Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The Gordian Knot of dysbiosis, obesity and NAFLD

Nature Reviews Gastroenterology & Hepatology volume 10, pages 637–644 (2013)Cite this article

Subjects

Abstract

The development of obesity and NAFLD is known to be determined by host genetics, diet and lack of exercise. In addition, the gut microbiota has been identified to influence the development of both obesity and NAFLD. Evidence for the role of the gut microbiota has been shown by preclinical studies of transfer of gut microbiota from lean and obese individuals, with the recipient developing the metabolic features of the donor. Many bidirectional interactions of the gut microbiota, including with food, bile and the intestinal epithelium, have been identified. These interactions might contribute to the distinct steps in the progression from lean to obese states, and to steatosis, steatohepatitis and eventually fibrosis. The predominant steps are efficient caloric extraction from the diet, intestinal epithelial damage and greater entry of bacterial components into the portal circulation. These steps result in activation of the innate immune system, liver inflammation and fibrosis. Fortunately, therapeutic interventions might not require a full understanding of these complex interactions. Although antibiotics are too unselective in their action, probiotics have shown efficacy in reversing obesity and NASH in experimental systems, and are under investigation in humans.

Key Points

  • The gastrointestinal tract contains a large and metabolically active microbial community that interacts with the diet and the host

  • The gut microbiota can influence the development of obesity and NAFLD

  • Microbiota characteristics such as efficiency of energy harvest, induction of epithelial damage and entry of microbial components into the portal circulation are probably important in the development of NAFLD

  • Activation of pattern-recognition receptors on hepatic cells by microbiota-derived ligands results in the stimulation of innate immune and profibrotic pathways

  • Therapeutic options under investigation for manipulating the microbiota in NAFLD are prebiotics and probiotics, as well as microbiota transfer

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The Gordian Knot of dysbiosis, obesity and NAFLD.
Figure 2: Environmental factors such as dietary fat can induce dysbiosis and increase intestinal permeability in NAFLD.
Figure 3: Multiple inflammasome components are present in the epithelial and haematopoietic compartments and have a role in obesity and NAFLD.

Similar content being viewed by others

References

  1. Hattori, M. & Taylor, T. D. The human intestinal microbiome: a new frontier of human biology. DNA Res. 16, 1–12 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Tremaroli, V. & Backhed, F. Functional interactions between the gut microbiota and host metabolism. Nature 489, 242–249 (2012).

    CAS  PubMed  Google Scholar 

  3. Hooper, L. V., Littman, D. R. & Macpherson, A. J. Interactions between the microbiota and the immune system. Science 336, 1268–1273 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Elinav, E. et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145, 745–757 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Fry, D. E. Prions: reassessment of the germ theory of disease. J. Am. Coll. Surg. 211, 546–552 (2010).

    PubMed  Google Scholar 

  6. Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gill, S. R. et al. Metagenomic analysis of the human distal gut microbiome. Science 312, 1355–1359 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Lagier, J. C. et al. Microbial culturomics: paradigm shift in the human gut microbiome study. Clin. Microbiol. Infect. 18, 1185–1193 (2012).

    CAS  PubMed  Google Scholar 

  9. Eckburg, P. B. et al. Diversity of the human intestinal microbial flora. Science 308, 1635–1638 (2005).

    PubMed  PubMed Central  Google Scholar 

  10. Weinstock, G. M. Genomic approaches to studying the human microbiota. Nature 489, 250–256 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Sayasone, S. et al. Diversity of human intestinal helminthiasis in Lao PDR. Trans. R. Soc. Trop. Med. Hyg. 103, 247–254 (2009).

    PubMed  Google Scholar 

  12. Lozupone, C. A., Stombaugh, J. I., Gordon, J. I., Jansson, J. K. & Knight, R. Diversity, stability and resilience of the human gut microbiota. Nature 489, 220–230 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Turnbaugh, P. J. & Gordon, J. I. The core gut microbiome, energy balance and obesity. J. Physiol. 587, 4153–4158 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Tschop, M. H., Hugenholtz, P. & Karp, C. L. Getting to the core of the gut microbiome. Nat. Biotechnol. 27, 344–346 (2009).

