Diet, Gut Dysbiosis and Liver Cirrhosis and their Influence upon Hepatic Encephalopathy
Main Article Content
Abstract
Cirrhosis is the end stage of progressive liver fibrosis, resulted from chronic inflammation and liver injury. Early identification of risk factors and appropriate treatment for hepatic decompensation is paramount for positive health outcomes. In this review study, we revisited mechanisms associated with gut dysbiosis and intestinal hyperpermeability in advanced liver disease, and further discussed nutritional strategies for the management of dysbiosis in liver cirrhosis. In gut dysbiosis, proportionally lower concentrations of bacteria belonging to beneficial taxa such as Lachnospiraceae, Clostridiales, Ruminococcaceae and Veillonellaceae and others are observed, in relation to pathogenic taxa such as Enterobacteriaceae, Bacteroidaceae and others. Cirrhotic patients present decreased bowel motility, bacterial overgrowth and increased intestinal permeability. Dysbiosis may further exacerbate such conditions due to the ability of pathogenic bacteria to adhere to the epithelium, produce endotoxin, disrupt bile acid metabolism, activate the immune system and trigger inflammation, in a vicious cycle. The triad hepatic encephalopathy – cirrhosis – gut dysbiosis is an evident entity, and primary prevention as well as management strategies for those three conditions aim strongly at improving intestinal health by focusing on nutritional interventions. High-protein diets may be recommended for cirrhosis patients, and the protein source is a key factor to consider, and so are dietary fibre and carbohydrate compositions. Attention is given to reduce saturated fat intake. Supplementation with branched-chain amino acids, probiotics and prebiotics have also shown positive results.
Keywords:
Diet, dysbiosis, microbiome, cirrhosis, hepatic encephalopathy
Article Details
How to Cite
DE JESUS, Rosângela Passos et al.
Diet, Gut Dysbiosis and Liver Cirrhosis and their Influence upon Hepatic Encephalopathy.
Medical Research Archives, [S.l.], v. 10, n. 8, aug. 2022.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2915>. Date accessed: 24 apr. 2024.
doi: https://doi.org/10.18103/mra.v10i8.2915.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. GBD 2017 Cirrhosis Collaborators. The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2020;5(3):245-266.doi:10.1016/S2468-1253(19)30349-8.
2. Asrani SK, Devarbhavi H, Eaton J, Kamath PS. Burden of liver diseases in the world. J Hepatol. 2019;70(1):151-71. doi:10.1016/j.jhep.2018.09.014.
3. Woodhouse CA, Patel VC, Singanayagam A, Shawcross DL. Review article: the gut microbiome as a therapeutic target in the pathogenesis and treatment of chronic liver disease. Aliment Pharmacol Ther. 2018;47(2):192-202. doi:10.1111/apt.14397.
4. Gunnarsdottir SA, Sadik R, Shev S, et al. Small intestinal motility disturbances and bacterial overgrowth in patients with liver cirrhosis and portal hypertension. Am J Gastroenterol. 2003;98(6):1362-70. doi:10.1016/S0002-9270(03)00250-8.
5. Thalheimer U, Triantos CK, Samonakis DN, Patch D, Burroughs AK. Infection, coagulation, and variceal bleeding in cirrhosis. Gut. 2005;54(4):556-63.doi:10.1136/gut.2004.048181.
6. Albillos A, de la Hera A, Gonzalez M, et al. Increased lipopolysaccharide binding protein in cirrhotic patients with marked immune and hemodynamic derangement. Hepatology. 2003;37(1):208-17.doi: 10.1053/jhep.2003.50038.
7. Gomez-Hurtado I, Such J, Sanz Y, Frances R. Gut microbiota-related complications in cirrhosis. World J Gastroenterol. 2014;20(42):15624-31. doi:10.3748/wjg.v20.i42.15624.
8. Thursby E, Juge N. Introduction to the human gut microbiota. Biochem J. 2017;474(11):1823-1836. doi:10.1042/BCJ20160510.
9. Ridlon JM, Alves JM, Hylemon PB, Bajaj JS. Cirrhosis, bile acids and gut microbiota: unraveling a complex relationship. Gut Microbes. 2013;4(5):382-7. doi:10.4161/gmic.25723.
10. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328-57.doi:10.1002/hep.29367.
11. Monteiro CA, Cannon G, Lawrence M, Costa Louzada ML, Pereira Machado P. 2019. Ultra-processed foods, diet quality, and health using the NOVA classification system. Rome, FAO.
12. Monteiro CA, Moubarac J., Cannon G, Ng S, Popkin B. Ultra-processed products are becoming dominant in the global food system. Obesity Rev. 2014; 2:21-28.doi: 10.1111/obr.12107.
13. Jarvis H, Craig D, Barker R, et al. Metabolic risk factors and incident advanced liver disease in non-alcoholic fatty liver disease (NAFLD): A systematic review and meta-analysis of population-based observational studies. PLoS Med.2020;17(4):e1003100. doi:10.1371/journal.pmed.1003100.
14. Zadeh SH, Mansoori A, Hosseinzadeh M. Relationship between dietary patterns and non-alcoholic fatty liver disease: A systematic review and meta-analysis. J Gastroenterol Hepatol. 2020.doi:10.1111/jgh.15363.
15. Eslam M, Newsome PN, Sarin SK, et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol. 2020;73(1):202-209. doi:10.1016/j.jhep.2020.03.039.
16. Di Lorenzo F, De Castro C, Silipo A, Molinaro A. Lipopolysaccharide structures of gram-negative populations in the gut microbiota and effects on host interactions. FEMS Microbiol Rev.2019;43(3):257-272. doi:10.1093/femsre/fuz002.
