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:

Non-alcoholic fatty liver disease: the interplay between metabolism, microbes and immunity

Nature Metabolism volume 3, pages 1596–1607 (2021)Cite this article

Subjects

Abstract

Non-alcoholic fatty liver disease (NAFLD) has emerged pandemically across the globe and particularly affects patients with obesity and type 2 diabetes. NAFLD is a complex systemic disease that is characterised by hepatic lipid accumulation, lipotoxicity, insulin resistance, gut dysbiosis and inflammation. In this review, we discuss how metabolic dysregulation, the gut microbiome, innate and adaptive immunity and their interplay contribute to NAFLD pathology. Lipotoxicity has been shown to instigate liver injury, inflammation and insulin resistance. Synchronous metabolic dysfunction, obesity and related nutritional perturbation may alter the gut microbiome, in turn fuelling hepatic and systemic inflammation by direct activation of innate and adaptive immune responses. We review evidence suggesting that, collectively, these unresolved exogenous and endogenous cues drive liver injury, culminating in liver fibrosis and advanced sequelae of this disorder such as liver cirrhosis and hepatocellular carcinoma. Understanding NAFLD as a complex interplay between metabolism, gut microbiota and the immune response will challenge the clinical perception of NAFLD and open new therapeutic avenues.

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

Fig. 1: Diet constituents and lipotoxicity as a fuel for NAFLD.
Fig. 2: Gut dysbiosis and bile acid metabolism in NAFLD.
Fig. 3: Innate and adaptive immunity pathways driving inflammation in NAFLD.
Fig. 4: Crosstalk between metabolism, immunity and the gut microbiota in NAFLD.

Similar content being viewed by others

References

  1. Diehl, A. M. & Day, C. Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis. N. Engl. J. Med. 377, 2063–2072 (2017).

    Article  CAS  PubMed  Google Scholar 

  2. Simon, T. G., Roelstraete, B., Khalili, H., Hagstrom, H. & Ludvigsson, J. F. Mortality in biopsy-confirmed nonalcoholic fatty liver disease: results from a nationwide cohort. Gut 70, 1375–1382 (2020).

  3. Targher, G., Byrne, C. D. & Tilg, H. NAFLD and increased risk of cardiovascular disease: clinical associations, pathophysiological mechanisms and pharmacological implications. Gut 69, 1691–1705 (2020).

    Article  CAS  PubMed  Google Scholar 

  4. Diehl, A. M., Farpour-Lambert, N. J., Zhao, L. & Tilg, H. Why we need to curb the emerging worldwide epidemic of nonalcoholic fatty liver disease. Nat. Metab. 1, 1027–1029 (2019).

    Article  PubMed  Google Scholar 

  5. Sheka, A. C. et al. Nonalcoholic steatohepatitis: a review. JAMA 323, 1175–1183 (2020).

    Article  CAS  PubMed  Google Scholar 

  6. Haldar, D. et al. Outcomes of liver transplantation for non-alcoholic steatohepatitis: a European Liver Transplant Registry study. J. Hepatol. 71, 313–322 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Younes, R. et al. Caucasian lean subjects with non-alcoholic fatty liver disease share long-term prognosis of non-lean: time for reappraisal of BMI-driven approach? Gut https://doi.org/10.1136/gutjnl-2020-322564 (2021).

  8. Ludwig, J., Viggiano, T. R., McGill, D. B. & Oh, B. J. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin. Proc. 55, 434–438 (1980).

    CAS  PubMed  Google Scholar 

  9. Eslam, M. et al. A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement. J. Hepatol. 73, 202–209 (2020).

    Article  PubMed  Google Scholar 

  10. Eslam, M., Sanyal, A. J., George, J. & International Consensus Panel. MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology 158, 1999–2014 (2020).

    Article  CAS  PubMed  Google Scholar 

  11. Polyzos, S. A. et al. Commentary: nonalcoholic or metabolic dysfunction-associated fatty liver disease? The epidemic of the 21st century in search of the most appropriate name. Metabolism 113, 154413 (2020).

    Article  CAS  PubMed  Google Scholar 

  12. Friedman, S. L., Neuschwander-Tetri, B. A., Rinella, M. & Sanyal, A. J. Mechanisms of NAFLD development and therapeutic strategies. Nat. Med. 24, 908–922 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Furman, D. et al. Chronic inflammation in the etiology of disease across the life span. Nat. Med. 25, 1822–1832 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sookoian, S., Pirola, C. J., Valenti, L. & Davidson, N. O. Genetic pathways in nonalcoholic fatty liver disease: insights from systems biology. Hepatology 72, 330–346 (2020).

