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DOI: 10.1055/s-0035-1562946
The Gut Microbiota and Nonalcoholic Fatty Liver Disease
Publication History
Publication Date:
17 September 2015 (online)
Abstract
With the recognition of the various metabolic functions of the gut microbiome and of its putative role in obesity, an investigation of the contribution of the bacterial populations of the gastrointestinal tract to the metabolic syndrome and its hepatic manifestation—nonalcoholic liver disease (NAFLD)—became inevitable. Furthermore, the central role of an altered microbiome in the precipitation of infectious and noninfectious complications of liver disease was described decades ago. The contribution of the microbiome to the pathogenesis of NAFLD has been extensively studied in animal models. Convincing evidence for a central role for an altered microbiome (through multiple mechanisms), coupled with such phenomena as impaired gut barrier function and an aberrant host immune response, has been amply demonstrated. The accumulation of a similar level of evidence from human studies has proven more challenging; however, incriminating data accumulate. Although animal studies have demonstrated the benefits of interventions that modulate the microbiome and of probiotics, in particular, in reducing steatosis and preventing progression to steatohepatitis, data in man are scanty and high-quality clinical trials of probiotics and other strategies are needed.
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References
- 1 Schnabl B, Brenner DA. Interactions between the intestinal microbiome and liver diseases. Gastroenterology 2014; 146 (6) 1513-1524
- 2 Abu-Shanab A, Quigley EM. The role of the gut microbiota in nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 2010; 7 (12) 691-701
- 3 Fraher MH, O'Toole PW, Quigley EMM. Techniques used to characterise the intestinal microbiota: a guide for the clinician. Nat Rev Gastroenterol Hepatol 2012; 9: 312-322
- 4 Nicholson JK, Holmes E, Kinross J , et al. Host-gut microbiota metabolic interactions. Science 2012; 336 (6086) 1262-1267
- 5 Cho I, Blaser MJ. The human microbiome: at the interface of health and disease. Nat Rev Genet 2012; 13 (4) 260-270
- 6 Miyake Y, Yamamoto K. Role of gut microbiota in liver diseases. Hepatol Res 2013; 43 (2) 139-146
- 7 Chassaing B, Etienne-Mesmin L, Gewirtz AT. Microbiota-liver axis in hepatic disease. Hepatology 2014; 59 (1) 328-339
- 8 Janssen AW, Kersten S. The role of the gut microbiota in metabolic health. FASEB J 2015; 29: 3111-3123
- 9 Quigley EM, Stanton C, Murphy EF. The gut microbiota and the liver. Pathophysiological and clinical implications. J Hepatol 2013; 58 (5) 1020-1027
- 10 Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci 2012; 13 (10) 701-712
- 11 Mayer EA, Tillisch K, Gupta A. Gut/brain axis and the microbiota. J Clin Invest 2015; 125 (3) 926-938
- 12 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 (5) 1716-24.e1 , 2
- 13 Moschen AR, Wieser V, Tilg H. Dietary factors: major regulators of the gut's microbiota. Gut Liver 2012; 6 (4) 411-416
- 14 Clarke SF, Murphy EF, Nilaweera K , et al. The gut microbiota and its relationship to diet and obesity: new insights. Gut Microbes 2012; 3 (3) 186-202
- 15 Claesson MJ, Jeffery IB, Conde S , et al. Gut microbiota composition correlates with diet and health in the elderly. Nature 2012; 488 (7410) 178-184
- 16 Hacquard S, Garrido-Oter R, González A , et al. Microbiota and Host Nutrition across Plant and Animal Kingdoms. Cell Host Microbe 2015; 17 (5) 603-616
- 17 Doré J, Blottière H. The influence of diet on the gut microbiota and its consequences for health. Curr Opin Biotechnol 2015; 32: 195-199
- 18 Yatsunenko T, Rey FE, Manary MJ , et al. Human gut microbiome viewed across age and geography. Nature 2012; 486 (7402) 222-227
- 19 Mutlu EA, Gillevet PM, Rangwala H , et al. Colonic microbiome is altered in alcoholism. Am J Physiol Gastrointest Liver Physiol 2012; 302 (9) G966-G978
- 20 Jernberg C, Löfmark S, Edlund C, Jansson JK. Long-term ecological impacts of antibiotic administration on the human intestinal microbiota. ISME J 2007; 1 (1) 56-66