    CAS  PubMed  Google Scholar 

  15. Shade, A. & Handelsman, J. Beyond the Venn diagram: the hunt for a core microbiome. Environ. Microbiol. 14, 4–12 (2012).

    CAS  PubMed  Google Scholar 

  16. Vael, C. & Desager, K. The importance of the development of the intestinal microbiota in infancy. Curr. Opin. Pediatr. 21, 794–800 (2009).

    PubMed  Google Scholar 

  17. De Filippo, C. et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc. Natl Acad. Sci. USA 107, 14691–14696 (2010).

    PubMed  PubMed Central  Google Scholar 

  18. Wu, G. D. et al. Linking long-term dietary patterns with gut microbial enterotypes. Science 334, 105–108 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Devkota, S. et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in IL10−/− mice. Nature 487, 104–108 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Sartor, R. B. Gut microbiota: Diet promotes dysbiosis and colitis in susceptible hosts. Nat. Rev. Gastroenterol. Hepatol. 9, 561–562 (2012).

    PubMed  Google Scholar 

  21. Cusi, K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology 142, 711–725 (2012).

    CAS  PubMed  Google Scholar 

  22. Ley, R. E., Turnbaugh, P. J., Klein, S. & Gordon, J. I. Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022–1023 (2006).

    CAS  PubMed  Google Scholar 

  23. Zhang, H. et al. Human gut microbiota in obesity and after gastric bypass. Proc. Natl Acad. Sci. USA 106, 2365–2370 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006).

    PubMed  Google Scholar 

  25. Hildebrandt, M. A. et al. High-fat diet determines the composition of the murine gut microbiome independently of obesity. Gastroenterology 137, 1716–1724.e2 (2009).

    CAS  PubMed  Google Scholar 

  26. Turnbaugh, P. J. et al. The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci. Transl. Med. 1, 6ra14 (2009).

    PubMed  PubMed Central  Google Scholar 

  27. Murphy, E. F. et al. Composition and energy harvesting capacity of the gut microbiota: relationship to diet, obesity and time in mouse models. Gut 59, 1635–1642 (2010).

    CAS  PubMed  Google Scholar 

  28. Fei, N. & Zhao, L. An opportunistic pathogen isolated from the gut of an obese human causes obesity in germfree mice. ISME J. 7, 880–884 (2013).

    CAS  PubMed  Google Scholar 

  29. Vrieze, A. et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 143, 913–916 (2012).

    CAS  PubMed  Google Scholar 

  30. Shen, J., Obin, M. S. & Zhao, L. The gut microbiota, obesity and insulin resistance. Mol. Aspects Med. 34, 39–58 (2012).

    PubMed  Google Scholar 

  31. Tarini, J. & Wolever, T. M. The fermentable fibre inulin increases postprandial serum short-chain fatty acids and reduces free-fatty acids and ghrelin in healthy subjects. Appl. Physiol. Nutr. Metab. 35, 9–16 (2010).

    CAS  PubMed  Google Scholar 

  32. Amar, J. et al. Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: molecular mechanisms and probiotic treatment. EMBO Mol. Med. 3, 559–572 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Cani, P. D. et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 58, 1091–1103 (2009).

    CAS  PubMed  Google Scholar 

  34. Backhed, F. et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl Acad. Sci. USA 101, 15718–15723 (2004).

    PubMed  PubMed Central  Google Scholar 

  35. Turnbaugh, P. J., Backhed, F., Fulton, L. & Gordon, J. I. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe 3, 213–223 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Velagapudi, V. R. et al. The gut microbiota modulates host energy and lipid metabolism in mice. J . Lipid Res. 51, 1101–1112 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Jumpertz, R. et al. Energy-balance studies reveal associations between gut microbes, caloric load, and nutrient absorption in humans. Am. J. Clin. Nutr. 94, 58–65 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Dewulf, E. M. et al. Inulin-type fructans with prebiotic properties counteract GPR43 overexpression and PPARγ-related adipogenesis in the white adipose tissue of high-fat diet-fed mice. J. Nutr. Biochem. 22, 712–722 (2010).