    Article  PubMed  Google Scholar 

  15. Samuel, V. T. & Shulman, G. I. Nonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases. Cell Metab. 27, 22–41 (2018).

    Article  CAS  PubMed  Google Scholar 

  16. Roden, M. & Shulman, G. I. The integrative biology of type 2 diabetes. Nature 576, 51–60 (2019).

    Article  CAS  PubMed  Google Scholar 

  17. Tilg, H., Moschen, A. R. & Roden, M. NAFLD and diabetes mellitus. Nat. Rev. Gastroenterol. Hepatol. 14, 32–42 (2017).

    Article  CAS  PubMed  Google Scholar 

  18. Donnelly, K. L. et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J. Clin. Invest. 115, 1343–1351 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Smith, G. I. et al. Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease. J. Clin. Invest. 130, 1453–1460 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Raichur, S. et al. CerS2 haploinsufficiency inhibits β-oxidation and confers susceptibility to diet-induced steatohepatitis and insulin resistance. Cell Metab. 20, 687–695 (2014).

    Article  CAS  PubMed  Google Scholar 

  21. Stefan, N., Kantartzis, K. & Haring, H. U. Causes and metabolic consequences of fatty liver. Endocr. Rev. 29, 939–960 (2008).

    Article  CAS  PubMed  Google Scholar 

  22. Wehmeyer, M. H. et al. Nonalcoholic fatty liver disease is associated with excessive calorie intake rather than a distinctive dietary pattern. Medicine 95, e3887 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Jacobs, K. et al. Association of nonalcoholic fatty liver disease with visceral adiposity but not coronary artery calcification in the elderly. Clin. Gastroenterol. Hepatol. 14, 1337–1344 (2016).

    Article  PubMed  Google Scholar 

  24. Nielsen, S., Guo, Z., Johnson, C. M., Hensrud, D. D. & Jensen, M. D. Splanchnic lipolysis in human obesity. J. Clin. Invest. 113, 1582–1588 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Herman, M. A. & Samuel, V. T. The sweet path to metabolic demise: fructose and lipid synthesis. Trends Endocrinol. Metab. 27, 719–730 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Todoric, J. et al. Fructose stimulated de novo lipogenesis is promoted by inflammation. Nat. Metab. 2, 1034–1045 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ioannou, G. N. The role of cholesterol in the pathogenesis of NASH. Trends Endocrinol. Metab. 27, 84–95 (2016).

    Article  CAS  PubMed  Google Scholar 

  28. Wang, X. et al. Hepatocyte TAZ/WWTR1 promotes inflammation and fibrosis in nonalcoholic steatohepatitis. Cell Metab. 24, 848–862 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mooring, M. et al. Hepatocyte stress increases expression of Yes-associated protein and transcriptional coactivator with PDZ-binding motif in hepatocytes to promote parenchymal inflammation and fibrosis. Hepatology 71, 1813–1830 (2020).

    Article  CAS  PubMed  Google Scholar 

  30. Alsamman, S. et al. Targeting acid ceramidase inhibits YAP/TAZ signaling to reduce fibrosis in mice. Sci. Transl. Med. 12, eaay8798 (2020).

  31. Mari, M. et al. Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis. Cell Metab. 4, 185–198 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Koh, E. H. et al. Sphingomyelin synthase 1 mediates hepatocyte pyroptosis to trigger non-alcoholic steatohepatitis. Gut 70, 1954–1964 (2020).

  33. Xie, C. et al. Activation of intestinal hypoxia-inducible factor 2α during obesity contributes to hepatic steatosis. Nat. Med. 23, 1298–1308 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Turpin-Nolan, S. M. & Bruning, J. C. The role of ceramides in metabolic disorders: when size and localization matters. Nat. Rev. Endocrinol. 16, 224–233 (2020).

    Article  CAS  PubMed  Google Scholar 

  35. Apostolopoulou, M. et al. Specific hepatic sphingolipids relate to insulin resistance, oxidative stress, and inflammation in nonalcoholic steatohepatitis. Diabetes Care 41, 1235–1243 (2018).