- 21 Fouhy F, Guinane CM, Hussey S , et al. High-throughput sequencing reveals the incomplete, short-term recovery of infant gut microbiota following parenteral antibiotic treatment with ampicillin and gentamicin. Antimicrob Agents Chemother 2012; 56 (11) 5811-5820
- 22 Cox LM, Blaser MJ. Antibiotics in early life and obesity. Nat Rev Endocrinol 2015; 11 (3) 182-190
- 23 Cho I, Yamanishi S, Cox L , et al. Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature 2012; 488 (7413) 621-626
- 24 Lobstein T, Jackson-Leach R, Moodie ML , et al. Child and adolescent obesity: part of a bigger picture. Lancet 2015; ;(e-pub ahead of print)
- 25 Nobili V, Alkhouri N, Alisi A , et al. Nonalcoholic fatty liver disease: a challenge for pediatricians. JAMA Pediatr 2015; 169 (2) 170-176
- 26 Sayin SI, Wahlström A, Felin J , et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab 2013; 17 (2) 225-235
- 27 Li F, Jiang C, Krausz KW , et al. Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nat Commun 2013; 4: 2384
- 28 Szabo G, Bala S, Petrasek J, Gattu A. Gut-liver axis and sensing microbes. Dig Dis 2010; 28 (6) 737-744
- 29 Quigley EMM, Marsh MN, Shaffer JL, Markin RS. Hepatobiliary complications of total parenteral nutrition. Gastroenterology 1993; 104 (1) 286-301
- 30 Terjung B, Spengler U. Atypical p-ANCA in PSC and AIH: a hint toward a “leaky gut”?. Clin Rev Allergy Immunol 2009; 36 (1) 40-51
- 31 Terjung B, Söhne J, Lechtenberg B , et al. p-ANCAs in autoimmune liver disorders recognise human beta-tubulin isotype 5 and cross-react with microbial protein FtsZ. Gut 2010; 59 (6) 808-816
- 32 Quigley EM. Gastrointestinal dysfunction in liver disease and portal hypertension. Gut-liver interactions revisited. Dig Dis Sci 1996; 41 (3) 557-561
- 33 Thalheimer U, Triantos CK, Samonakis DN, Patch D, Burroughs AK. Infection, coagulation, and variceal bleeding in cirrhosis. Gut 2005; 54 (4) 556-563
- 34 Fukui H. Gut-liver axis in liver cirrhosis: How to manage leaky gut and endotoxemia. World J Hepatol 2015; 7 (3) 425-442
- 35 Teltschik Z, Wiest R, Beisner J , et al. Intestinal bacterial translocation in rats with cirrhosis is related to compromised Paneth cell antimicrobial host defense. Hepatology 2012; 55 (4) 1154-1163
- 36 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 (2) 206-211
- 37 Shanab AA, Scully P, Crosbie O , et al. Small intestinal bacterial overgrowth in nonalcoholic steatohepatitis: association with toll-like receptor 4 expression and plasma levels of interleukin 8. Dig Dis Sci 2011; 56 (5) 1524-1534
- 38 Bajaj JS, Hylemon PB, Ridlon JM , et al. Colonic mucosal microbiome differs from stool microbiome in cirrhosis and hepatic encephalopathy and is linked to cognition and inflammation. Am J Physiol Gastrointest Liver Physiol 2012; 303 (6) G675-G685
- 39 Qin N, Yang F, Li A , et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 2014; 513 (7516) 59-64
- 40 Bajaj JS, Heuman DM, Hylemon PB , et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J Hepatol 2014; 60 (5) 940-947
- 41 Machado MV, Cortez-Pinto H. Gut microbiota and nonalcoholic fatty liver disease. Ann Hepatol 2012; 11 (4) 440-449
- 42 Ley RE, Bäckhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI. Obesity alters gut microbial ecology. Proc Natl Acad Sci U S A 2005; 102 (31) 11070-11075
- 43 Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006; 444 (7122) 1027-1031
- 44 Turnbaugh PJ, Gordon JI. The core gut microbiome, energy balance and obesity. J Physiol 2009; 587 (Pt 17) 4153-4158
- 45 Turnbaugh PJ, Hamady M, Yatsunenko T , et al. A core gut microbiome in obese and lean twins. Nature 2009; 457 (7228) 480-484
- 46 Murphy EF, Cotter PD, Healy S , et al. Composition and energy harvesting capacity of the gut microbiota: relationship to diet, obesity and time in mouse models. Gut 2010; 59 (12) 1635-1642
- 47 Parks BW, Nam E, Org E , et al. Genetic control of obesity and gut microbiota composition in response to high-fat, high-sucrose diet in mice. Cell Metab 2013; 17 (1) 141-152
- 48 Everard A, Belzer C, Geurts L , et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A 2013; 110 (22) 9066-9071
- 49 Greenblum S, Turnbaugh PJ, Borenstein E. Metagenomic systems biology of the human gut microbiome reveals topological shifts associated with obesity and inflammatory bowel disease. Proc Natl Acad Sci U S A 2012; 109 (2) 594-599
