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The Influence of Gut Microbial Metabolism on the Development and Progression of Non-alcoholic Fatty Liver Disease

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Obesity, Fatty Liver and Liver Cancer

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1061))

Abstract

Non-alcoholic fatty liver disease (NAFLD) is defined as the presence of excess fat in the liver parenchyma in the absence of excess alcohol consumption and overt inflammation. It has also been described as the hepatic manifestation of metabolic syndrome (Than NN, Newsome PN, Atherosclerosis. 239:192–202, 2015). The incidence of NAFLD has been reported to be 43–60% in diabetics, ~90% in patients with hyperlipidemia and 91% in morbidly obese patients (Than NN, Newsome PN, Atherosclerosis. 239:192–202, 2015, Machado M, Marques-Vidal P, Cortez-Pinto H, J Hepatol, 45:600–606, 2006, Vernon G, Baranova A, Younossi ZM, Aliment Pharmacol Ther, 34:274–285, 2011). The risk factors that have been associated with the development of NAFLD include male gender, increasing age, obesity, insulin resistance, diabetes and hyperlipidemia (Attar BM, Van Thiel DH, Sci World J, 2013:481893, 2013, Gaggini M, Morelli M, Buzzigoli E, DeFronzo RA, Bugianesi E, Gastaldelli A, Forum Nutr, 5:1544–1460, 2013). All of these risk factors have been linked to alterations of the gut microbiota, ie., gut dysbiosis (He X, Ji G, Jia W, Li H, Int J Mol Sci, 17:300, 2016). However, it must be pointed out that the prevalence of NAFLD in normal weight individuals without metabolic risk factors is ~16% (Than NN, Newsome PN, Atherosclerosis. 239:192–202, 2015). This fact has led some investigators to hypothesize that the gut microbiota can impact lipid metabolism in the liver independently of obesity-related metabolic factors (Marchesi JR, Adams DH, Fava F, Hermes GD, Hirschfield GM, Hold g, et al., Gut, 65:330 339, 2016) (Le Roy T, Llopis M, Lepage P, Bruneau A, Rabot S, Bevilacqua C, et al., Gut, 62:1787–1794, 2013). In this chapter, we will explore the effect of the gut microbiota on hepatic lipid metabolism and how this affects the development of NAFLD.

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References

  1. Than NN, Newsome PN. A concise review of non-alcoholic fatty liver disease. Atherosclerosis. 2015;239:192–202.

    Article  CAS  PubMed  Google Scholar 

  2. Machado M, Marques-Vidal P, Cortez-Pinto H. Hepatic histology in obese patients undergoing bariatric surgery. J Hepatol. 2006;45:600–6.

    Article  PubMed  Google Scholar 

  3. Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011;34:274–85.

    Article  CAS  PubMed  Google Scholar 

  4. Attar BM, Van Thiel DH. Current concepts and management approaches in nonalcoholic fatty liver disease. Sci World J. 2013;2013:481893.

    Article  CAS  Google Scholar 

  5. Gaggini M, Morelli M, Buzzigoli E, DeFronzo RA, Bugianesi E, Gastaldelli A. Non-alcoholic fatty liver disease (NAFLD) and its connection with insulin resistance, dyslipidemia, atherosclerosis and coronary heart disease. Forum Nutr. 2013;5:1544–60.

    CAS  Google Scholar 

  6. He X, Ji G, Jia W, Li H. Gut microbiota and nonalcoholic fatty liver disease: insights on mechanism and application of metabolomics. Int J Mol Sci. 2016;17:300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Marchesi JR, Adams DH, Fava F, Hermes GD, Hirschfield GM, Hold G, et al. The gut microbiota and host health: a new clinical frontier. Gut. 2016;65:330–9.

    Article  PubMed  Google Scholar 

  8. Le Roy T, Llopis M, Lepage P, Bruneau A, Rabot S, Bevilacqua C, et al. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut. 2013;62:1787–94.

    Article  CAS  PubMed  Google Scholar 

  9. Fearnside JF, Dumas ME, Rothwell AR, Wilder SP, Cloarec O, Toye A, et al. Phylometabonomic patterns of adaptation to high fat diet feeding in inbred mice. PLoS One. 2008;3:e1668.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Rabot S, Membrez M, Bruneau A, Gerard P, Harach T, Moser M, et al. Germ-free C57BL/6J mice are resistant to high-fat-diet-induced insulin resistance and have altered cholesterol metabolism. FASEB J. 2010;24:4948–59.