    Article  CAS  PubMed  Google Scholar 

  36. Luukkonen, P. K. et al. Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease. J. Hepatol. 64, 1167–1175 (2016).

    Article  CAS  PubMed  Google Scholar 

  37. Teruel, T., Hernandez, R. & Lorenzo, M. Ceramide mediates insulin resistance by tumor necrosis factor-α in brown adipocytes by maintaining Akt in an inactive dephosphorylated state. Diabetes 50, 2563–2571 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Xia, J. Y. et al. Targeted induction of ceramide degradation leads to improved systemic metabolism and reduced hepatic steatosis. Cell Metab. 22, 266–278 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Anand, P. K. Lipids, inflammasomes, metabolism, and disease. Immunol. Rev. 297, 108–122 (2020).

    Article  CAS  PubMed  Google Scholar 

  40. Wen, H. et al. Fatty acid-induced NLRP3–ASC inflammasome activation interferes with insulin signaling. Nat. Immunol. 12, 408–415 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17, 179–188 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Karasawa, T. et al. Saturated fatty acids undergo intracellular crystallization and activate the NLRP3 inflammasome in macrophages. Arterioscler. Thromb. Vasc. Biol. 38, 744–756 (2018).

    Article  CAS  PubMed  Google Scholar 

  43. Gianfrancesco, M. A. et al. Saturated fatty acids induce NLRP3 activation in human macrophages through K+ efflux resulting from phospholipid saturation and Na, K-ATPase disruption. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1864, 1017–1030 (2019).

    Article  CAS  PubMed  Google Scholar 

  44. Yan, Y. et al. Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation. Immunity 38, 1154–1163 (2013).

    Article  CAS  PubMed  Google Scholar 

  45. Lopategi, A. et al. Frontline science: specialized proresolving lipid mediators inhibit the priming and activation of the macrophage NLRP3 inflammasome. J. Leukoc. Biol. 105, 25–36 (2019).

    Article  CAS  PubMed  Google Scholar 

  46. Yang, G., Lee, H. E. & Lee, J. Y. A pharmacological inhibitor of NLRP3 inflammasome prevents non-alcoholic fatty liver disease in a mouse model induced by high fat diet. Sci. Rep. 6, 24399 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Chen, Y. & Ma, K. NLRC4 inflammasome activation regulated by TNF-α promotes inflammatory responses in nonalcoholic fatty liver disease. Biochem. Biophys. Res. Commun. 511, 524–530 (2019).

    Article  CAS  PubMed  Google Scholar 

  48. Fu, S., Watkins, S. M. & Hotamisligil, G. S. The role of endoplasmic reticulum in hepatic lipid homeostasis and stress signaling. Cell Metab. 15, 623–634 (2012).

    Article  CAS  PubMed  Google Scholar 

  49. Kim, J. Y. et al. ER stress drives lipogenesis and steatohepatitis via caspase-2 activation of S1P. Cell 175, 133–145 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ozcan, U. et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306, 457–461 (2004).

    Article  PubMed  Google Scholar 

  51. Dara, L., Ji, C. & Kaplowitz, N. The contribution of endoplasmic reticulum stress to liver diseases. Hepatology 53, 1752–1763 (2011).

    Article  CAS  PubMed  Google Scholar 

  52. Lebeaupin, C. et al. Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. J. Hepatol. 69, 927–947 (2018).

    Article  CAS  PubMed  Google Scholar 

  53. Malhi, H. & Kaufman, R. J. Endoplasmic reticulum stress in liver disease. J. Hepatol. 54, 795–809 (2011).

    Article  CAS  PubMed  Google Scholar 

  54. Tirosh, A. et al. Intercellular transmission of hepatic ER stress in obesity disrupts systemic metabolism. Cell Metab. 33, 319–333 (2021).

    Article  CAS  PubMed  Google Scholar 

  55. Samuel, V. T. & Shulman, G. I. The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. J. Clin. Invest. 126, 12–22 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Marchesini, G. et al. Association of nonalcoholic fatty liver disease with insulin resistance. Am. J. Med. 107, 450–455 (1999).

    Article  CAS  PubMed  Google Scholar 

  57. Marchesini, G. et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 50, 1844–1850 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. Randle, P. J., Garland, P. B., Hales, C. N. & Newsholme, E. A. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1, 785–789 (1963).

    Article  CAS  PubMed  Google Scholar 

  59. Belfort, R. et al. Dose–response effect of elevated plasma free fatty acid on insulin signaling. Diabetes 54, 1640–1648 (2005).

    Article  CAS  PubMed  Google Scholar 

  60. Roden, M. et al. Effects of free fatty acid elevation on postabsorptive endogenous glucose production and gluconeogenesis in humans. Diabetes 49, 701–707 (2000).

    Article  CAS  PubMed  Google Scholar 

  61. Gastaldelli, A. et al. Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects. Gastroenterology 133, 496–506 (2007).