17. Moszak M, Szulińska M, Bogdański P. You Are What You Eat-The Relationship between Diet, Microbiota, and Metabolic Disorders-A Review. Nutrients. 2020;12(4):1096.doi: 10.3390/nu12041096.
18. Gentile CL, Weir T.L. The gut microbiota at the intersection of diet and human health. Science. 2018; 362:776–780.doi: 10.1126/science.aau5812.
19. Madsen L, Myrmel LS, Fjære E, Liaset B, Kristiansen K. Links between Dietary Protein Sources, the Gut Microbiota, and Obesity. Front Physiol. 2017; 8:1047.doi: 10.3389/fphys.2017.01047.
20. Zhao F, Huang Z, Zhou G, Li H, Xu X, Li C. Dietary proteins rapidly altered the microbial composition in rat caecum. Curr. Microbiol. 2017; 74:1447–1452. doi:10.1007/s00284-017-1339-2.
21. Fava F, Gitau R, Griffin BA, Gibson GR, Tuohy KM, Lovegrove JA. The type and quantity of dietary fat and carbohydrate alter faecal microbiome and short-chain fatty acid excretion in a metabolic syndrome 'at-risk' population. Int J Obes (Lond). 2013; 37(2):216-23. doi:10.1038/ijo.2012.33.
22. de Velasco P, Ferreira A, Crovesy L, Marine T, do Carmo MDGT. Biochemistry and Health Benefits of Fatty Acids. IntechOpen; London, UK: 2018. Fatty acids, gut microbiota, and the genesis of obesity.
23. Chiang JYL, Ferrell JM. Bile Acids as Metabolic Regulators and Nutrient Sensors. Annu Rev Nutr. 2019;39:175-200.doi:10.1146/annurev-nutr-082018-124344.
24. O'Flaherty S, Briner Crawley A, Theriot CM, Barrangou R. The Lactobacillus Bile Salt Hydrolase Repertoire Reveals Niche-Specific Adaptation. mSphere. 2018;3(3):e00140-18. doi:10.1128/mSphere.00140-18.
25. Zinöcker MK, Lindseth IA. The Western Diet-Microbiome-Host Interaction and Its Role in Metabolic Disease. Nutrients. 2018;10(3):365. doi:10.3390/nu10030365.
26. David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505(7484):559-63.doi: 10.1038/nature12820.
27. Sonnenburg ED, Smits SA, Tikhonov M, Higginbottom SK, Wingreen NS, Sonnenburg JL. Diet-induced extinctions in the gut microbiota compound over generations. Nature. 2016; 529(7585):212-5.doi: 10.1038/nature16504.
28. Agus A, Denizot J, Thévenot J, et al. Western diet induces a shift in microbiota composition enhancing susceptibility to Adherent-Invasive E. coli infection and intestinal inflammation. Sci Rep. 2016; 6:19032.doi:10.1038/srep19032.
29. Hildebrandt MA, Hoffmann C, Sherrill-Mix SA, et al. High-fat diet determines the composition of the murine gut microbiome independently of obesity. Gastroenterology 2009; 137:1716–24. doi:10.1053/j.gastro.2009.08.042 .
30. Caesar R, Tremaroli V, Kovatcheva-Datchary P, Cani PD, Bäckhed F. Crosstalk between Gut Microbiota and Dietary Lipids Aggravates WAT Inflammation through TLR Signaling. Cell Metab. 2015; 22(4):658-68. doi:10.1016/j.cmet.2015.07.026.
31. Wolters M, Ahrens J, Romaní-Pérez M, Watkins C, Sanz Y, Benítez-Páez A, et al. Dietary fat, the gut microbiota, and metabolic health - A systematic review conducted within the MyNewGut project. Clin Nutr. 2019; 38(6):2504-2520. doi:10.1016/j.clnu.2018.12.024.
32. Partridge D, Lloyd KA, Rhodes JM, Walker AW, Johnstone AM, Campbell BJ. Food additives: Assessing the impact of exposure to permitted emulsifiers on bowel and metabolic health - introducing the FADiets study. Nutr Bull. 2019;44(4):329-349.doi:10.1111/nbu.12408.
33. Schroeder BO, Birchenough GMH, Ståhlman M, et al. Bifidobacteria or Fiber Protects against Diet-Induced Microbiota-Mediated Colonic Mucus Deterioration. Cell Host Microbe. 2018; 23(1):27-40.e7. doi:10.1016/j.chom.2017.11.004.
34. Litwinowicz K., Choroszy M., Waszczuk E. Changes in the composition of the human intestinal microbiome in alcohol use disorder: A systematic review. Am. J. Drug Alcohol Abuse. 2020;46:4–12. doi:10.1080/00952990.2019.1669629.
35. Cani PD, Bibiloni R, Knauf C, et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008; 57:1470–81. doi:10.2337/db07-1403.
36. Desai MS, Seekatz AM, Koropatkin NM, et al. A Dietary Fiber-Deprived Gut Microbiota Degrades the Colonic Mucus Barrier and Enhances Pathogen Susceptibility. Cell. 2016;167(5):1339-1353.e21. doi:10.1016/j.cell.2016.10.043.
37. Mai BH, Yan LJ. The negative and detrimental effects of high fructose on the liver, with special reference to metabolic disorders. Diabetes Metab Syndr Obes. 2019;12:821-826. doi: 10.2147/DMSO.S198968.
38. Jensen T, Abdelmalek MF, Sullivan S, et al. Fructose and sugar: A major mediator of non-alcoholic fatty liver disease. J Hepatol. 2018;68(5):1063–1075. doi:10.1016/j.jhep.2018.01.019.
