 Bajaj JS, Shamsaddini A, Fagan A. et al. Fecal microbiota transplant in cirrhosis reduces gut microbial antibiotic resistance genes: analysis of two trials. Hepatol Commun 2020; 5 (02) 258-271
    CrossrefPubMedGoogle Scholar
  • 72 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
  • 73 Bajaj JS, Gavis EA, Fagan A. et al. A randomized clinical trial of fecal microbiota transplant for alcohol use disorder. Hepatology 2021; 73 (05) 1688-1700
    CrossrefPubMedGoogle Scholar
  • 74 DeFilipp Z, Bloom PP, Torres Soto M. et al. Drug-resistant E. coli bacteremia transmitted by fecal microbiota transplant. N Engl J Med 2019; 381 (21) 2043-2050
    CrossrefPubMedGoogle Scholar
  • 75 Couch RD, Dailey A, Zaidi F. et al. Alcohol induced alterations to the human fecal VOC metabolome. PLoS One 2015; 10 (03) e0119362
    CrossrefPubMedGoogle Scholar
  • 76 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
  • 77 Yang Z, Kusumanchi P, Ross RA. et al. Serum metabolomic profiling identifies key metabolic signatures associated with pathogenesis of alcoholic liver disease in humans. Hepatol Commun 2019; 3 (04) 542-557
    CrossrefPubMedGoogle Scholar