    Article  CAS  PubMed  Google Scholar 

  62. Kotronen, A., Juurinen, L., Tiikkainen, M., Vehkavaara, S. & Yki-Jarvinen, H. Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes. Gastroenterology 135, 122–130 (2008).

    Article  CAS  PubMed  Google Scholar 

  63. Yki-Jarvinen, H. Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol. 2, 901–910 (2014).

    Article  CAS  PubMed  Google Scholar 

  64. Gehrke, N. & Schattenberg, J. M. Metabolic inflammation—a role for hepatic inflammatory pathways as drivers of comorbidities in nonalcoholic fatty liver disease? Gastroenterology 158, 1929–1947 (2020).

    Article  CAS  PubMed  Google Scholar 

  65. Saltiel, A. R. & Olefsky, J. M. Inflammatory mechanisms linking obesity and metabolic disease. J. Clin. Invest. 127, 1–4 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Uysal, K. T., Wiesbrock, S. M., Marino, M. W. & Hotamisligil, G. S. Protection from obesity-induced insulin resistance in mice lacking TNF-α function. Nature 389, 610–614 (1997).

    Article  CAS  PubMed  Google Scholar 

  67. Larsen, C. M. et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 356, 1517–1526 (2007).

    Article  CAS  PubMed  Google Scholar 

  68. Arkan, M. C. et al. IKK-β links inflammation to obesity-induced insulin resistance. Nat. Med. 11, 191–198 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. Cai, D. et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB. Nat. Med. 11, 183–190 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Yuan, M. et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkβ. Science 293, 1673–1677 (2001).

    Article  CAS  PubMed  Google Scholar 

  71. Hirosumi, J. et al. A central role for JNK in obesity and insulin resistance. Nature 420, 333–336 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Shimobayashi, M. et al. Insulin resistance causes inflammation in adipose tissue. J. Clin. Invest. 128, 1538–1550 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Sharpton, S. R., Schnabl, B., Knight, R. & Loomba, R. Current concepts, opportunities, and challenges of gut microbiome-based personalized medicine in nonalcoholic fatty liver disease. Cell Metab. 33, 21–32 (2021).

    Article  CAS  PubMed  Google Scholar 

  74. Loomba, R. et al. Gut microbiome-based metagenomic signature for non-invasive detection of advanced fibrosis in human nonalcoholic fatty liver disease. Cell Metab. 25, 1054–1062 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Alferink, L. J. et al. Microbiomics, metabolomics, predicted metagenomics and hepatic steatosis in a population-based study of 1355 adults. Hepatology 73, 968–982 (2020).

  76. Oh, T. G. et al. A universal gut-microbiome-derived signature predicts cirrhosis. Cell Metab. 32, 878–888 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Lee, G. et al. Distinct signatures of gut microbiome and metabolites associated with significant fibrosis in non-obese NAFLD. Nat. Commun. 11, 4982 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Loomba, R. et al. The commensal microbe Veillonella as a marker for response to an FGF19 analog in NASH. Hepatology 73, 126–143 (2021).

    Article  CAS  PubMed  Google Scholar 

  79. Frost, F. et al. Long-term instability of the intestinal microbiome is associated with metabolic liver disease, low microbiota diversity, diabetes mellitus and impaired exocrine pancreatic function. Gut 70, 522–530 (2021).

    Article  CAS  PubMed  Google Scholar 

  80. Lang, S. & Schnabl, B. Microbiota and fatty liver disease—the known, the unknown, and the future. Cell Host Microbe 28, 233–244 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  82. Tilg, H., Zmora, N., Adolph, T. E. & Elinav, E. The intestinal microbiota fuelling metabolic inflammation. Nat. Rev. Immunol. 20, 40–54 (2020).

    Article  CAS  PubMed  Google Scholar 

  83. Balmer, M. L. et al. The liver may act as a firewall mediating mutualism between the host and its gut commensal microbiota. Sci. Transl. Med. 6, 237ra266 (2014).

    Article  Google Scholar 

  84. Koh, A. et al. Microbially produced imidazole propionate impairs insulin signaling through mTORC1. Cell 175, 947–961 (2018).

    Article  CAS  PubMed  Google Scholar 

  85. Zhao, M. et al. TMAVA, a metabolite of intestinal microbes, is increased in plasma from patients with liver steatosis, inhibits γ-butyrobetaine hydroxylase, and exacerbates fatty liver in mice. Gastroenterology 158, 2266–2281 (2020).