39. Choi Y, Abdelmegeed MA, Song BJ. Diet high in fructose promotes liver steatosis and hepatocyte apoptosis in C57BL/6J female mice: role of disturbed lipid homeostasis and increased oxidative stress. Food Chem Toxicol. 2017;103:111–121. doi:10.1016/j.fct.2017.02.039.
40. Sarin SK, Pande A, Schnabl B. Microbiome as a therapeutic target in alcohol-related liver disease. J Hepatol. 2019;70(2):260-72.doi: 10.1016/j.jhep.2018.10.019.
41. Lambertz J, Weiskirchen S, Landert S, Weiskirchen R. Fructose: a dietary sugar in crosstalk with microbiota contributing to the development and progression of non-alcoholic liver disease. Front Immunol. 2017;8:1159. doi:10.3389/fimmu.2017.01159.
42. Bajaj JS, Khoruts A. Microbiota changes and intestinal microbiota transplantation in liver diseases and cirrhosis. Journal of Hepatology. 2020; 72(5):1003-1027. doi:10.1016/j.jhep.2020.01.017.
43. Acharya C, Bajaj JS. Altered Microbiome in Patients With Cirrhosis and Complications. Clin Gastroenterol Hepatol. 2019;17(2):307-21. doi:10.1016/j.cgh.2018.08.008.
44. Kalaitzakis E. Gastrointestinal dysfunction in liver cirrhosis. World J Gastroenterol.2014; 20(40): 14686-14695. doi: 10.3748/wjg.v20.i40.14686.
45. Wang Y, Pan CQ, Xing H. Advances in Gut Microbiota of Viral Hepatitis Cirrhosis. BioMed Research International. 2019; doi:10.1155/2019/9726786.
46. Giannelli V, Di Gregorio V, Iebba V, et al. Microbiota and the gut-liver axis: bacterial translocation, inflammation and infection in cirrhosis. World J Gastroenterol. 2014;20(45):16795-810. doi:10.3748/wjg.v20.i45.16795.
47. Fukui H, Wiest R. Changes of Intestinal Functions in Liver Cirrhosis. Inflamm Intest Dis. 2016;1(1):24-40. doi:10.1159/000444436.
48. Nagasako CK, de Oliveira Figueiredo MJ, de Souza Almeida JR, et al. Investigation of autonomic function and orocecal transit time in patients with nonalcoholic cirrhosis and the potential influence of these factors on disease outcome. J Clin Gastroenterol. 2009;43(9):884-9. doi:10.1097/MCG.0b013e31818de34c.
49. Kalaitzakis E, Sadik R, Holst JJ, Ohman L, Björnsson E. Gut transit is associated with gastrointestinal symptoms and gut hormone profile in patients with cirrhosis. Clin Gastroenterol Hepatol. 2009;7(3):346-52.doi: 10.1016/j.cgh.2008.11.022.
50. 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):940-7. doi:10.1016/j.jhep.2013.12.019.
51. Saboo K, Shamsaddini A, Iyer MV, et al. Sex is associated with differences in gut microbial compositionand function in hepatic encephalopathy. J. Hepatol. 2021, 74, 80–88. doi:10.1016/j.jhep.2020.06.046.
52. Shah A, Shanahan E, Macdonald GA, et al. Systematic Review and Meta-Analysis: Prevalence of Small Intestinal Bacterial Overgrowth in Chronic Liver Disease. Semin Liver Dis. 2017;37(4):388-400. doi:10.1055/s-0037-1608832.
53. Campion D, Giovo I, Ponzo P, Saracco GM, Balzola F, Alessandria C. Dietary approach and gut microbiota modulation for chronic hepatic encephalopathy in cirrhosis. World J Hepatol. 2019;11(6):489-512. doi:10.4254/wjh.v11.i6.489.
54. Fasullo M, Rau P, Liu DQ, et al. Proton pump inhibitors increase the severity of hepatic encephalopathy in cirrhotic patients. World J Hepatol. 2019;11(6):522-30. doi:10.4254/wjh.v11.i6.522.
55. Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014;60(2):715-35. doi:10.1002/hep.27210.
56. Bale A, Pai CG, Shetty S, Balaraju G, Shetty A. Prevalence of and Factors Associated With Minimal Hepatic Encephalopathy in Patients With Cirrhosis of Liver. J Clin Exp Hepatol. 2018;8(2):156-61.doi:10.1016/j.jceh.2017.06.005.
57. EASL Clinical Practice Guidelines on nutrition in chronic liver disease. J Hepatol (2018). doi: 10.1016/j.jhep.2018.06.024.
58. Bajaj JS, Ridlon JM, Hylemon PB, et al. Linkage of gut microbiome with cognition in hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol. 2012;302(1):G168-G175. doi:10.1152/ajpgi.00190.2011.
59. Levitt DG, Levitt MD. A model of blood-ammonia homeostasis based on a quantitative analysis of nitrogen metabolism in the multiple organs involved in the production, catabolism, and excretion of ammonia in humans. Clin Exp Gastroenterol. 2018;11:193-215. doi: 10.2147/CEG.S160921.
60. Bajaj JS, Salzman NH, Acharya C, et al. Fecal Microbial Transplant Capsules Are Safe in Hepatic Encephalopathy: A Phase 1, Randomized, Placebo-Controlled Trial [published correction appears in Hepatology. 2020 Oct;72(4):1501]. Hepatology. 2019;70(5):1690-1703. doi:10.1002/hep.30690.
