Metabolic Brain Disease

, Volume 28, Issue 2, pp 321–326 | Cite as

Gut microbiota and hepatic encephalopathy

Original Paper


There is a strong relationship between liver and gut; while the portal venous system receives blood from the gut, and its contents may affect liver functions, liver in turn, affects intestinal functions through bile secretion. There is robust evidence that the pathogenesis of hepatic encephalopathy (HE) is linked to alterations in gut microbiota and their by-products such as ammonia, indoles, oxindoles, endotoxins, etc. In the setting of intestinal barrier and immune dysfunction, these by-products are involved in the pathogenesis of complications of liver cirrhosis including HE and systemic inflammation plays an important role. Prebiotics, probiotics and synbiotics may exhibit efficacy in the treatment of HE by modulating the gut flora. They improve derangement in flora by decreasing the counts of pathogenic bacteria and thus improving the endotoxemia, HE and the liver disease. Current evidence suggest that the trials evaluating the role of probiotics in the treatment of HE are of not high quality and all trials had high risk of bias and high risk of random errors. Therefore, the use of probiotics for patients with HE cannot be currently recommended. Further RCTs are required. This review summarizes the main literature findings about the relationships between gut flora and HE, both in terms of the pathogenesis and the treatment of HE.


Gut microbiome Gut microecology Hepatic encephalopathy Inflammation Probiotics Prebiotics Synbiotics 