    Article  CAS  PubMed  Google Scholar 

  86. Hoyles, L. et al. Publisher Correction: Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women. Nat. Med. 24, 1628 (2018).

    Article  CAS  PubMed  Google Scholar 

  87. Fukui, H., Brauner, B., Bode, J. C. & Bode, C. Plasma endotoxin concentrations in patients with alcoholic and non-alcoholic liver disease: reevaluation with an improved chromogenic assay. J. Hepatol. 12, 162–169 (1991).

    Article  CAS  PubMed  Google Scholar 

  88. Day, C. P. & James, O. F. Steatohepatitis: a tale of two “hits”? Gastroenterology 114, 842–845 (1998).

    Article  CAS  PubMed  Google Scholar 

  89. Tilg, H., Adolph, T. E. & Moschen, A. R. Multiple parallel hits hypothesis in nonalcoholic fatty liver disease: revisited after a decade. Hepatology 73, 833–842 (2021).

    Article  PubMed  Google Scholar 

  90. Carpino, G. et al. Neoplastic transformation of the peribiliary stem cell niche in cholangiocarcinoma arisen in primary sclerosing cholangitis. Hepatology 69, 622–638 (2019).

    Article  CAS  PubMed  Google Scholar 

  91. Fei, N. et al. Endotoxin producers overgrowing in human gut microbiota as the causative agents for nonalcoholic fatty liver disease. mBio 11, e03263-19 (2020).

  92. Arab, J. P., Karpen, S. J., Dawson, P. A., Arrese, M. & Trauner, M. Bile acids and nonalcoholic fatty liver disease: molecular insights and therapeutic perspectives. Hepatology 65, 350–362 (2017).

    Article  PubMed  Google Scholar 

  93. Chavez-Talavera, O., Haas, J., Grzych, G., Tailleux, A. & Staels, B. Bile acid alterations in nonalcoholic fatty liver disease, obesity, insulin resistance and type 2 diabetes: what do the human studies tell? Curr. Opin. Lipidol. 30, 244–254 (2019).

    Article  CAS  PubMed  Google Scholar 

  94. Bechmann, L. P. et al. Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepatitis. Hepatology 57, 1394–1406 (2013).

    Article  CAS  PubMed  Google Scholar 

  95. Legry, V. et al. Bile acid alterations are associated with insulin resistance, but not with NASH, in obese subjects. J. Clin. Endocrinol. Metab. 102, 3783–3794 (2017).

    Article  PubMed  Google Scholar 

  96. Younossi, Z. M. et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 394, 2184–2196 (2019).

    Article  CAS  PubMed  Google Scholar 

  97. Traussnigg, S. et al. Norursodeoxycholic acid versus placebo in the treatment of non-alcoholic fatty liver disease: a double-blind, randomised, placebo-controlled, phase 2 dose-finding trial. Lancet Gastroenterol. Hepatol. 4, 781–793 (2019).

    Article  PubMed  Google Scholar 

  98. Arab, J. P., Arrese, M. & Trauner, M. Recent insights into the pathogenesis of nonalcoholic fatty liver disease. Annu Rev. Pathol. 13, 321–350 (2018).

    Article  CAS  PubMed  Google Scholar 

  99. Molinaro, A., Wahlstrom, A. & Marschall, H. U. Role of bile acids in metabolic control. Trends Endocrinol. Metab. 29, 31–41 (2018).

    Article  CAS  PubMed  Google Scholar 

  100. Vujkovic-Cvijin, I. et al. Host variables confound gut microbiota studies of human disease. Nature 587, 448–454 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Kurilshikov, A. et al. Large-scale association analyses identify host factors influencing human gut microbiome composition. Nat. Genet. 53, 156–165 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Hotamisligil, G. S. Inflammation, metaflammation and immunometabolic disorders. Nature 542, 177–185 (2017).

    Article  CAS  PubMed  Google Scholar 

  103. Angulo, P. et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 149, 389–397 (2015).

    Article  PubMed  Google Scholar 

  104. Loomba, R. & Adams, L. A. Advances in non-invasive assessment of hepatic fibrosis. Gut 69, 1343–1352 (2020).

    Article  CAS  PubMed  Google Scholar 

  105. Tilg, H. & Moschen, A. R. Food, immunity, and the microbiome. Gastroenterology 148, 1107–1119 (2015).

    Article  PubMed  Google Scholar 

  106. Azzu, V., Vacca, M., Virtue, S., Allison, M. & Vidal-Puig, A. Adipose tissue–liver cross talk in the control of whole-body metabolism: implications in nonalcoholic fatty liver disease. Gastroenterology 158, 1899–1912 (2020).