61. Bajaj JS, Heuman DM, Sterling RK, et al. Validation of EncephalApp, Smartphone-Based Stroop Test, for the Diagnosis of Covert Hepatic Encephalopathy. Clin Gastroenterol Hepatol. 2015;13(10):1828-1835.e1. doi:10.1016/j.cgh.2014.05.011.
62. Ni J, Huang R, Zhou H, et al. Analysis of the Relationship Between the Degree of Dysbiosis in Gut Microbiota and Prognosis at Different Stages of Primary Hepatocellular Carcinoma. Front Microbiol. 2019;10:1458. doi:10.3389/fmicb.2019.01458
63. Grohmann M, Wiede F, Dodd GT, et al. Obesity Drives STAT-1-Dependent NASH and STAT-3-Dependent HCC. Cell. 2018;175(5):1289-1306.e20. doi:10.1016/j.cell.2018.09.053.
64. Liu Q, Li F, Zhuang Y, et al. Alteration in gut microbiota associated with hepatitis B and non-hepatitis virus related hepatocellular carcinoma. Gut Pathog. 2019;11:1. doi:10.1186/s13099-018-0281-6.
65. Behary J, Amorim N, Jiang XT, et al. Gut microbiota impact on the peripheral immune response in non-alcoholic fatty liver disease related hepatocellular carcinoma. Nat Commun. 2021;12(1):187.doi:10.1038/s41467-020-20422-7.
66. Solé C, Guilly S, Da Silva K, et al. Alterations in Gut Microbiome in Cirrhosis as Assessed by Quantitative Metagenomics: Relationship With Acute-on-Chronic Liver Failure and Prognosis. Gastroenterology. 2021;160(1):206-218.e13. doi:10.1053/j.gastro.2020.08.054.
67. Bischoff SC, Bernal W, Dasarathy S, et al. ESPEN practical guideline: Clinical nutrition in liver disease. Clin Nutr. 2020;39(12):3533-3562. doi:10.1016/j.clnu.2020.09.001.
68. Tsien CD, McCullough AJ, Dasarathy S. Late evening snack: exploiting a period of anabolic opportunity in cirrhosis. J Gastroenterol Hepatol. 2012;27(3):430-441. doi:10.1111/j.1440-1746.2011.06951.x.
69. Bajaj JS, Torre A, Rojas ML, et al. Cognition and hospitalizations are linked with salivary and faecal microbiota in cirrhosis cohorts from the USA and Mexico. Liver Int 2020;40:1395–1407. doi: 10.1111/liv.14437.
70. Bajaj JS, Idilman R, Mabudian L, et al. Diet affects gut microbiota and modulates hospitalization risk differentially in an international cirrhosis cohort. Hepatology. 2018;68(1):234-247. doi:10.1002/hep.29791.
71. Kumar Singh A, Cabral C, Kumar R, et al. Beneficial Effects of Dietary Polyphenols on Gut Microbiota and Strategies to Improve Delivery Efficiency. Nutrients. 2019;11(9):2216. doi:10.3390/nu11092216.
72. Goh GB, Chow WC, Wang R, Yuan JM, Koh WP. Coffee, alcohol and other beverages in relation to cirrhosis mortality: the Singapore Chinese Health Study. Hepatology. 2014;60(2):661-669. doi:10.1002/hep.27054.
73. Jaquet M, Rochat I, Moulin J, Cavin C, Bibiloni R. Impact of coffee consumption on the gut microbiota: a human volunteer study. Int J Food Microbiol. 2009;130(2):117-121. doi:10.1016/j.ijfoodmicro.2009.01.011.
74. De Gottardi A, Berzigotti A, Seijo S, et al. Postprandial effects of dark chocolate on portal hypertension in patients with cirrhosis: results of a phase 2, double-blind, randomized controlled trial. Am J Clin Nutr. 2012;96(3):584-590. doi:10.3945/ajcn.112.040469.
75. Hussain SK, Dong TS, Agopian V, et al. Dietary Protein, Fiber and Coffee Are Associated with Small Intestine Microbiome Composition and Diversity in Patients with Liver Cirrhosis. Nutrients. 2020;12(5):1395.doi:10.3390/nu12051395.
76. Velasquez MT, Ramezani A, Manal A, Raj DS. Trimethylamine N-Oxide: The Good, the Bad and the Unknown. Toxins (Basel). 2016;8(11):326. doi:10.3390/toxins8110326.
77. Iebba V, Guerrieri F, Di Gregorio V, et al. Combining amplicon sequencing and metabolomics in cirrhotic patients highlights distinctive microbiota features involved in bacterial translocation, systemic inflammation and hepatic encephalopathy. Sci Rep. 2018;8(1):8210. doi:10.1038/s41598-018-26509-y.
78. Aragonès G, Colom-Pellicer M, Aguilar C, et al. Circulating microbiota-derived metabolites: a "liquid biopsy?. Int J Obes (Lond). 2020;44(4):875-885. doi:10.1038/s41366-019-0430-0.
79. Medina-Vera I, Sanchez-Tapia M, Noriega-López L, et al. A dietary intervention with functional foods reduces metabolic endotoxaemia and attenuates biochemical abnormalities by modifying faecal microbiota in people with type 2 diabetes. Diabetes Metab. 2019;45(2):122-131. doi:10.1016/j.diabet.2018.09.004.
80. 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. doi:10.1016/j.cgh.2013.11.006.
81. Agrawal A, Sharma BC, Sharma P, Sarin SK. Secondary prophylaxis of hepatic encephalopathy in cirrhosis: an open-label, randomized controlled trial of lactulose, probiotics, and no therapy. Am J Gastroenterol. 2012;107(7):1043-1050. doi:10.1038/ajg.2012.113.