hepatic encephalopathy


minimal HE


health-related quality of life


pathogen-associated molecular patterns


small intestinal bacterial overgrowth




model for end-stage liver disease


tumor necrosis factor


  1. Arora S, Martin CL, Myth HM (2006) interpretation of a single ammonia level in patients with chronic liver disease can confirm or rule out hepatic encephalopathy. CJEM 8:433–435PubMedGoogle Scholar
  2. Atluri DK, Prakash R, Mullen KD (2011) Pathogenesis, diagnosis, and treatment of hepatic encephalopathy. J ClinExpHepatol 1:77–86Google Scholar
  3. Bajaj JS, Saeian K, Christensen KM, Hafeezullah M, Varma RR, Franco J, Pleuss JA, Krakower G, Hoffmann RG, Binion DG (2008) Probiotic yogurt for the treatment of minimal hepatic encephalopathy. Am J Gastroenterol 103:1707–1715PubMedCrossRefGoogle Scholar
  4. Bajaj JS, Ridlon JM, Hylemon PB, Thacker LR, Heuman DM, Smith S, Sikaroodi M, Gillevet PM (2012a) Linkage of gut microbiome with cognition in hepatic encephalopathy. Am J PhysiolGastrointest Liver Physiol 302:G168–G175CrossRefGoogle Scholar
  5. Bajaj JS, Gillevet PM, Patel NR, Ahluwalia V, Ridlon JM, Kettenmann B, Schubert CM, Sikaroodi M, Heuman DM, Crossey MM, Bell DE, Hylemon PB, Fatouros PP, Taylor-Robinson SD (2012b). A longitudinal systems biology analysis of lactulose withdrawal in hepatic encephalopathy.Metab Brain Dis. 2012;27:205–15Google Scholar
  6. Bajaj JS, Hylemon PB, Ridlon JM, Heuman DM, Daita K, White MB, Monteith P, Noble NA, Sikaroodi M, Gillevet PM (2012c). The colonic mucosal microbiome differs from stool microbiome in cirrhosis and hepatic Encephalopathy and is linked to cognition and inflammation. Am J PhysiolGastrointest Liver Physiol. 2012 Jul 19. [Epub ahead of print]Google Scholar
  7. Bustamante J, Rimola A, Ventura PJ, Navasa M, Cirera I, Reggiardo V, Rodés J (1999) Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol 30:890–895PubMedCrossRefGoogle Scholar
  8. Butterworth RF (2011) Hepatic encephalopathy: a central neuroinflammatory disorder? Hepatology 53:1372–1376PubMedCrossRefGoogle Scholar
  9. Chen Y, Yang F, Lu H, Wang B, Chen Y, Lei D, Wang Y, Zhu B, Li L (2011) Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 54:562–572PubMedCrossRefGoogle Scholar
  10. Dhiman RK (2012a) Gut microbiota, inflammation and hepatic encephalopathy: a puzzle with a solution in sight. J ClinExpHepatol 2:207–210Google Scholar
  11. Dhiman RK, Chawla YK (2009) Minimal hepatic encephalopathy. Indian J Gastroenterol 28:5–16PubMedCrossRefGoogle Scholar
  12. Dhiman RK, Sawhney MS, Chawla YK, Das G, Ram S, Dilawari JB (2000) Efficacy of lactulose in cirrhotic patients with sub-clinical hepatic encephalopathy. Dig Dis Sci 45:1549–1552PubMedCrossRefGoogle Scholar
  13. Dhiman RK, Saraswat VA, Sharma BK, Sarin SK, Chawla YK, Butterworth R, Duseja A, Aggarwal R, Amarapurkar D, Sharma P, Madan K, Shah S, Seth AK, Gupta RK, Koshy A, Rai RR, Dilawari JB, Mishra SP, Acharya SK, Indian National Association for Study of the Liver (2010) Minimal hepatic encephalopathy: consensus statement of a working party of the Indian National Association for Study of the Liver. J GastroenterolHepatol 25:1029–1041Google Scholar
  14. Dhiman RK, Rana B, Garg A, Khattri A, Chopra M, Thumburu KK, Malhotra S, Duseja A, Chawla YK (2012b) Efficacy and safety of a probiotic preparation in the secondary prophylaxis of hepatic encephalopathy in cirrhotic patients: interim results of a double blind, randomized, placebo controlled study. Hepatology 56:255A [Abstract]Google Scholar
  15. Green GL, Brostoff J, Hudspith B, Michael M, Mylonaki M, Rayment N, Staines N, Sanderson J, Rampton DS, Bruce KD (2006) Molecular characterization of the bacteria adherent to human colorectal mucosa. J ApplMicrobiol 100:460–469Google Scholar
  16. Gupta A, Dhiman RK, Kumari S, Rana S, Agarwal R, Duseja A, Chawla Y (2010) Role of small intestinal bacterial overgrowth and delayed gastrointestinal transit time in cirrhotic patients with minimal hepatic encephalopathy. J Hepatol 53:849–855PubMedCrossRefGoogle Scholar
  17. Hakansson A, Molin G (2011) Gut microbiota and inflammation. Nutrients 3:637–682PubMedCrossRefGoogle Scholar
  18. Holte K, Krag A, Gluud LL (2012) Systematic review and meta-analysis of randomized trials on probiotics for hepatic encephalopathy. Hepatol Res 42:1008–1015PubMedCrossRefGoogle Scholar
  19. Horsmans Y, Solbreux PM, Daenens C, Desager JP, Geubel AP (1997) Lactulose improves psychometric testing in cir-rhotic patients with subclinical encepha-lopathy. Aliment PharmacolTher 11:165–170CrossRefGoogle Scholar
  20. Lata J, Jurankova J, Pribramska V, Juránková J, Fric P, Kroupa R, Stibůrek O (2006) Effect of administration of Escherichia coli Nissle (Mutaflor) on intestinal colonisation, endo-toxemia, liver function and minimal hepatic encephalopathy in patients with liver cirrhosis. VnitrLek 52:215–219Google Scholar
  21. Liu Q, Duan ZP, Ha DK, Bengmark S, Kurtovic J, Riordan SM (2004) Synbiotic modulation of gut flora: effect on minimal hepatic encephalop-athy in patients with cirrhosis. Hepatology 39:1441–1449PubMedCrossRefGoogle Scholar