    Article  CAS  PubMed  Google Scholar 

  107. Moschen, A. R. et al. Anti-inflammatory effects of excessive weight loss: potent suppression of adipose interleukin 6 and tumour necrosis factor α expression. Gut 59, 1259–1264 (2010).

    Article  CAS  PubMed  Google Scholar 

  108. Moschen, A. R. et al. Adipose and liver expression of interleukin (IL)-1 family members in morbid obesity and effects of weight loss. Mol. Med. 17, 840–845 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Netea, M. G. et al. A guiding map for inflammation. Nat. Immunol. 18, 826–831 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Crespo, J. et al. Gene expression of tumor necrosis factor α and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology 34, 1158–1163 (2001).

    Article  CAS  PubMed  Google Scholar 

  111. Kamari, Y. et al. Lack of interleukin-1α or interleukin-1β inhibits transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice. J. Hepatol. 55, 1086–1094 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Whitham, M. et al. Adipocyte-specific deletion of IL-6 does not attenuate obesity-induced weight gain or glucose intolerance in mice. Am. J. Physiol. Endocrinol. Metab. 317, E597–E604 (2019).

    Article  CAS  PubMed  Google Scholar 

  113. Widjaja, A. A. et al. Inhibiting interleukin 11 signaling reduces hepatocyte death and liver fibrosis, inflammation, and steatosis in mouse models of nonalcoholic steatohepatitis. Gastroenterology 157, 777–792 (2019).

    Article  CAS  PubMed  Google Scholar 

  114. Hackstein, C. P. et al. Gut microbial translocation corrupts myeloid cell function to control bacterial infection during liver cirrhosis. Gut 66, 507–518 (2017).

    Article  CAS  PubMed  Google Scholar 

  115. Arroyo, V. et al. The systemic inflammation hypothesis: towards a new paradigm of acute decompensation and multiorgan failure in cirrhosis. J. Hepatol. 74, 670–685 (2021).

    Article  CAS  PubMed  Google Scholar 

  116. Stienstra, R. et al. Inflammasome is a central player in the induction of obesity and insulin resistance. Proc. Natl Acad. Sci. USA 108, 15324–15329 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Lee, J. Y., Sohn, K. H., Rhee, S. H. & Hwang, D. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. J. Biol. Chem. 276, 16683–16689 (2001).

    Article  CAS  PubMed  Google Scholar 

  118. Lee, J. Y. et al. Differential modulation of Toll-like receptors by fatty acids: preferential inhibition by n-3 polyunsaturated fatty acids. J. Lipid Res. 44, 479–486 (2003).

    Article  CAS  PubMed  Google Scholar 

  119. Spruss, A. et al. Toll-like receptor 4 is involved in the development of fructose-induced hepatic steatosis in mice. Hepatology 50, 1094–1104 (2009).

    Article  CAS  PubMed  Google Scholar 

  120. Vijay-Kumar, M. et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328, 228–231 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Rehermann, B. Pathogenesis of chronic viral hepatitis: differential roles of T cells and NK cells. Nat. Med. 19, 859–868 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Baeck, C. et al. Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury. Gut 61, 416–426 (2012).

    Article  CAS  PubMed  Google Scholar 

  124. Henning, J. R. et al. Dendritic cells limit fibroinflammatory injury in nonalcoholic steatohepatitis in mice. Hepatology 58, 589–602 (2013).

    Article  CAS  PubMed  Google Scholar 

  125. Deczkowska, A. et al. XCR1+ type 1 conventional dendritic cells drive liver pathology in non-alcoholic steatohepatitis. Nat. Med. 27, 1043–1054 (2021).

    Article  CAS  PubMed  Google Scholar 

  126. Richter, M. L. et al. Single-nucleus RNA-seq2 reveals functional crosstalk between liver zonation and ploidy. Nat. Commun. 12, 4264 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Sutti, S. & Albano, E. Adaptive immunity: an emerging player in the progression of NAFLD. Nat. Rev. Gastroenterol. Hepatol. 17, 81–92 (2020).

    Article  CAS  PubMed  Google Scholar 

  128. Albano, E. et al. Immune response towards lipid peroxidation products as a predictor of progression of non-alcoholic fatty liver disease to advanced fibrosis. Gut 54, 987–993 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Heier, E. C. et al. Murine CD103+ dendritic cells protect against steatosis progression towards steatohepatitis. J. Hepatol. 66, 1241–1250 (2017).