82. McGee RG, Bakens A, Wiley K, Riordan SM, Webster AC. Probiotics for patients with hepatic encephalopathy. Cochrane Database Syst Rev. 2011;(11):CD008716. doi:10.1002/14651858.CD008716.pub2
83. Elwir S, Rahimi RS. Hepatic Encephalopathy: An Update on the Pathophysiology and Therapeutic Options. J Clin Tran sl Hepatol. 2017;5(2):142-51. doi: 10.14218/JCTH.2016.00069.
84. Liu JE, Zhang Y, Zhang J, Dong PL, Chen M, Duan ZP. Probiotic yogurt effects on intestinal flora of patients with chronic liver disease. Nurs Res. 2010;59(6):426-432. doi:10.1097/NNR.0b013e3181fa4dc6.
85. Cao Q, Yu CB, Yang SG, et al. Effect of probiotic treatment on cirrhotic patients with minimal hepatic encephalopathy: A meta-analysis. Hepatobiliary Pancreat Dis Int. 2018;17(1):9-16. doi:10.1016/j.hbpd.2018.01.005.
2. Asrani SK, Devarbhavi H, Eaton J, Kamath PS. Burden of liver diseases in the world. J Hepatol. 2019;70(1):151-71. doi:10.1016/j.jhep.2018.09.014.
3. Woodhouse CA, Patel VC, Singanayagam A, Shawcross DL. Review article: the gut microbiome as a therapeutic target in the pathogenesis and treatment of chronic liver disease. Aliment Pharmacol Ther. 2018;47(2):192-202. doi:10.1111/apt.14397.
4. Gunnarsdottir SA, Sadik R, Shev S, et al. Small intestinal motility disturbances and bacterial overgrowth in patients with liver cirrhosis and portal hypertension. Am J Gastroenterol. 2003;98(6):1362-70. doi:10.1016/S0002-9270(03)00250-8.
5. Thalheimer U, Triantos CK, Samonakis DN, Patch D, Burroughs AK. Infection, coagulation, and variceal bleeding in cirrhosis. Gut. 2005;54(4):556-63.doi:10.1136/gut.2004.048181.
6. Albillos A, de la Hera A, Gonzalez M, et al. Increased lipopolysaccharide binding protein in cirrhotic patients with marked immune and hemodynamic derangement. Hepatology. 2003;37(1):208-17.doi: 10.1053/jhep.2003.50038.
7. Gomez-Hurtado I, Such J, Sanz Y, Frances R. Gut microbiota-related complications in cirrhosis. World J Gastroenterol. 2014;20(42):15624-31. doi:10.3748/wjg.v20.i42.15624.
8. Thursby E, Juge N. Introduction to the human gut microbiota. Biochem J. 2017;474(11):1823-1836. doi:10.1042/BCJ20160510.
9. Ridlon JM, Alves JM, Hylemon PB, Bajaj JS. Cirrhosis, bile acids and gut microbiota: unraveling a complex relationship. Gut Microbes. 2013;4(5):382-7. doi:10.4161/gmic.25723.
10. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328-57.doi:10.1002/hep.29367.
11. Monteiro CA, Cannon G, Lawrence M, Costa Louzada ML, Pereira Machado P. 2019. Ultra-processed foods, diet quality, and health using the NOVA classification system. Rome, FAO.
12. Monteiro CA, Moubarac J., Cannon G, Ng S, Popkin B. Ultra-processed products are becoming dominant in the global food system. Obesity Rev. 2014; 2:21-28.doi: 10.1111/obr.12107.
13. Jarvis H, Craig D, Barker R, et al. Metabolic risk factors and incident advanced liver disease in non-alcoholic fatty liver disease (NAFLD): A systematic review and meta-analysis of population-based observational studies. PLoS Med.2020;17(4):e1003100. doi:10.1371/journal.pmed.1003100.
14. Zadeh SH, Mansoori A, Hosseinzadeh M. Relationship between dietary patterns and non-alcoholic fatty liver disease: A systematic review and meta-analysis. J Gastroenterol Hepatol. 2020.doi:10.1111/jgh.15363.
15. Eslam M, Newsome PN, Sarin SK, et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol. 2020;73(1):202-209. doi:10.1016/j.jhep.2020.03.039.
16. Di Lorenzo F, De Castro C, Silipo A, Molinaro A. Lipopolysaccharide structures of gram-negative populations in the gut microbiota and effects on host interactions. FEMS Microbiol Rev.2019;43(3):257-272. doi:10.1093/femsre/fuz002.
17. Moszak M, Szulińska M, Bogdański P. You Are What You Eat-The Relationship between Diet, Microbiota, and Metabolic Disorders-A Review. Nutrients. 2020;12(4):1096.doi: 10.3390/nu12041096.
18. Gentile CL, Weir T.L. The gut microbiota at the intersection of diet and human health. Science. 2018; 362:776–780.doi: 10.1126/science.aau5812.
19. Madsen L, Myrmel LS, Fjære E, Liaset B, Kristiansen K. Links between Dietary Protein Sources, the Gut Microbiota, and Obesity. Front Physiol. 2017; 8:1047.doi: 10.3389/fphys.2017.01047.
20. Zhao F, Huang Z, Zhou G, Li H, Xu X, Li C. Dietary proteins rapidly altered the microbial composition in rat caecum. Curr. Microbiol. 2017; 74:1447–1452. doi:10.1007/s00284-017-1339-2.