  22. Loguercio C, Del Vecchio BC, Coltorti M (1987) Enterococcus lactic acid bacteria strain SF68 and lactulose in hepatic encephalopathy: a controlled study. J Int Med Res 15:335–343PubMedGoogle Scholar
  23. Malaguarnera M, Greco F, Barone G, Gargante MP, Toscano MA (2007) Bifidobacte-riumlongumwithfructo-oligosaccharide (FOS) treatment in minimal hepatic encephalopathy: a randomized, double-blind, placebo-controlled study. Dig Dis Sci 52:3259–3265PubMedCrossRefGoogle Scholar
  24. Malaguarnera M, Gargante MP, Malaguarnera G, Salmeri M, Mastrojeni S, Rampello L, Pennisi G, Li Volti G, Galvano F (2010) Bifidobacterium combined with fructo-oligosaccharide versus lactulose in the treatment of patients with hepatic encephalopathy. Eur J Gastroenterol Hepatol 22:199–206PubMedCrossRefGoogle Scholar
  25. McGee RG, Bakens A, Wiley K, Riordan SM, Webster AC (2011) Probiotics for patients with hepatic encephalopathy. Cochrane Database Syst Rev 9(11), CD008716Google Scholar
  26. Mittal VV, Sharma BC, Sharma P, Sarin SK (2011) A randomized controlled trial comparing lactulose, probiotics, and L-ornithine L-aspartate in treatment of minimal hepatic encephalopathy. Eur J GastroenterolHepatol 23:725–732CrossRefGoogle Scholar
  27. Mullen K, Prakash R (2010) Rifaximin for the treatment of hepatic encephalopathy. Expert Rev GastroenterolHepatol 4:665–677CrossRefGoogle Scholar
  28. Pande C, Kumar A, Sarin SK (2009) Small-intestinal bacterial overgrowth in cirrhosis is related to the severity of liver disease. Aliment PharmacolTher 29:1273–1281CrossRefGoogle Scholar
  29. Pereg D, Kotliroff A, Gadoth N, Hadary R, Lishner M, Kitay-Cohen Y (2011) Probiotics for patients with compensated liver cirrhosis: a double-blind placebo-controlled study. Nutrition 27:177–181PubMedCrossRefGoogle Scholar
  30. Prasad S, Dhiman RK, Duseja A, Chawla YK, Sharma A, Agarwal R (2007) Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy. Hepatology 45:549–559PubMedCrossRefGoogle Scholar
  31. Schrezenmeir J, de Vrese M (2001) Probiotics, prebiotics, and synbiotics–approaching a definition. Am J ClinNutr 73(2 Suppl):361S–364SGoogle Scholar
  32. Seyan AS, Hughes RD, Shawcross DL (2010) Changing face of hepatic encephalopathy: role of in flammation and oxidative stress. World J Gastroenterol 16:3347–3357PubMedCrossRefGoogle Scholar
  33. Sharma P, Sharma BC, Puri V, Sarin SK (2008) An open-label randomized controlled trial of lactulose and probiotics in the treatment of minimal hepatic encephalopathy. Eur J Gastroenterol Hepatol 20:506–511PubMedCrossRefGoogle Scholar
  34. Shawcross DL, Davies NA, Williams R, Jalan R (2004) Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol 40:247–254PubMedCrossRefGoogle Scholar
  35. Shawcross DL, Wright G, OldeDamink SW, Jalan R (2007) Role of ammonia and inflammation in minimal hepatic encephalopathy. Metab Brain Dis 22:125–138PubMedCrossRefGoogle Scholar
  36. Shawcross DL, Sharifi Y, Canavan JB, Yeoman AD, Abeles RD, Taylor NJ, Auzinger G, Bernal W, Wendon JA (2011) Infection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis. J Hepatol 54:640–649PubMedCrossRefGoogle Scholar
  37. Shukla S, Shukla A, Mehboob S, Guha S (2011) Meta-analysis: the effects of gut flora modulation using prebiotics, probiotics and synbiotics on minimal hepatic encephalopathy. Aliment PharmacolTher 33:662–671CrossRefGoogle Scholar
  38. Solga SF (2003) Probiotics can treat hepatic encephalopathy. Med Hypotheses 61:307–313PubMedCrossRefGoogle Scholar
  39. Solga SF, Diehl AM (2004) Gut flora-based therapy in liver disease? The liver cares about the gut. Hepatology 39:1197–1200PubMedCrossRefGoogle Scholar
  40. Tranah TH, Vijay GK, Ryan JM, Shawcross DL (2012) Systemic inflammation and ammonia in hepatic encephalopathy.Metab Brain Dis. 2012 Dec 7. [Epub ahead of print]Google Scholar
  41. Watanabe A, Sakai T, Sato S, Imai F, Ohto M, Arakawa Y, Toda G, Kobayashi K, Muto Y, Tsujii T, Kawasaki H, Okita K, Tanikawa K, Fujiyama S, Shimada S (1997) Clinical efficacy of lactulose in cirrhotic patients with and without subclinical hepatic encephalopathy. Hepatology 26:1410–1414PubMedCrossRefGoogle Scholar
  42. Wright G, Davies NA, Shawcross DL, Hodges SJ, Zwingmann C, Brooks HF, Mani AR, Harry D, Stadlbauer V, Zou Z, Williams R, Davies C, Moore KP, Jalan R (2007) Endotoxemia produces coma and brain swelling in bile duct ligated rats. Hepatology 45:1517–1526PubMedCrossRefGoogle Scholar
  43. Zeng Z, Li YY (2003) Effects of lactulose treat-ment on the course of subclinical hepatic encephalopathy. Zhonghua Yi XueZaZhi 83:1126–1129Google Scholar
  44. Zoetendal EG, von Wright A, Vilpponen-Salmela T, Ben-Amor K, Akkermans AD, de Vos WM (2002) Mucosa-associated bacteria in the human gastrointestinal tract are uniformly distributed along the colon and differ from the community recovered from feces. Appl Environ Microbiol 68:3401–3407PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of HepatologyPostgraduate Institute of Medical Education and ResearchChandigarhIndia

Personalised recommendations