eISSN: 1896-9151
ISSN: 1734-1922
Archives of Medical Science
Current issue Archive Manuscripts accepted About the journal Special issues Editorial board Abstracting and indexing Subscription Contact Instructions for authors
SCImago Journal & Country Rank
vol. 14

The role of intestinal microbiota in the pathogenesis of NAFLD: starting points for intervention

Umberto Vespasiani-Gentilucci, Paolo Gallo, Antonio Picardi

Arch Med Sci 2018; 14, 3: 701–706
Online publish date: 2016/03/23
View full text
Get citation
JabRef, Mendeley
Papers, Reference Manager, RefWorks, Zotero
In recent years, close links between intestinal microbiota and host metabolism have been recognized. Intestinal bacteria can participate in the extraction of calories from food, and circulation of bacterial products, in particular lipopolysaccharides (LPS), is responsible for the “metabolic endotoxemia”, which contributes to insulin resistance and its complications, such as non-alcoholic fatty liver disease (NAFLD). Indeed, qualitative and quantitative intestinal dysbiotic changes have been clearly documented in NAFLD patients, and several mechanisms by which the intestinal microbiota can directly promote liver fat deposition, inflammation and fibrosis have also been described. Consistently, although with some differences concerning type and proportion of results, experimental and clinical studies are quite concordant in demonstrating beneficial effects of probiotic and/or prebiotic therapy in NAFLD. Although some physiopathological bases have been produced, major doubts still remain concerning how and when to intervene. Indeed, most of the available works were performed with mixtures of probiotics and/or prebiotics, and a baseline assessment of dysbiosis aimed at selecting the best candidates for treatment and predicting response has not been performed in any of the clinical studies in NAFLD. While future research is expected to solve these issues, the particularly favorable safety profile suggests that probiotic/prebiotic therapy could already be “tested” in NAFLD patients on an individual basis, at least once all the measures recommended by the latest guidelines have failed.

intestinal microbiota, non-alcoholic fatty liver disease, dysbiosis, small intestinal bacterial overgrowth, probiotics, prebiotics, lipopolysaccharides, lipopolysaccharide binding protein