- 50 de Vos WM, Nieuwdorp M. Genomics: A gut prediction. Nature 2013; 498 (7452) 48-49
- 51 Karlsson FH, Tremaroli V, Nookaew I , et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 2013; 498 (7452) 99-103
- 52 Zupancic ML, Cantarel BL, Liu Z , et al. Analysis of the gut microbiota in the old order Amish and its relation to the metabolic syndrome. PLoS ONE 2012; 7 (8) e43052
- 53 Penas-Steinhardt A, Barcos LS, Belforte FS , et al. Functional characterization of TLR4 +3725 G/C polymorphism and association with protection against overweight. PLoS ONE 2012; 7 (12) e50992
- 54 Kim K-A, Gu W, Lee I-A, Joh E-H, Kim D-H. High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway. PLoS ONE 2012; 7 (10) e47713
- 55 Vijay-Kumar M, Aitken JD, Carvalho FA , et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 2010; 328 (5975) 228-231
- 56 Raman M, Ahmed I, Gillevet PM , et al. Fecal microbiome and volatile organic compound metabolome in obese humans with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2013; 11 (7) 868-75.e1 , 3
- 57 Mouzaki M, Comelli EM, Arendt BM , et al. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology 2013; 58 (1) 120-127
- 58 Zhu L, Baker SS, Gill C , et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 2013; 57 (2) 601-609
- 59 Le Roy T, Llopis M, Lepage P , et al. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut 2013; 62 (12) 1787-1794
- 60 Wong VW-S, Tse C-H, Lam TT-Y , et al. Molecular characterization of the fecal microbiota in patients with nonalcoholic steatohepatitis—a longitudinal study. PLoS ONE 2013; 8 (4) e62885
- 61 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
- 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
- 63 Spencer MD, Hamp TJ, Reid RW, Fischer LM, Zeisel SH, Fodor AA. Association between composition of the human gastrointestinal microbiome and development of fatty liver with choline deficiency. Gastroenterology 2011; 140 (3) 976-986
- 64 Michail S, Lin M, Frey MR , et al. Altered gut microbial energy and metabolism in children with non-alcoholic fatty liver disease. FEMS Microbiol Ecol 2015; 91 (2) 1-9
- 65 Engstler AJ, Aumiller T, Degen C , et al. Insulin resistance alters hepatic ethanol metabolism: studies in mice and children with non-alcoholic fatty liver disease. Gut 2015; ; [Epub ahead of print]
- 66 Henao-Mejia J, Elinav E, Jin C , et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 2012; 482 (7384) 179-185
- 67 Sawada K, Ohtake T, Hasebe T , et al. Augmented hepatic Toll-like receptors by fatty acids trigger the pro-inflammatory state of non-alcoholic fatty liver disease in mice. Hepatol Res 2014; 44 (8) 920-934
- 68 Wagnerberger S, Spruss A, Kanuri G , et al. Toll-like receptors 1-9 are elevated in livers with fructose-induced hepatic steatosis. Br J Nutr 2012; 107 (12) 1727-1738
- 69 Miura K, Ohnishi H. Role of gut microbiota and Toll-like receptors in nonalcoholic fatty liver disease. World J Gastroenterol 2014; 20 (23) 7381-7391
- 70 Seki E, Schnabl B. Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut. J Physiol 2012; 590 (Pt 3) 447-458
- 71 Jiang C, Xie C, Li F , et al. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J Clin Invest 2015; 125 (1) 386-402
- 72 Crispe IN. The liver as a lymphoid organ. Annu Rev Immunol 2009; 27: 147-163
- 73 Seo YS, Shah VH. The role of gut-liver axis in the pathogenesis of liver cirrhosis and portal hypertension. Clin Mol Hepatol 2012; 18 (4) 337-346
- 74 Catalá M, Antón A, Portolés MT. Characterization of the simultaneous binding of Escherichia coli endotoxin to Kupffer and endothelial liver cells by flow cytometry. Cytometry 1999; 36 (2) 123-130
- 75 Deng M, Scott MJ, Loughran P , et al. Lipopolysaccharide clearance, bacterial clearance, and systemic inflammatory responses are regulated by cell type-specific functions of TLR4 during sepsis. J Immunol 2013; 190 (10) 5152-5160
- 76 Hoque R, Vodovotz Y, Mehal W. Therapeutic strategies in inflammasome mediated diseases of the liver. J Hepatol 2013; 58 (5) 1047-1052
- 77 De Minicis S, Rychlicki C, Agostinelli L , et al. Dysbiosis contributes to fibrogenesis in the course of chronic liver injury in mice. Hepatology 2014; 59 (5) 1738-1749