    Article  CAS  PubMed  Google Scholar 

  11. Backhed F, Manchester JK, Semenkovich CF, Gordon JI. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci U S A. 2007;104:979–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Serino M, Luche E, Gres S, Baylac A, Berge M, Cenac C, et al. Metabolic adaptation to a high-fat diet is associated with a change in the gut microbiota. Gut. 2012;61:543–53.

    Article  CAS  PubMed  Google Scholar 

  13. Musso G, Gambino R, Cassader M. Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD). Prog Lipid Res. 2009;48:1–26.

    Article  CAS  PubMed  Google Scholar 

  14. Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature. 2012;482:179–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wu X, Ma C, Han L, Nawaz M, Gao F, Zhang X, et al. Molecular characterisation of the faecal microbiota in patients with type II diabetes. Curr Microbiol. 2010;61:69–78.

    Article  CAS  PubMed  Google Scholar 

  16. Bechmann LP, Hannivoort RA, Gerken G, Hotamisligil GS, Trauner M, Canbay A. The interaction of hepatic lipid and glucose metabolism in liver diseases. J Hepatol. 2012;56:952–64.

    Article  CAS  PubMed  Google Scholar 

  17. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115:1343–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Liu HY, Han J, Cao SY, Hong T, Zhuo D, Shi J, et al. Hepatic autophagy is suppressed in the presence of insulin resistance and hyperinsulinemia: inhibition of FoxO1-dependent expression of key autophagy genes by insulin. J Biol Chem. 2009;284:31484–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Dentin R, Girard J, Postic C. Carbohydrate responsive element binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c): two key regulators of glucose metabolism and lipid synthesis in liver. Biochimie. 2005;87:81–6.

    Article  CAS  PubMed  Google Scholar 

  20. Denechaud PD, Dentin R, Girard J, Postic C. Role of ChREBP in hepatic steatosis and insulin resistance. FEBS Lett. 2008;582:68–73.

    Article  CAS  PubMed  Google Scholar 

  21. Berlanga A, Guiu-Jurado E, Porras JA, Auguet T. Molecular pathways in non-alcoholic fatty liver disease. Clin Exp Gastroenterol. 2014;7:221–39.

    PubMed  PubMed Central  Google Scholar 

  22. Li T, Chiang JY. Bile acid signaling in metabolic disease and drug therapy. Pharmacol Rev. 2014;66:948–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhang Y, Lee FY, Barrera G, Lee H, Vales C, Gonzalez FJ, et al. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc Natl Acad Sci U S A. 2006;103:1006–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Li Y, Jadhav K, Zhang Y. Bile acid receptors in non-alcoholic fatty liver disease. Biochem Pharmacol. 2013;86:1517–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ip E, Farrell GC, Robertson G, Hall P, Kirsch R, Leclercq I. Central role of PPARalpha-dependent hepatic lipid turnover in dietary steatohepatitis in mice. Hepatology. 2003;38:123–32.

    Article  CAS  PubMed  Google Scholar 

  26. Kashireddy PV, Rao MS. Lack of peroxisome proliferator-activated receptor alpha in mice enhances methionine and choline deficient diet-induced steatohepatitis. Hepatol Res. 2004;30:104–10.

    Article  CAS  PubMed  Google Scholar 

  27. Ip E, Farrell G, Hall P, Robertson G, Leclercq I. Administration of the potent PPARalpha agonist, Wy-14,643, reverses nutritional fibrosis and steatohepatitis in mice. Hepatology. 2004;39:1286–96.

    Article  CAS  PubMed  Google Scholar 

  28. Tailleux A, Wouters K, Staels B. Roles of PPARs in NAFLD: potential therapeutic targets. Biochim Biophys Acta. 2012;1821:809–18.

    Article  CAS  PubMed  Google Scholar 

  29. Holland WL, Adams AC, Brozinick JT, Bui HH, Miyauchi Y, Kusminski CM, et al. An FGF21-adiponectin-ceramide axis controls energy expenditure and insulin action in mice. Cell Metab. 2013;17:790–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ge X, Chen C, Hui X, Wang Y, Lam KS, Xu A. Fibroblast growth factor 21 induces glucose transporter-1 expression through activation of the serum response factor/Ets-like protein-1 in adipocytes. J Biol Chem. 2011;286:34533–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Claudel T, Inoue Y, Barbier O, Duran-Sandoval D, Kosykh V, Fruchart J, et al. Farnesoid X receptor agonists suppress hepatic apolipoprotein CIII expression. Gastroenterology. 2003;125:544–55.

    Article  CAS  PubMed  Google Scholar 

  32. Claudel T, Sturm E, Duez H, Torra IP, Sirvent A, Kosykh V, et al. Bile acid-activated nuclear receptor FXR suppresses apolipoprotein A-I transcription via a negative FXR response element. J Clin Invest. 2002;109:961–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, et al. Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. Cell Metab. 2007;5:415–25.