    PubMed  Google Scholar 

  39. Ge, H. et al. Activation of G protein-coupled receptor 43 in adipocytes leads to inhibition of lipolysis and suppression of plasma free fatty acids. Endocrinology 149, 4519–4526 (2008).

    CAS  PubMed  Google Scholar 

  40. Henao-Mejia, J. et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179–185 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Figueiredo, R. T., Bittencourt, V. C., Lopes, L. C., Sassaki, G. & Barreto-Bergter, E. Toll-like receptors (TLR2 and TLR4) recognize polysaccharides of Pseudallescheria boydii cell wall. Carbohydr. Res. 356, 260–264 (2012).

    CAS  PubMed  Google Scholar 

  42. Caricilli, A. M. et al. Gut microbiota is a key modulator of insulin resistance in TLR 2 knockout mice. PLoS Biol. 9, e1001212 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Amar, J. et al. Energy intake is associated with endotoxemia in apparently healthy men. Am. J. Clin. Nutr. 87, 1219–1223 (2008).

    CAS  PubMed  Google Scholar 

  44. Ruan, X. et al. Encapsulated Bifidobacteria reduced bacterial translocation in rats following hemorrhagic shock and resuscitation. Nutrition 23, 754–761 (2007).

    CAS  PubMed  Google Scholar 

  45. Brun, P. et al. Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis. Am. J. Physiol. Gastrointest. Liver Physiol. 292, G518–G525 (2007).

    CAS  PubMed  Google Scholar 

  46. Wang, Z. et al. The role of bifidobacteria in gut barrier function after thermal injury in rats. J. Trauma 61, 650–657 (2006).

    PubMed  Google Scholar 

  47. Sun, L. et al. A marker of endotoxemia is associated with obesity and related metabolic disorders in apparently healthy Chinese. Diabetes Care 33, 1925–1932 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Amar, J. et al. Involvement of tissue bacteria in the onset of diabetes in humans: evidence for a concept. Diabetologia 54, 3055–3061 (2011).

    CAS  PubMed  Google Scholar 

  49. Cani, P. D. et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761–1772 (2007).

    CAS  PubMed  Google Scholar 

  50. Anstee, Q. M., Targher, G. & Day, C. P. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat. Rev. Gastroenterol. Hepatol. 10, 330–344 (2013).

    CAS  PubMed  Google Scholar 

  51. Lichtman, S. N., Keku, J., Schwab, J. H. & Sartor, R. B. Hepatic injury associated with small bowel bacterial overgrowth in rats is prevented by metronidazole and tetracycline. Gastroenterology 100, 513–519 (1991).

    CAS  PubMed  Google Scholar 

  52. Crispe, I. N. The liver as a lymphoid organ. Annu. Rev. Immunol. 27, 147–163 (2009).

    CAS  PubMed  Google Scholar 

  53. Mehal, W. Z. The gut–liver axis: A busy two way street. Hepatology 55, 1647–1649 (2012).

    PubMed  Google Scholar 

  54. Kubes, P. & Mehal, W. Z. Sterile inflammation in the liver. Gastroenterology 143, 1158–1172 (2012).

    CAS  PubMed  Google Scholar 

  55. Tordjman, J., Guerre-Millo, M. & Clement, K. Adipose tissue inflammation and liver pathology in human obesity. Diabetes Metab. 34, 658–663 (2008).

    CAS  PubMed  Google Scholar 

  56. Aron-Wisnewsky, J., Gaborit, B., Dutour, A. & Clement, K. Gut microbiota and non-alcoholic fatty liver disease: new insights. Clin. Microbiol. Infect. 19, 338–348 (2013).

    CAS  PubMed  Google Scholar 

  57. Vance, D. E. Role of phosphatidylcholine biosynthesis in the regulation of lipoprotein homeostasis. Curr. Opin. Lipidol. 19, 229–234 (2008).

    CAS  PubMed  Google Scholar 

  58. Zeisel, S. H., Wishnok, J. S. & Blusztajn, J. K. Formation of methylamines from ingested choline and lecithin. J. Pharmacol. Exp. Ther. 225, 320–324 (1983).