21. Fava F, Gitau R, Griffin BA, Gibson GR, Tuohy KM, Lovegrove JA. The type and quantity of dietary fat and carbohydrate alter faecal microbiome and short-chain fatty acid excretion in a metabolic syndrome 'at-risk' population. Int J Obes (Lond). 2013; 37(2):216-23. doi:10.1038/ijo.2012.33.
22. de Velasco P, Ferreira A, Crovesy L, Marine T, do Carmo MDGT. Biochemistry and Health Benefits of Fatty Acids. IntechOpen; London, UK: 2018. Fatty acids, gut microbiota, and the genesis of obesity.
23. Chiang JYL, Ferrell JM. Bile Acids as Metabolic Regulators and Nutrient Sensors. Annu Rev Nutr. 2019;39:175-200.doi:10.1146/annurev-nutr-082018-124344.
24. O'Flaherty S, Briner Crawley A, Theriot CM, Barrangou R. The Lactobacillus Bile Salt Hydrolase Repertoire Reveals Niche-Specific Adaptation. mSphere. 2018;3(3):e00140-18. doi:10.1128/mSphere.00140-18.
25. Zinöcker MK, Lindseth IA. The Western Diet-Microbiome-Host Interaction and Its Role in Metabolic Disease. Nutrients. 2018;10(3):365. doi:10.3390/nu10030365.
26. David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505(7484):559-63.doi: 10.1038/nature12820.
27. Sonnenburg ED, Smits SA, Tikhonov M, Higginbottom SK, Wingreen NS, Sonnenburg JL. Diet-induced extinctions in the gut microbiota compound over generations. Nature. 2016; 529(7585):212-5.doi: 10.1038/nature16504.
28. Agus A, Denizot J, Thévenot J, et al. Western diet induces a shift in microbiota composition enhancing susceptibility to Adherent-Invasive E. coli infection and intestinal inflammation. Sci Rep. 2016; 6:19032.doi:10.1038/srep19032.
29. Hildebrandt MA, Hoffmann C, Sherrill-Mix SA, et al. High-fat diet determines the composition of the murine gut microbiome independently of obesity. Gastroenterology 2009; 137:1716–24. doi:10.1053/j.gastro.2009.08.042 .
30. Caesar R, Tremaroli V, Kovatcheva-Datchary P, Cani PD, Bäckhed F. Crosstalk between Gut Microbiota and Dietary Lipids Aggravates WAT Inflammation through TLR Signaling. Cell Metab. 2015; 22(4):658-68. doi:10.1016/j.cmet.2015.07.026.
31. Wolters M, Ahrens J, Romaní-Pérez M, Watkins C, Sanz Y, Benítez-Páez A, et al. Dietary fat, the gut microbiota, and metabolic health - A systematic review conducted within the MyNewGut project. Clin Nutr. 2019; 38(6):2504-2520. doi:10.1016/j.clnu.2018.12.024.
32. Partridge D, Lloyd KA, Rhodes JM, Walker AW, Johnstone AM, Campbell BJ. Food additives: Assessing the impact of exposure to permitted emulsifiers on bowel and metabolic health - introducing the FADiets study. Nutr Bull. 2019;44(4):329-349.doi:10.1111/nbu.12408.
33. Schroeder BO, Birchenough GMH, Ståhlman M, et al. Bifidobacteria or Fiber Protects against Diet-Induced Microbiota-Mediated Colonic Mucus Deterioration. Cell Host Microbe. 2018; 23(1):27-40.e7. doi:10.1016/j.chom.2017.11.004.
34. Litwinowicz K., Choroszy M., Waszczuk E. Changes in the composition of the human intestinal microbiome in alcohol use disorder: A systematic review. Am. J. Drug Alcohol Abuse. 2020;46:4–12. doi:10.1080/00952990.2019.1669629.
35. Cani PD, Bibiloni R, Knauf C, et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008; 57:1470–81. doi:10.2337/db07-1403.
36. Desai MS, Seekatz AM, Koropatkin NM, et al. A Dietary Fiber-Deprived Gut Microbiota Degrades the Colonic Mucus Barrier and Enhances Pathogen Susceptibility. Cell. 2016;167(5):1339-1353.e21. doi:10.1016/j.cell.2016.10.043.
37. Mai BH, Yan LJ. The negative and detrimental effects of high fructose on the liver, with special reference to metabolic disorders. Diabetes Metab Syndr Obes. 2019;12:821-826. doi: 10.2147/DMSO.S198968.
38. Jensen T, Abdelmalek MF, Sullivan S, et al. Fructose and sugar: A major mediator of non-alcoholic fatty liver disease. J Hepatol. 2018;68(5):1063–1075. doi:10.1016/j.jhep.2018.01.019.
39. Choi Y, Abdelmegeed MA, Song BJ. Diet high in fructose promotes liver steatosis and hepatocyte apoptosis in C57BL/6J female mice: role of disturbed lipid homeostasis and increased oxidative stress. Food Chem Toxicol. 2017;103:111–121. doi:10.1016/j.fct.2017.02.039.
40. Sarin SK, Pande A, Schnabl B. Microbiome as a therapeutic target in alcohol-related liver disease. J Hepatol. 2019;70(2):260-72.doi: 10.1016/j.jhep.2018.10.019.
41. Lambertz J, Weiskirchen S, Landert S, Weiskirchen R. Fructose: a dietary sugar in crosstalk with microbiota contributing to the development and progression of non-alcoholic liver disease. Front Immunol. 2017;8:1159. doi:10.3389/fimmu.2017.01159.
42. Bajaj JS, Khoruts A. Microbiota changes and intestinal microbiota transplantation in liver diseases and cirrhosis. Journal of Hepatology. 2020; 72(5):1003-1027. doi:10.1016/j.jhep.2020.01.017.