    Article  CAS  PubMed  Google Scholar 

  130. Kim, Y. H., Choi, B. H., Cheon, H. G. & Do, M. S. B cell activation factor (BAFF) is a novel adipokine that links obesity and inflammation. Exp. Mol. Med. 41, 208–216 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Miyake, T. et al. B cell-activating factor is associated with the histological severity of nonalcoholic fatty liver disease. Hepatol. Int. 7, 539–547 (2013).

    Article  PubMed  Google Scholar 

  132. Nakamura, Y. et al. Depletion of B cell-activating factor attenuates hepatic fat accumulation in a murine model of nonalcoholic fatty liver disease. Sci. Rep. 9, 977 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Bandyopadhyay, K., Marrero, I. & Kumar, V. NKT cell subsets as key participants in liver physiology and pathology. Cell. Mol. Immunol. 13, 337–346 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Wolf, M. J. et al. Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell 26, 549–564 (2014).

    Article  CAS  PubMed  Google Scholar 

  135. Syn, W. K. et al. Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease. Hepatology 51, 1998–2007 (2010).

    Article  CAS  PubMed  Google Scholar 

  136. Tajiri, K., Shimizu, Y., Tsuneyama, K. & Sugiyama, T. Role of liver-infiltrating CD3+CD56+ natural killer T cells in the pathogenesis of nonalcoholic fatty liver disease. Eur. J. Gastroenterol. Hepatol. 21, 673–680 (2009).

    Article  CAS  PubMed  Google Scholar 

  137. Qiu, J. et al. Acetate promotes T cell effector function during glucose restriction. Cell Rep. 27, 2063–2074 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013).

    Article  CAS  PubMed  Google Scholar 

  139. Yang, W. et al. Intestinal microbiota-derived short-chain fatty acids regulation of immune cell IL-22 production and gut immunity. Nat. Commun. 11, 4457 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Caussy, C. et al. Serum bile acid patterns are associated with the presence of NAFLD in twins, and dose-dependent changes with increase in fibrosis stage in patients with biopsy-proven NAFLD. Aliment. Pharm. Ther. 49, 183–193 (2019).

    Article  CAS  Google Scholar 

  141. Hang, S. et al. Bile acid metabolites control TH17 and Treg cell differentiation. Nature 576, 143–148 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Breuer, D. A. et al. CD8+ T cells regulate liver injury in obesity-related nonalcoholic fatty liver disease. Am. J. Physiol. Gastrointest. Liver Physiol. 318, G211–G224 (2020).

    Article  CAS  PubMed  Google Scholar 

  143. Dudek, M. et al. Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH. Nature 592, 444–449 (2021).

    Article  CAS  PubMed  Google Scholar 

  144. Jabri, B. & Abadie, V. IL-15 functions as a danger signal to regulate tissue-resident T cells and tissue destruction. Nat. Rev. Immunol. 15, 771–783 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Martinez-Chantar, M. L., Delgado, T. C. & Beraza, N. Revisiting the role of natural killer cells in non-alcoholic fatty liver disease. Front. Immunol. 12, 640869 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Cepero-Donates, Y. et al. Interleukin-15-mediated inflammation promotes non-alcoholic fatty liver disease. Cytokine 82, 102–111 (2016).

    Article  CAS  PubMed  Google Scholar 

  147. Gong, T., Liu, L., Jiang, W. & Zhou, R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat. Rev. Immunol. 20, 95–112 (2020).

    Article  CAS  PubMed  Google Scholar 

  148. Borges da Silva, H. et al. The purinergic receptor P2RX7 directs metabolic fitness of long-lived memory CD8+ T cells. Nature 559, 264–268 (2018).

    Article  CAS  PubMed  Google Scholar 

  149. Haas, J. T. et al. Transcriptional network analysis implicates altered hepatic immune function in NASH development and resolution. Nat. Metab. 1, 604–614 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Pfister, D. et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature 592, 450–456 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Romeo, S., Sanyal, A. & Valenti, L. Leveraging human genetics to identify potential new treatments for fatty liver disease. Cell Metab. 31, 35–45 (2020).

    Article  CAS  PubMed  Google Scholar 

  152. Patel, K. et al. Cilofexor, a nonsteroidal FXR agonist, in patients with noncirrhotic NASH: a phase 2 randomized controlled trial. Hepatology 72, 58–71 (2020).