    CAS  PubMed  Google Scholar 

  59. Corbin, K. D. & Zeisel, S. H. Choline metabolism provides novel insights into nonalcoholic fatty liver disease and its progression. Curr. Opin. Gastroenterol. 28, 159–165 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Spencer, M. D. et al. Association between composition of the human gastrointestinal microbiome and development of fatty liver with choline deficiency. Gastroenterology 140, 976–986 (2011).

    CAS  PubMed  Google Scholar 

  61. Pott, J. & Hornef, M. Innate immune signalling at the intestinal epithelium in homeostasis and disease. EMBO Rep. 13, 684–698 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Lamkanfi, M. & Dixit, V. M. Inflammasomes and their roles in health and disease. Annu. Rev. Cell Dev. Biol. 28, 137–161 (2012).

    CAS  PubMed  Google Scholar 

  63. Davis, B. K., Wen, H. & Ting, J. P. The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu. Rev. Immunol. 29, 707–735 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Franchi, L. et al. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1β in salmonella-infected macrophages. Nat. Immunol. 7, 576–582 (2006).

    CAS  PubMed  Google Scholar 

  65. Lara-Tejero, M. et al. Role of the caspase-1 inflammasome in Salmonella typhimurium pathogenesis. J. Exp. Med. 203, 1407–1412 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Miao, E. A. et al. Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome. Proc. Natl Acad. Sci. USA 107, 3076–3080 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Suzuki, T. et al. Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages. PLoS Pathog . 3, e111 (2007).

    PubMed  PubMed Central  Google Scholar 

  68. Elinav, E., Henao-Mejia, J. & Flavell, R. A. Integrative inflammasome activity in the regulation of intestinal mucosal immune responses. Mucosal Immunol. 6, 4–13 (2013).

    CAS  PubMed  Google Scholar 

  69. Hirota, S. A. et al. NLRP3 inflammasome plays a key role in the regulation of intestinal homeostasis. Inflamm. Bowel Dis. 17, 1359–1372 (2011).

    PubMed  Google Scholar 

  70. Elinav, E. et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145, 745–757 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Henao-Mejia, J., Elinav, E., Strowig, T. & Flavell, R. A. Inflammasomes: far beyond inflammation. Nat. Immunol. 13, 321–324 (2012).

    CAS  PubMed  Google Scholar 

  72. Miura, K. et al. Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1β in mice. Gastroenterology 139, 323–334 (2010).

    CAS  PubMed  Google Scholar 

  73. Szabo, G., Velayudham, A., Romics, L. Jr & Mandrekar, P. Modulation of non-alcoholic steatohepatitis by pattern recognition receptors in mice: the role of toll-like receptors 2 and 4. Alcohol Clin. Exp. Res. 29, 140S–145S (2005).

    CAS  PubMed  Google Scholar 

  74. Starley, B. Q., Calcagno, C. J. & Harrison, S. A. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 51, 1820–1832 (2010).

    PubMed  Google Scholar 

  75. Stickel, F. & Hellerbrand, C. Non-alcoholic fatty liver disease as a risk factor for hepatocellular carcinoma: mechanisms and implications. Gut 59, 1303–1307 (2010).

    CAS  PubMed  Google Scholar 

  76. Ertle, J. et al. Non-alcoholic fatty liver disease progresses to hepatocellular carcinoma in the absence of apparent cirrhosis. Int. J. Cancer 128, 2436–2443 (2011).

    CAS  PubMed  Google Scholar 

  77. Dapito, D. H. et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21, 504–516 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Hernandez-Gea, V., Toffanin, S., Friedman, S. L. & Llovet, J. M. Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology 144, 512–527 (2013).

    PubMed  Google Scholar 

  79. Irvine, K. M., Schroder, K. & Powell, E. E. Liver repercussions of defective gut surveillance. Hepatology 56, 1174–1177 (2012).