    Article  CAS  PubMed  Google Scholar 

  34. Jiang C, Xie C, Lv Y, Li J, Krausz KW, Shi J, et al. Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nat Commun. 2015;6:10166.

    Article  CAS  PubMed  Google Scholar 

  35. Gonzalez FJ, Jiang C, Patterson AD. An intestinal microbiota-Farnesoid X receptor Axis modulates metabolic disease. Gastroenterology. 2016;151:845–59.

    Article  CAS  PubMed  Google Scholar 

  36. Kir S, Beddow SA, Samuel VT, Miller P, Previs SF, Suino-Powell K, et al. FGF19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis. Science. 2011;331:1621–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Copple BL, Li T. Pharmacology of bile acid receptors: evolution of bile acids from simple detergents to complex signaling molecules. Pharmacol Res. 2016;104:9–21.

    Article  CAS  PubMed  Google Scholar 

  38. Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, Kliewer SA, et al. Bile acids: natural ligands for an orphan nuclear receptor. Science. 1999;284:1365–8.

    Article  CAS  PubMed  Google Scholar 

  39. Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A, et al. Identification of a nuclear receptor for bile acids. Science. 1999;284:1362–5.

    Article  CAS  PubMed  Google Scholar 

  40. Kawamata Y, Fujii R, Hosoya M, Harada M, Yoshida H, Miwa M, et al. A G protein-coupled receptor responsive to bile acids. J Biol Chem. 2003;278:9435–40.

    Article  CAS  PubMed  Google Scholar 

  41. Maruyama T, Miyamoto Y, Nakamura T, Tamai Y, Okada H, Sugiyama E, et al. Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun. 2002;298:714–9.

    Article  CAS  PubMed  Google Scholar 

  42. Thomas C, Pellicciari R, Pruzanski M, Auwerx J, Schoonjans K. Targeting bile-acid signalling for metabolic diseases. Nat Rev Drug Discov. 2008;7:678–93.

    Article  CAS  PubMed  Google Scholar 

  43. Fujisaka S, Ussar S, Clish C, Devkota S, Dreyfuss JM, Sakaguchi M, et al. Antibiotic effects on gut microbiota and metabolism are host dependent. J Clin Invest. 2016;126:4430–43.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Moschen AR, Kaser S, Tilg H. Non-alcoholic steatohepatitis: a microbiota-driven disease. Trends Endocrinol Metab. 2013;24:537–45.

    Article  CAS  PubMed  Google Scholar 

  45. Ley RE, Backhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI. Obesity alters gut microbial ecology. Proc Natl Acad Sci U S A. 2005;102:11070–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature. 2006;444:1022–3.

    Article  CAS  PubMed  Google Scholar 

  47. Musso G, Gambino R, Cassader M. Obesity, diabetes, and gut microbiota: the hygiene hypothesis expanded? Diabetes Care. 2010;33:2277–84.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Backhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A. 2004;101:15718–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Aronsson L, Huang Y, Parini P, Korach-Andre M, Hakansson J, Gustafsson JA, et al. Decreased fat storage by lactobacillus paracasei is associated with increased levels of angiopoietin-like 4 protein (ANGPTL4). PLoS One. 2010;5:e13087.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Alex S, Lichtenstein L, Dijk W, Mensink RP, Tan NS, Kersten S. ANGPTL4 is produced by entero-endocrine cells in the human intestinal tract. Histochem Cell Biol. 2014;141:383–91.

    Article  CAS  PubMed  Google Scholar 

  51. Alex S, Lange K, Amolo T, Grinstead JS, Haakonsson AK, Szalowska E, et al. Short-chain fatty acids stimulate angiopoietin-like 4 synthesis in human colon adenocarcinoma cells by activating peroxisome proliferator-activated receptor. gamma Mol Cell Biol. 2013;33:1303–16.

    Article  CAS  PubMed  Google Scholar 

  52. Nicholson JK, Holmes E, Kinross J, Burcelin R, Gibson G, Jia W, et al. Host-gut microbiota metabolic interactions. Science. 2012;336:1262–7.

    Article  CAS  PubMed  Google Scholar 

  53. Buchman AL, Dubin MD, Moukarzel AA, Jenden DJ, Roch M, Rice KM, et al. Choline deficiency: a cause of hepatic steatosis during parenteral nutrition that can be reversed with intravenous choline supplementation. Hepatology. 1995;22:1399–403.