- 78 Fox JG, Feng Y, Theve EJ , et al. Gut microbes define liver cancer risk in mice exposed to chemical and viral transgenic hepatocarcinogens. Gut 2010; 59 (1) 88-97
- 79 Yoshimoto S, Loo TM, Atarashi K , et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 2013; 499 (7456) 97-101
- 80 Bindels LB, Porporato P, Dewulf EM , et al. Gut microbiota-derived propionate reduces cancer cell proliferation in the liver. Br J Cancer 2012; 107 (8) 1337-1344
- 81 Barclay AR, Beattie LM, Weaver LT, Wilson DC. Systematic review: medical and nutritional interventions for the management of intestinal failure and its resultant complications in children. Aliment Pharmacol Ther 2011; 33 (2) 175-184
- 82 Li Z, Yang S, Lin H , et al. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology 2003; 37 (2) 343-350
- 83 Ma X, Hua J, Li Z. Probiotics improve high fat diet-induced hepatic steatosis and insulin resistance by increasing hepatic NKT cells. J Hepatol 2008; 49 (5) 821-830
- 84 Velayudham A, Dolganiuc A, Ellis M , et al. VSL#3 probiotic treatment attenuates fibrosis without changes in steatohepatitis in a diet-induced nonalcoholic steatohepatitis model in mice. Hepatology 2009; 49 (3) 989-997
- 85 Xu RY, Wan YP, Fang QY, Lu W, Cai W. Supplementation with probiotics modifies gut flora and attenuates liver fat accumulation in rat nonalcoholic fatty liver disease model. J Clin Biochem Nutr 2012; 50 (1) 72-77
- 86 Wagnerberger S, Spruss A, Kanuri G , et al. Lactobacillus casei Shirota protects from fructose-induced liver steatosis: a mouse model. J Nutr Biochem 2013; 24 (3) 531-538
- 87 Okubo H, Sakoda H, Kushiyama A , et al. Lactobacillus casei strain Shirota protects against nonalcoholic steatohepatitis development in a rodent model. Am J Physiol Gastrointest Liver Physiol 2013; 305 (12) G911-G918
- 88 Ritze Y, Bárdos G, Claus A , et al. Lactobacillus rhamnosus GG protects against non-alcoholic fatty liver disease in mice. PLoS ONE 2014; 9 (1) e80169
- 89 Cani PD, Possemiers S, Van de Wiele T , et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 2009; 58 (8) 1091-1103
- 90 Pachikian BD, Essaghir A, Demoulin JB , et al. Prebiotic approach alleviates hepatic steatosis: implication of fatty acid oxidative and cholesterol synthesis pathways. Mol Nutr Food Res 2013; 57 (2) 347-359
- 91 Ferolla SM, Armiliato GN, Couto CA, Ferrari TC. Probiotics as a complementary therapeutic approach in nonalcoholic fatty liver disease. World J Hepatol 2015; 7 (3) 559-565
- 92 Lirussi F, Mastropasqua E, Orando S, Orlando R. Probiotics for non-alcoholic fatty liver disease and/or steatohepatitis. Cochrane Database Syst Rev 2007; (1) CD005165
- 93 Tarantino G, Finelli C. Systematic review on intervention with prebiotics/probiotics in patients with obesity-related nonalcoholic fatty liver disease. Future Microbiol 2015; 10: 889-902
- 94 Gratz SW, Mykkanen H, El-Nezami HS. Probiotics and gut health: a special focus on liver diseases. World J Gastroenterol 2010; 16 (4) 403-410
- 95 Lata J, Jurankova J, Kopacova M, Vitek P. Probiotics in hepatology. World J Gastroenterol 2011; 17 (24) 2890-2896
- 96 Paolella G, Mandato C, Pierri L, Poeta M, Di Stasi M, Vajro P. Gut-liver axis and probiotics: their role in non-alcoholic fatty liver disease. World J Gastroenterol 2014; 20 (42) 15518-15531
- 97 Buss C, Valle-Tovo C, Miozzo S, Alves de Mattos A. Probiotics and synbiotics may improve liver aminotransferases levels in non-alcoholic fatty liver disease patients. Ann Hepatol 2014; 13 (5) 482-488
- 98 Compare D, Coccoli P, Rocco A , et al. Gut—liver axis: the impact of gut microbiota on non alcoholic fatty liver disease. Nutr Metab Cardiovasc Dis 2012; 22 (6) 471-476
- 99 Ma YY, Li L, Yu CH, Shen Z, Chen LH, Li YM. Effects of probiotics on nonalcoholic fatty liver disease: a meta-analysis. World J Gastroenterol 2013; 19 (40) 6911-6918
- 100 Malaguarnera M, Vacante M, Antic T , et al. Bifidobacterium longum with fructo-oligosaccharides in patients with non alcoholic steatohepatitis. Dig Dis Sci 2012; 57 (2) 545-553
- 101 Alisi A, Bedogni G, Baviera G , et al. Randomised clinical trial: The beneficial effects of VSL#3 in obese children with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2014; 39 (11) 1276-1285
- 102 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 (4) 913-6.e7