    Article  CAS  PubMed  Google Scholar 

  153. Harrison, S. A. et al. Efficacy and safety of aldafermin, an engineered FGF19 analog, in a randomized, double-blind, placebo-controlled trial of patients with nonalcoholic steatohepatitis. Gastroenterology 160, 219–231 (2021).

    Article  CAS  PubMed  Google Scholar 

  154. Sanyal, A. et al. Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet 392, 2705–2717 (2019).

    Article  PubMed  Google Scholar 

  155. Newsome, P. N. et al. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N. Engl. J. Med. 384, 1113–1124 (2021).

    Article  CAS  PubMed  Google Scholar 

  156. Ratziu, V. et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 150, 1147–1159 (2016).

    Article  CAS  PubMed  Google Scholar 

  157. Francque, S. M. et al. A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH. N. Engl. J. Med. 385, 1547–1558 (2021).

    Article  CAS  PubMed  Google Scholar 

  158. Sanyal, A. J. et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N. Engl. J. Med. 362, 1675–1685 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Harrison, S. A. et al. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 394, 2012–2024 (2019).

    Article  CAS  PubMed  Google Scholar 

  160. Scorletti, E. et al. Synbiotics alter fecal microbiomes, but not liver fat or fibrosis, in a randomized trial of patients with nonalcoholic fatty liver disease. Gastroenterology 158, 1597–1610 (2020).

    Article  CAS  PubMed  Google Scholar 

  161. Craven, L. et al. Allogenic fecal microbiota transplantation in patients with nonalcoholic fatty liver disease improves abnormal small intestinal permeability: a randomized control trial. Am. J. Gastroenterol. 115, 1055–1065 (2020).

    Article  PubMed  Google Scholar 

  162. Ratziu, V. et al. Cenicriviroc treatment for adults with nonalcoholic steatohepatitis and fibrosis: final analysis of the phase 2b CENTAUR study. Hepatology 72, 892–905 (2020).

    Article  CAS  PubMed  Google Scholar 

  163. Poore, G. D. et al. Microbiome analyses of blood and tissues suggest cancer diagnostic approach. Nature 579, 567–574 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Sookoian, S. et al. Intrahepatic bacterial metataxonomic signature in non-alcoholic fatty liver disease. Gut 69, 1483–1491 (2020).

    Article  CAS  PubMed  Google Scholar 

  165. Anhe, F. F. et al. Type 2 diabetes influences bacterial tissue compartmentalisation in human obesity. Nat. Metab. 2, 233–242 (2020).

    Article  PubMed  Google Scholar 

  166. Cani, P. D. & Van Hul, M. Microbial signatures in metabolic tissues: a novel paradigm for obesity and diabetes? Nat. Metab. 2, 211–212 (2020).

    Article  PubMed  Google Scholar 

  167. Massier, L. et al. Adipose tissue derived bacteria are associated with inflammation in obesity and type 2 diabetes. Gut 69, 1796–1806 (2020).

    Article  CAS  PubMed  Google Scholar 

  168. Gola, A. et al. Commensal-driven immune zonation of the liver promotes host defence. Nature 589, 131–136 (2021).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

H.T. is supported by the excellence initiative VASCage (Centre for Promoting Vascular Health in the Ageing Community), an R&D K-Centre award (COMET programme (Competence Centers for Excellent Technologies)) funded by the Austrian Ministry for Transport, Innovation and Technology, the Austrian Ministry for Digital and Economic Affairs and the federal states Tyrol, Salzburg and Vienna. P.K. is supported by CRC TRR179 and the German Center for Infection Research, Munich site. T.E.A. is supported by the Austrian Science Fund (FWF P33070).

Author information

Authors and Affiliations

  1. Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria

    Herbert Tilg & Timon E. Adolph

  2. Institute of Molecular Immunology and Experimental Oncology, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany

    Michael Dudek & Percy Knolle

Authors
  1. Herbert Tilg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Timon E. Adolph
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael Dudek
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Percy Knolle
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

H.T., T.E.A., M.D. and P.K. researched data for the article and wrote, reviewed and edited the manuscript.

Corresponding author

Correspondence to Herbert Tilg.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature Metabolism thanks Amir Zarrinpar and the other, anonymous, reviewers for their contribution to the peer review of this work. Primary handling editor: Isabella Samuelson.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tilg, H., Adolph, T.E., Dudek, M. et al. Non-alcoholic fatty liver disease: the interplay between metabolism, microbes and immunity. Nat Metab 3, 1596–1607 (2021). https://doi.org/10.1038/s42255-021-00501-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s42255-021-00501-9

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