    PubMed  CAS  Google Scholar 

  54. Dumas ME, Barton RH, Toye A, Cloarec O, Blancher C, Rothwell 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;103:12511–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sherriff JL, O’Sullivan TA, Properzi C, Oddo JL, Adams LA. Choline, its potential role in nonalcoholic fatty liver disease, and the case for human and bacterial genes. Adv Nutr. 2016;7:5–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Krahmer N, Guo Y, Wilfling F, Hilger M, Lingrell S, Heger K, et al. Phosphatidylcholine synthesis for lipid droplet expansion is mediated by localized activation of CTP: phosphocholine cytidylyltransferase. Cell Metab. 2011;14:504–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Geiger O, Lopez-Lara IM, Sohlenkamp C. Phosphatidylcholine biosynthesis and function in bacteria. Biochim Biophys Acta. 2013;1831:503–13.

    Article  CAS  PubMed  Google Scholar 

  58. Romano KA, Vivas EI, Amador-Noguez D, Rey FE. Intestinal microbiota composition modulates choline bioavailability from diet and accumulation of the proatherogenic metabolite trimethylamine-N-oxide. MBio. 2015;6:e02481.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 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.

    Article  CAS  PubMed  Google Scholar 

  60. Russell WR, Hoyles L, Flint HJ, Dumas ME. Colonic bacterial metabolites and human health. Curr Opin Microbiol. 2013;16:246–54.

    Article  CAS  PubMed  Google Scholar 

  61. Vajro P, Mandato C, Licenziati MR, Franzese A, Vitale DF, Lenta S, et al. Effects of lactobacillus rhamnosus strain GG in pediatric obesity-related liver disease. J Pediatr Gastroenterol Nutr. 2011;52:740–3.

    Article  PubMed  Google Scholar 

  62. Aller R, De Luis DA, Izaola O, Conde R, Gonzalez Sagrado M, Primo D, et al. Effect of a probiotic on liver aminotransferases in nonalcoholic fatty liver disease patients: a double blind randomized clinical trial. Eur Rev Med Pharmacol Sci. 2011;15:1090–5.

    PubMed  CAS  Google Scholar 

  63. Nabavi S, Rafraf M, Somi MH, Homayouni-Rad A, Asghari-Jafarabadi M. Effects of probiotic yogurt consumption on metabolic factors in individuals with nonalcoholic fatty liver disease. J Dairy Sci. 2014;97:7386–93.

    Article  CAS  PubMed  Google Scholar 

  64. Alisi A, Bedogni G, Baviera G, Giorgio V, Porro E, Paris C, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 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;50:72–7.

    Article  CAS  PubMed  Google Scholar 

  66. Wang J, Tang H, Zhang C, Zhao Y, Derrien M, Rocher E, et al. Modulation of gut microbiota during probiotic-mediated attenuation of metabolic syndrome in high fat diet-fed mice. ISME J. 2015;9:1–15.

    Article  CAS  PubMed  Google Scholar 

  67. Loguercio C, Federico A, Tuccillo C, Terracciano F, D’Auria MV, De Simone 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.

    Article  PubMed  Google Scholar 

  68. Malaguarnera M, Vacante M, Antic T, Giordano M, Chisari G, Acquaviva R, et al. Bifidobacterium longum with fructo-oligosaccharides in patients with non alcoholic steatohepatitis. Dig Dis Sci. 2012;57:545–53.

    Article  PubMed  Google Scholar 

  69. Eslamparast T, Poustchi H, Zamani F, Sharafkhah M, Malekzadeh R, Hekmatdoost A. Synbiotic supplementation in nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled pilot study. Am J Clin Nutr. 2014;99:535–42.

    Article  CAS  PubMed  Google Scholar 

  70. Mofidi F, Poustchi H, Yari Z, Nourinayyer B, Merat S, Sharafkhah M, et al. Synbiotic supplementation in lean patients with non-alcoholic fatty liver disease: a pilot, randomised, double-blind, placebo-controlled, clinical trial. Br J Nutr. 2017;117:662–8.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. University of Hawaii Cancer Center, Honolulu, HI, USA

    Wei Jia & Cynthia Rajani

  2. Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Wei Jia

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Correspondence to Wei Jia .

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  1. Institute of Digestive Disease and Department of Medicine & Therapeutics State Key Laboratory of Digestive Disease LKS Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong

    Jun Yu

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Jia, W., Rajani, C. (2018). The Influence of Gut Microbial Metabolism on the Development and Progression of Non-alcoholic Fatty Liver Disease. In: Yu, J. (eds) Obesity, Fatty Liver and Liver Cancer. Advances in Experimental Medicine and Biology, vol 1061. Springer, Singapore. https://doi.org/10.1007/978-981-10-8684-7_8

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