Tremaroli V, Bäckhed F. Functional interactions between the gut microbiota and host metabolism. Nature 2012; 489: 242-9.
Kau AL, Ahern PP, Griffin NW, Goodman AL, Gordon JI. Human nutrition, the gut microbiome and the immune system. Nature 2011; 474: 327-36.
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: 1027-131.
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.
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: 1091-103.
Tilg H, Moschen AR. Inflammatory mechanisms in the regulation of insulin resistance. Mol Med Camb Mass 2008; 14: 222-31.
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: 868-75.
Mouzaki M, Comelli EM, Arendt BM, et al. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatol Baltim Md 2013; 58: 120-7.
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: 601-9.
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: 976-86.
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: e62885.
Miele L, Valenza V, La Torre G, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 2009; 49: 1877-87.
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: 371-7.
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: 206-11.
Vespasiani-Gentilucci U, Carotti S, Onetti-Muda A, et al. Toll-like receptor-4 expression by hepatic progenitor cells and biliary epithelial cells in HCV-related chronic liver disease. Mod Pathol 2012; 25: 576-89.
Vespasiani-Gentilucci U, Carotti S, Perrone G, et al. Hepatic toll-like receptor 4 expression is associated with portal inflammation and fibrosis in patients with NAFLD. Liver Int 2015; 35: 569-81.
Carotti S, Vespasiani-Gentilucci U, Perrone G, Picardi A, Morini S. Portal inflammation during NAFLD is frequent and associated with the early phases of putative hepatic progenitor cell activation. J Clin Pathol 2015; 68: 883-90.
Moschen AR, Kaser S, Tilg H. Non-alcoholic steatohepatitis: a microbiota-driven disease. Trends Endocrinol Metab 2013; 24: 537-45.
Cope K, Risby T, Diehl AM. Increased gastrointestinal ethanol production in obese mice: implications for fatty liver disease pathogenesis. Gastroenterology 2000; 119: 1340-7.
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 USA 2006; 103: 12511-6.
Abu-Shanab A, Quigley EM. The role of the gut microbiota in nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 2010;7: 691-701.
Hylemon PB, Zhou H, Pandak WM, Ren S, Gil G, Dent P. Bile acids as regulatory molecules. J Lipid Res 2009; 50: 1509-20.
Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, Gonzalez FJ. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 2000; 102: 731-44.
Prawitt J, Abdelkarim M, Stroeve JHM, et al. Farnesoid X receptor deficiency improves glucose homeostasis in mouse models of obesity. Diabetes 2011; 60: 1861-71.
Thomas C, Gioiello A, Noriega L, et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab 2009; 10: 167-77.
Duboc H, Rajca S, Rainteau D, et al. Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases. Gut 2013; 62: 531-9.
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: 15518-31.
Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota. Introducing the concept of prebiotics. J Nutr 1995; 125: 1401-12.
Havenaar R, Huis In’t Veld MJH. Probiotics: a general view. In: Lactic acid bacteria in health and disease. Vol 1. Amsterdam: Elsevier Applied Science Publishers 1992.
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: 343-50.
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: 821-30.
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: 989-97.
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: 540-3.
Aller R, De Luis DA, Izaola O, et al. Effect of a probiotic on liver aminotransferase in nonalcoholic fatty liver disease patients: a double blind randomized clinical trial. Eur Rev Med Pharmacol Sci 2011; 5: 1090-5.
Wong VW1, Won GL, Chim AM, et al. Treatment of nonalcoholic steatohepatitis with probiotics. A proof-of-concept study. Ann Hepatol 2013; 12: 256-62.
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: 1276-85.
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: 531-8.
Raso GM, Simeoli R, Iacono A, et al. Effects of a Lactobacillus paracasei B21060 based synbiotic on steatosis, insulin signaling and toll-like receptor expression in rats fed a high-fat diet. J Nutr Biochem 2014; 25: 81-90.
Endo H, Niioka M, Kobayashi N, Tanaka M, Watanabe T. Butyrate-producing probiotics reduce nonalcoholic fatty liver disease progression in rats: new insight into the probiotics for the gut-liver axis. PloS One 2013; 8: e63388.
Suzuki T. Regulation of intestinal epithelial permeability by tight junctions. Cell Mol Life Sci 2013; 70: 631-59.
Lirussi F, Mastropasqua E, Orando S, Orlando R. Probiotics for non-alcoholic fatty liver disease and/or steatohepatitis. Cochrane Database Syst Rev 2007; 24: CD005165.
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: 6911-8.
Shavakhi A, Minakari M, Firouzian H, Assali R, Hekmatdoost A, Ferns G. Effect of a probiotic and metformin on liver aminotransferases in non-alcoholic steatohepatitis: a double blind randomized clinical trial. Int J Prev Med 2013; 4: 531-7.
NCT02009592. Efficacy of rifaximin on hepatosteatosis and steatohepatitis patients.
Kalambokis GN, Tsianos EV. Rifaximin reduces endotoxemia and improves liver function and disease severity in patients with decompensated cirrhosis. Hepatology 2012; 55: 655-6.
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: 913-6.
Grace E, Shaw C, Whelan K, Andreyev HJN. Review article: small intestinal bacterial overgrowth: prevalence, clinical features, current and developing diagnostic tests, and treatment. Aliment Pharmacol Ther 2013; 38: 674-88.
Novitsky TJ. Limitations of the Limulus Amebocyte Lysate Test in demonstrating circulating lipopolysaccharides. Ann N Y Acad Sci 1998; 851: 416-21.
Schumann RR, Leong SR, Flaggs GW, et al. Structure and function of lipopolysaccharide binding protein. Science 1990; 249: 1429-31.
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: 1374-80.
Papaetis GS, Papakyriakou P, Panagiotou TN. Central obesity, type 2 diabetes and insulin: exploring a pathway full of thorns. Arch Med Sci 2015; 11: 463-82.
Bhagat U, Das UN. Potential role of dietary lipids in the prophylaxis of some clinical conditions. Arch Med Sci 2015; 11: 807-18.
Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012; 55: 2005-23.
Quick links
© 2019 Termedia Sp. z o.o. All rights reserved.
Developed by Bentus.
PayU - płatności internetowe