43. Acharya C, Bajaj JS. Altered Microbiome in Patients With Cirrhosis and Complications. Clin Gastroenterol Hepatol. 2019;17(2):307-21. doi:10.1016/j.cgh.2018.08.008.
44. Kalaitzakis E. Gastrointestinal dysfunction in liver cirrhosis. World J Gastroenterol.2014; 20(40): 14686-14695. doi: 10.3748/wjg.v20.i40.14686.
45. Wang Y, Pan CQ, Xing H. Advances in Gut Microbiota of Viral Hepatitis Cirrhosis. BioMed Research International. 2019; doi:10.1155/2019/9726786.
46. Giannelli V, Di Gregorio V, Iebba V, et al. Microbiota and the gut-liver axis: bacterial translocation, inflammation and infection in cirrhosis. World J Gastroenterol. 2014;20(45):16795-810. doi:10.3748/wjg.v20.i45.16795.
47. Fukui H, Wiest R. Changes of Intestinal Functions in Liver Cirrhosis. Inflamm Intest Dis. 2016;1(1):24-40. doi:10.1159/000444436.
48. Nagasako CK, de Oliveira Figueiredo MJ, de Souza Almeida JR, et al. Investigation of autonomic function and orocecal transit time in patients with nonalcoholic cirrhosis and the potential influence of these factors on disease outcome. J Clin Gastroenterol. 2009;43(9):884-9. doi:10.1097/MCG.0b013e31818de34c.
49. Kalaitzakis E, Sadik R, Holst JJ, Ohman L, Björnsson E. Gut transit is associated with gastrointestinal symptoms and gut hormone profile in patients with cirrhosis. Clin Gastroenterol Hepatol. 2009;7(3):346-52.doi: 10.1016/j.cgh.2008.11.022.
50. 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):940-7. doi:10.1016/j.jhep.2013.12.019.
51. Saboo K, Shamsaddini A, Iyer MV, et al. Sex is associated with differences in gut microbial compositionand function in hepatic encephalopathy. J. Hepatol. 2021, 74, 80–88. doi:10.1016/j.jhep.2020.06.046.
52. Shah A, Shanahan E, Macdonald GA, et al. Systematic Review and Meta-Analysis: Prevalence of Small Intestinal Bacterial Overgrowth in Chronic Liver Disease. Semin Liver Dis. 2017;37(4):388-400. doi:10.1055/s-0037-1608832.
53. Campion D, Giovo I, Ponzo P, Saracco GM, Balzola F, Alessandria C. Dietary approach and gut microbiota modulation for chronic hepatic encephalopathy in cirrhosis. World J Hepatol. 2019;11(6):489-512. doi:10.4254/wjh.v11.i6.489.
54. Fasullo M, Rau P, Liu DQ, et al. Proton pump inhibitors increase the severity of hepatic encephalopathy in cirrhotic patients. World J Hepatol. 2019;11(6):522-30. doi:10.4254/wjh.v11.i6.522.
55. Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014;60(2):715-35. doi:10.1002/hep.27210.
56. Bale A, Pai CG, Shetty S, Balaraju G, Shetty A. Prevalence of and Factors Associated With Minimal Hepatic Encephalopathy in Patients With Cirrhosis of Liver. J Clin Exp Hepatol. 2018;8(2):156-61.doi:10.1016/j.jceh.2017.06.005.
57. EASL Clinical Practice Guidelines on nutrition in chronic liver disease. J Hepatol (2018). doi: 10.1016/j.jhep.2018.06.024.
58. Bajaj JS, Ridlon JM, Hylemon PB, et al. Linkage of gut microbiome with cognition in hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol. 2012;302(1):G168-G175. doi:10.1152/ajpgi.00190.2011.
59. Levitt DG, Levitt MD. A model of blood-ammonia homeostasis based on a quantitative analysis of nitrogen metabolism in the multiple organs involved in the production, catabolism, and excretion of ammonia in humans. Clin Exp Gastroenterol. 2018;11:193-215. doi: 10.2147/CEG.S160921.
60. Bajaj JS, Salzman NH, Acharya C, et al. Fecal Microbial Transplant Capsules Are Safe in Hepatic Encephalopathy: A Phase 1, Randomized, Placebo-Controlled Trial [published correction appears in Hepatology. 2020 Oct;72(4):1501]. Hepatology. 2019;70(5):1690-1703. doi:10.1002/hep.30690.
61. Bajaj JS, Heuman DM, Sterling RK, et al. Validation of EncephalApp, Smartphone-Based Stroop Test, for the Diagnosis of Covert Hepatic Encephalopathy. Clin Gastroenterol Hepatol. 2015;13(10):1828-1835.e1. doi:10.1016/j.cgh.2014.05.011.
62. Ni J, Huang R, Zhou H, et al. Analysis of the Relationship Between the Degree of Dysbiosis in Gut Microbiota and Prognosis at Different Stages of Primary Hepatocellular Carcinoma. Front Microbiol. 2019;10:1458. doi:10.3389/fmicb.2019.01458
63. Grohmann M, Wiede F, Dodd GT, et al. Obesity Drives STAT-1-Dependent NASH and STAT-3-Dependent HCC. Cell. 2018;175(5):1289-1306.e20. doi:10.1016/j.cell.2018.09.053.
64. Liu Q, Li F, Zhuang Y, et al. Alteration in gut microbiota associated with hepatitis B and non-hepatitis virus related hepatocellular carcinoma. Gut Pathog. 2019;11:1. doi:10.1186/s13099-018-0281-6.