    PubMed  Google Scholar 

  80. Yoshimoto, S. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97–101 (2013).

    CAS  PubMed  Google Scholar 

  81. Kirpich, I. A. & McClain, C. J. Probiotics in the treatment of the liver diseases. J. Am. Coll. Nutr. 31, 14–23 (2012).

    CAS  PubMed  Google Scholar 

  82. Cesaro, C. et al. Gut microbiota and probiotics in chronic liver diseases. Dig. Liver Dis. 43, 431–438 (2011).

    PubMed  Google Scholar 

  83. Frazier, T. H., DiBaise, J. K. & McClain, C. J. Gut microbiota, intestinal permeability, obesity-induced inflammation, and liver injury. JPEN J. Parenter. Enteral. Nutr. 35, 14S–20S (2011).

    CAS  PubMed  Google Scholar 

  84. Li, Z. et al. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology 37, 343–350 (2003).

    CAS  PubMed  Google Scholar 

  85. Ma, X., Hua, J. & Li, Z. Probiotics improve high fat diet-induced hepatic steatosis and insulin resistance by increasing hepatic NKT cells. J. Hepatol. 49, 821–830 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Velayudham, A. et al. VSL#3 probiotic treatment attenuates fibrosis without changes in steatohepatitis in a diet-induced nonalcoholic steatohepatitis model in mice. Hepatology 49, 989–997 (2009).

    CAS  PubMed  Google Scholar 

  87. Nardone, G. et al. Protective effects of Lactobacillus paracasei F19 in a rat model of oxidative and metabolic hepatic injury. Am. J. Physiol. Gastroin test. Liver Physiol. 299, G669–G676 (2010).

    CAS  Google Scholar 

  88. Vajro, P. et al. Effects of Lactobacillus rhamnosus strain GG in pediatric obesity-related liver disease. J. Pediatr. Gastroenterol . Nutr. 52, 740–743 (2011).

    PubMed  Google Scholar 

  89. Aller, R. 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. 15, 1090–1095 (2011).

    CAS  PubMed  Google Scholar 

  90. Hemmi, H. et al. A Toll-like receptor recognizes bacterial DNA. Nature 408, 740–745 (2000).

    CAS  PubMed  Google Scholar 

  91. Parnell, J. A., Raman, M., Rioux, K. P. & Reimer, R. A. The potential role of prebiotic fibre for treatment and management of non-alcoholic fatty liver disease and associated obesity and insulin resistance. Liver Int. 32, 701–711 (2011).

    PubMed  Google Scholar 

  92. Macfarlane, S., Macfarlane, G. T. & Cummings, J. H. Review article: prebiotics in the gastrointestinal tract. Aliment. Pharmacol. Ther. 24, 701–714 (2006).

    CAS  PubMed  Google Scholar 

  93. Schwiertz, A. et al. Microbiota and SCFA in lean and overweight healthy subjects. Obesity (Silver Spring) 18, 190–195 (2010).

    Google Scholar 

  94. Kok, N., Roberfroid, M., Robert, A. & Delzenne, N. Involvement of lipogenesis in the lower VLDL secretion induced by oligofructose in rats. Br. J. Nutr. 76, 881–890 (1996).

    CAS  PubMed  Google Scholar 

  95. Delzenne, N. M. & Williams, C. M. Prebiotics and lipid metabolism. Curr. Opin. Lipidol. 13, 61–67 (2002).

    CAS  PubMed  Google Scholar 

  96. Sugatani, J. et al. Dietary inulin alleviates hepatic steatosis and xenobiotics-induced liver injury in rats fed a high-fat and high-sucrose diet: association with the suppression of hepatic cytochrome P450 and hepatocyte nuclear factor 4alpha expression. Drug. Metab. Dispos. 34, 1677–1687 (2006).

    CAS  PubMed  Google Scholar 

  97. Agheli, N. et al. Plasma lipids and fatty acid synthase activity are regulated by short-chain fructo-oligosaccharides in sucrose-fed insulin-resistant rats. J. Nutr. 128, 1283–1288 (1998).