65. Behary J, Amorim N, Jiang XT, et al. Gut microbiota impact on the peripheral immune response in non-alcoholic fatty liver disease related hepatocellular carcinoma. Nat Commun. 2021;12(1):187.doi:10.1038/s41467-020-20422-7.
66. Solé C, Guilly S, Da Silva K, et al. Alterations in Gut Microbiome in Cirrhosis as Assessed by Quantitative Metagenomics: Relationship With Acute-on-Chronic Liver Failure and Prognosis. Gastroenterology. 2021;160(1):206-218.e13. doi:10.1053/j.gastro.2020.08.054.
67. Bischoff SC, Bernal W, Dasarathy S, et al. ESPEN practical guideline: Clinical nutrition in liver disease. Clin Nutr. 2020;39(12):3533-3562. doi:10.1016/j.clnu.2020.09.001.
68. Tsien CD, McCullough AJ, Dasarathy S. Late evening snack: exploiting a period of anabolic opportunity in cirrhosis. J Gastroenterol Hepatol. 2012;27(3):430-441. doi:10.1111/j.1440-1746.2011.06951.x.
69. Bajaj JS, Torre A, Rojas ML, et al. Cognition and hospitalizations are linked with salivary and faecal microbiota in cirrhosis cohorts from the USA and Mexico. Liver Int 2020;40:1395–1407. doi: 10.1111/liv.14437.
70. Bajaj JS, Idilman R, Mabudian L, et al. Diet affects gut microbiota and modulates hospitalization risk differentially in an international cirrhosis cohort. Hepatology. 2018;68(1):234-247. doi:10.1002/hep.29791.
71. Kumar Singh A, Cabral C, Kumar R, et al. Beneficial Effects of Dietary Polyphenols on Gut Microbiota and Strategies to Improve Delivery Efficiency. Nutrients. 2019;11(9):2216. doi:10.3390/nu11092216.
72. Goh GB, Chow WC, Wang R, Yuan JM, Koh WP. Coffee, alcohol and other beverages in relation to cirrhosis mortality: the Singapore Chinese Health Study. Hepatology. 2014;60(2):661-669. doi:10.1002/hep.27054.
73. Jaquet M, Rochat I, Moulin J, Cavin C, Bibiloni R. Impact of coffee consumption on the gut microbiota: a human volunteer study. Int J Food Microbiol. 2009;130(2):117-121. doi:10.1016/j.ijfoodmicro.2009.01.011.
74. De Gottardi A, Berzigotti A, Seijo S, et al. Postprandial effects of dark chocolate on portal hypertension in patients with cirrhosis: results of a phase 2, double-blind, randomized controlled trial. Am J Clin Nutr. 2012;96(3):584-590. doi:10.3945/ajcn.112.040469.
75. Hussain SK, Dong TS, Agopian V, et al. Dietary Protein, Fiber and Coffee Are Associated with Small Intestine Microbiome Composition and Diversity in Patients with Liver Cirrhosis. Nutrients. 2020;12(5):1395.doi:10.3390/nu12051395.
76. Velasquez MT, Ramezani A, Manal A, Raj DS. Trimethylamine N-Oxide: The Good, the Bad and the Unknown. Toxins (Basel). 2016;8(11):326. doi:10.3390/toxins8110326.
77. Iebba V, Guerrieri F, Di Gregorio V, et al. Combining amplicon sequencing and metabolomics in cirrhotic patients highlights distinctive microbiota features involved in bacterial translocation, systemic inflammation and hepatic encephalopathy. Sci Rep. 2018;8(1):8210. doi:10.1038/s41598-018-26509-y.
78. Aragonès G, Colom-Pellicer M, Aguilar C, et al. Circulating microbiota-derived metabolites: a "liquid biopsy?. Int J Obes (Lond). 2020;44(4):875-885. doi:10.1038/s41366-019-0430-0.
79. Medina-Vera I, Sanchez-Tapia M, Noriega-López L, et al. A dietary intervention with functional foods reduces metabolic endotoxaemia and attenuates biochemical abnormalities by modifying faecal microbiota in people with type 2 diabetes. Diabetes Metab. 2019;45(2):122-131. doi:10.1016/j.diabet.2018.09.004.
80. 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. doi:10.1016/j.cgh.2013.11.006.
81. Agrawal A, Sharma BC, Sharma P, Sarin SK. Secondary prophylaxis of hepatic encephalopathy in cirrhosis: an open-label, randomized controlled trial of lactulose, probiotics, and no therapy. Am J Gastroenterol. 2012;107(7):1043-1050. doi:10.1038/ajg.2012.113.
82. McGee RG, Bakens A, Wiley K, Riordan SM, Webster AC. Probiotics for patients with hepatic encephalopathy. Cochrane Database Syst Rev. 2011;(11):CD008716. doi:10.1002/14651858.CD008716.pub2
83. Elwir S, Rahimi RS. Hepatic Encephalopathy: An Update on the Pathophysiology and Therapeutic Options. J Clin Tran sl Hepatol. 2017;5(2):142-51. doi: 10.14218/JCTH.2016.00069.
84. Liu JE, Zhang Y, Zhang J, Dong PL, Chen M, Duan ZP. Probiotic yogurt effects on intestinal flora of patients with chronic liver disease. Nurs Res. 2010;59(6):426-432. doi:10.1097/NNR.0b013e3181fa4dc6.
85. Cao Q, Yu CB, Yang SG, et al. Effect of probiotic treatment on cirrhotic patients with minimal hepatic encephalopathy: A meta-analysis. Hepatobiliary Pancreat Dis Int. 2018;17(1):9-16. doi:10.1016/j.hbpd.2018.01.005.