    CAS  PubMed  Google Scholar 

  98. Sugatani, J. et al. Comparison of enzymatically synthesized inulin, resistant maltodextrin and clofibrate effects on biomarkers of metabolic disease in rats fed a high-fat and high-sucrose (cafeteria) diet. Eur. J. Nutr. 47, 192–200 (2008).

    CAS  PubMed  Google Scholar 

  99. Daubioul, C. et al. Dietary fructans, but not cellulose, decrease triglyceride accumulation in the liver of obese Zucker fa/fa rats. J. Nutr. 132, 967–973 (2002).

    CAS  PubMed  Google Scholar 

  100. Levrat, M. A., Remesy, C. & Demigne, C. High propionic acid fermentations and mineral accumulation in the cecum of rats adapted to different levels of inulin. J. Nutr. 121, 1730–1737 (1991).

    CAS  PubMed  Google Scholar 

  101. Topping, D. L. & Clifton, P. M. Short-chain fatty acids and human colonic function: roles of resistant starch and nonstarch polysaccharides. Physiol. Rev. 81, 1031–1064 (2001).

    CAS  PubMed  Google Scholar 

  102. Urias-Silvas, J. E. et al. Physiological effects of dietary fructans extracted from Agave tequilana Gto. and Dasylirion spp. Br. J . Nutr. 99, 254–261 (2008).

    CAS  PubMed  Google Scholar 

  103. Cani, P. D., Neyrinck, A. M., Maton, N. & Delzenne, N. M. Oligofructose promotes satiety in rats fed a high-fat diet: involvement of glucagon-like Peptide-1. Obes. Res. 13, 1000–1007 (2005).

    CAS  PubMed  Google Scholar 

  104. Daubioul, C. A., Horsmans, Y., Lambert, P., Danse, E. & Delzenne, N. M. Effects of oligofructose on glucose and lipid metabolism in patients with nonalcoholic steatohepatitis: results of a pilot study. Eur. J. Clin. Nutr. 59, 723–726 (2005).

    CAS  PubMed  Google Scholar 

  105. Wickremesekera, K., Miller, G., Naotunne, T. D., Knowles, G. & Stubbs, R. S. Loss of insulin resistance after Roux-en-Y gastric bypass surgery: a time course study. Obes. Surg. 15, 474–481 (2005).

    PubMed  Google Scholar 

  106. Mathurin, P. et al. Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease. Gastroenterology 137, 532–540 (2009).

    CAS  PubMed  Google Scholar 

  107. Mai, V., Ukhanova, M., Visone, L., Abuladze, T. & Sulakvelidze, A. Bacteriophage administration reduces the concentration of Listeria monocytogenes in the gastrointestinal tract and its translocation to spleen and liver in experimentally infected mice. Int. J. Microbiol . 2010, 624234 (2010).

    PubMed  PubMed Central  Google Scholar 

  108. Mills, S. et al. Movers and shakers: influence of bacteriophages in shaping the mammalian gut microbiota. Gut Microbes 4, 4–16 (2013).

    PubMed  PubMed Central  Google Scholar 

  109. Imaeda, A. B. et al. Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome. J. Clin. Invest. 119, 305–314 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Hoque, R. et al. TLR9 and the NLRP3 inflammasome link acinar cell death with inflammation in acute pancreatitis. Gastroenterology 141, 358–369 (2011).

    CAS  PubMed  Google Scholar 

  111. Hoque, R. et al. A novel small-molecule enantiomeric analogue of traditional (–)-morphinans has specific TLR9 antagonist properties and reduces sterile inflammation induced organ damage. J. Immunol. 190, 4297–4304 (2013).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The work of the author is supported by a VA Merit award.

Author information

Authors and Affiliations

  1. Section of Digestive Diseases, Yale University, 300 Cedar Street, TAC S241, PO Box 208019, New Haven, 06520-8019, CT, USA

    Wajahat Z. Mehal

Authors
  1. Wajahat Z. Mehal
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mehal, W. The Gordian Knot of dysbiosis, obesity and NAFLD. Nat Rev Gastroenterol Hepatol 10, 637–644 (2013). https://doi.org/10.1038/nrgastro.2013.146

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrgastro.2013.146

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing