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:

Developmental origins of NAFLD: a womb with a clue

Nature Reviews Gastroenterology & Hepatology volume 14, pages 81–96 (2017)Cite this article

Subjects

Key Points

  • Exposure to maternal overnutrition or undernutrition increases susceptibility to NAFLD in childhood and hastens progression to NASH across the lifespan, especially when offspring are exposed postnatally to a high-fat (Western-style) diet

  • Maternal obesity and insulin resistance acting through the placenta produce intrauterine exposures including increased fetal insulin, lipids, inflammation and possibly hypoxia, which cause developmental programming of hepatosteatosis before birth

  • Programming of hepatic pathways including de novo lipogenesis, oxidative stress, mitochondrial dysfunction and inflammation persists in juvenile offspring born to and breastfed by mothers with obesity, despite weaning to a healthy diet

  • Pioneering microorganisms transmitted to the neonate at birth and microorganisms and bioactive milk products transferred during breastfeeding educate the infant immune system with lifelong implications for disease susceptibility

  • Pro-inflammatory and pro-remodelling phenotypes in liver macrophages might be programmed in infancy through alteration of intracellular metabolic and epigenetic pathways, increasing responsiveness to subsequent inflammatory stimuli

  • Supplements in preclinical models targeting novel pathways and receptors might be emerging therapies for use in tandem with a dietary shift to more complex carbohydrates during pregnancy

Abstract

Changes in the maternal environment leading to an altered intrauterine milieu can result in subtle insults to the fetus, promoting increased lifetime disease risk and/or disease acceleration in childhood and later in life. Particularly worrisome is that the prevalence of NAFLD is rapidly increasing among children and adults, and is being diagnosed at increasingly younger ages, pointing towards an early-life origin. A wealth of evidence, in humans and non-human primates, suggests that maternal nutrition affects the placenta and fetal tissues, leading to persistent changes in hepatic metabolism, mitochondrial function, the intestinal microbiota, liver macrophage activation and susceptibility to NASH postnatally. Deleterious exposures in utero include fetal hypoxia, increased nutrient supply, inflammation and altered gut microbiota that might produce metabolic clues, including fatty acids, metabolites, endotoxins, bile acids and cytokines, which prime the infant liver for NAFLD in a persistent manner and increase susceptibility to NASH. Mechanistic links to early disease pathways might involve shifts in lipid metabolism, mitochondrial dysfunction, pioneering gut microorganisms, macrophage programming and epigenetic changes that alter the liver microenvironment, favouring liver injury. In this Review, we discuss how maternal, fetal, neonatal and infant exposures provide developmental clues and mechanisms to help explain NAFLD acceleration and increased disease prevalence. Mechanisms identified in clinical and preclinical models suggest important opportunities for prevention and intervention that could slow down the growing epidemic of NAFLD in the next generation.

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: Early in utero factors programming NAFLD.
Figure 2: Postnatal events contributing to steatosis and progression to NASH.
Figure 3: Early liver microenvironment influences macrophage programming.

Similar content being viewed by others

References

  1. Welsh, J. A., Karpen, S. & Vos, M. B. Increasing prevalence of nonalcoholic fatty liver disease among United States adolescents, 1988–1994 to 2007–2010. J. Pediatr. 162, 496–500 (2013).

    Article  PubMed  Google Scholar 

  2. Ogden, C. L. et al. Trends in obesity prevalence among children and adolescents in the United States, 1988–1994 through 2013–2014. JAMA 315, 2292–2299 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Armstrong, M. J., Adams, L. A., Canbay, A. & Syn, W. K. Extrahepatic complications of nonalcoholic fatty liver disease. Hepatology 59, 1174–1197 (2014).

    Article  CAS  PubMed  Google Scholar 

  4. Masuzaki, R., Karp, S. J. & Omata, M. NAFLD as a risk factor for HCC: new rules of engagement? Hepatol. Int. 10, 533–534 (2016).

    Article  PubMed  Google Scholar 

  5. Goyal, N. P. & Schwimmer, J. B. The progression and natural history of pediatric nonalcoholic fatty liver disease. Clin. Liver Dis. 20, 325–338 (2016).

    Article  PubMed  Google Scholar 

  6. Leung, J. C. et al. Histological severity and clinical outcomes of nonalcoholic fatty liver disease in nonobese patients. Hepatology http://dx.doi.org/10.1002/hep.28697 (2016).

  7. Wree, A., Broderick, L., Canbay, A., Hoffman, H. M. & Feldstein, A. E. From NAFLD to NASH to cirrhosis-new insights into disease mechanisms. Nat. Rev. Gastroenterol. Hepatol. 10, 627–636 (2013).

    Article  CAS  PubMed  Google Scholar 

  8. Heerwagen, M. J., Miller, M. R., Barbour, L. A. & Friedman, J. E. Maternal obesity and fetal metabolic programming: a fertile epigenetic soil. Am. J. Physiol. Regul. Integr. Comp. Physiol. 299, R711–R722 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gluckman, P. D., Hanson, M. A., Cooper, C. & Thornburg, K. L. Effect of in utero and early-life conditions on adult health and disease. N. Engl. J. Med. 359, 61–73 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Weng, S. F. et al. Estimating overweight risk in childhood from predictors during infancy. Pediatrics 132, e414–e421 (2013).

    Article  PubMed  Google Scholar 

  11. Poston, L., Harthoorn, L. F. & Van Der Beek, E. M. Obesity in pregnancy: implications for the mother and lifelong health of the child. A consensus statement. Pediatr. Res. 69, 175–180 (2011).

    Article  PubMed  Google Scholar 

  12. Anderson, E. L. et al. The prevalence of non-alcoholic fatty liver disease in children and adolescents: a systematic review and meta-analysis. PLoS ONE 10, e0140908 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Agopian, V. G. et al. Liver transplantation for nonalcoholic steatohepatitis: the new epidemic. Ann. Surg. 256, 624–633 (2012).

    Article  PubMed  Google Scholar 

  14. Gluckman, P. D. & Hanson, M. A. Living with the past: evolution, development, and patterns of disease. Science 305, 1733–1736 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Dabelea, D. & Crume, T. Maternal environment and the transgenerational cycle of obesity and diabetes. Diabetes 60, 1849–1855 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Boyle, K. E. et al. Mesenchymal stem cells from infants born to obese mothers exhibit greater potential for adipogenesis: the healthy start BabyBUMP project. Diabetes 65, 647–659 (2016).

    Article  CAS  PubMed  Google Scholar 

  17. Brumbaugh, D. E. et al. Intrahepatic fat is increased in the neonatal offspring of obese women with gestational diabetes. J. Pediatr. 162, 930–936 (2013).

    Article  CAS  PubMed  Google Scholar 

  18. Modi, N. et al. The influence of maternal body mass index on infant adiposity and hepatic lipid content. Pediatr. Res. 70, 287–291 (2011).

    Article  PubMed  Google Scholar 

  19. Feldstein, A. E. et al. The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years. Gut 58, 1538–1544 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Gale, C. et al. Adiposity and hepatic lipid in healthy full-term, breastfed, and formula-fed human infants: a prospective short-term longitudinal cohort study. Am. J. Clin. Nutr. 99, 1034–1040 (2014).

    Article  CAS  PubMed  Google Scholar 

  21. Patel, K. R., White, F. V. & Deutsch, G. H. Hepatic steatosis is prevalent in stillborns delivered to women with diabetes mellitus. J. Pediatr. Gastroenterol. Nutr. 60, 152–158 (2015).

    Article  CAS  PubMed  Google Scholar 

  22. Alisi, A., Panera, N., Agostoni, C. & Nobili, V. Intrauterine growth retardation and nonalcoholic fatty liver disease in children. Int. J. Endocrinol. 2011, 269853 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Nobili, V., Alisi, A., Panera, N. & Agostoni, C. Low birth weight and catch-up-growth associated with metabolic syndrome: a ten year systematic review. Pediatr. Endocrinol. Rev. 6, 241–247 (2008).

    PubMed  Google Scholar 

  24. Baker, R. et al. Dysregulated lipid metabolism in adipocyte differentiated umbilical-derived mesenchymal stem cells predicts increased infant adiposity at 5 months of age. Diabetes 65 (Suppl. 1), A65 (2016).

    Google Scholar 

  25. Baker, R. et al. Metabolomic and proteomic analysis of neonatal plasma reveals novel evidence of early metabolic dysregulation from maternal obesity. Diabetes 65 (Suppl. 1), A8 (2016).

    Google Scholar 

  26. Stewart, M. S., Heerwagen, M. J. & Friedman, J. E. Developmental programming of pediatric nonalcoholic fatty liver disease: redefining the “first hit”. Clin. Obstet. Gynecol. 56, 577–590 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Heerwagen, M. J., Stewart, M. S., de la Houssaye, B. A., Janssen, R. C. & Friedman, J. E. Transgenic increase in n-3/n-6 fatty acid ratio reduces maternal obesity-associated inflammation and limits adverse developmental programming in mice. PLoS ONE 8, e67791 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. McCurdy, C. E. et al. Maternal high-fat diet triggers lipotoxicity in the fetal livers of nonhuman primates. J. Clin. Invest. 119, 323–335 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Thorn, S. R. et al. Early life exposure to maternal insulin resistance has persistent effects on hepatic NAFLD in juvenile nonhuman primates. Diabetes 63, 2702–2713 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Grant, W. F. et al. Maternal high fat diet is associated with decreased plasma n-3 fatty acids and fetal hepatic apoptosis in nonhuman primates. PLoS ONE 6, e17261 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bayol, S. A., Simbi, B. H., Fowkes, R. C. & Stickland, N. C. A maternal “junk food” diet in pregnancy and lactation promotes nonalcoholic fatty liver disease in rat offspring. Endocrinology 151, 1451–1461 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bruce, K. D. et al. Maternal high-fat feeding primes steatohepatitis in adult mice offspring, involving mitochondrial dysfunction and altered lipogenesis gene expression. Hepatology 50, 1796–1808 (2009).

    Article  CAS  PubMed  Google Scholar 

  33. Mouralidarane, A. et al. Maternal obesity programs offspring nonalcoholic fatty liver disease by innate immune dysfunction in mice. Hepatology 58, 128–138 (2013).

    Article  CAS  PubMed  Google Scholar 

  34. Oben, J. A. et al. Maternal obesity during pregnancy and lactation programs the development of offspring non-alcoholic fatty liver disease in mice. J. Hepatol. 52, 913–920 (2010).

    Article  CAS  PubMed  Google Scholar 

  35. Wolfe, D. et al. Nutrient sensor-mediated programmed nonalcoholic fatty liver disease in low birthweight offspring. Am. J. Obstet. Gynecol. 207, 308.e1–308.e6 (2012).

    Article  CAS  Google Scholar 

  36. Sarr, O. et al. The differential effects of low birth weight and Western diet consumption upon early life hepatic fibrosis development in guinea pig. J. Physiol. 594, 1753–1772 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hyatt, M. A. et al. Suboptimal maternal nutrition, during early fetal liver development, promotes lipid accumulation in the liver of obese offspring. Reproduction 141, 119–126 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Pramfalk, C. et al. Sex-specific differences in hepatic fat oxidation and synthesis may explain the higher propensity for NAFLD in men. J. Clin. Endocrinol. Metab. 100, 4425–4433 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Strakovsky, R. S., Zhang, X., Zhou, D. & Pan, Y. X. The regulation of hepatic Pon1 by a maternal high-fat diet is gender specific and may occur through promoter histone modifications in neonatal rats. J. Nutr. Biochem. 25, 170–176 (2014).

    Article  CAS  PubMed  Google Scholar 

  40. Zhou, D., Wang, H., Cui, H., Chen, H. & Pan, Y. X. Early-life exposure to high-fat diet may predispose rats to gender-specific hepatic fat accumulation by programming Pepck expression. J. Nutr. Biochem. 26, 433–440 (2015).

    Article  CAS  PubMed  Google Scholar 

  41. Catalano, P. M. & Hauguel-De Mouzon, S. Is it time to revisit the Pedersen hypothesis in the face of the obesity epidemic? Am. J. Obstet. Gynecol. 204, 479–487 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Schaefer-Graf, U. M. et al. Differences in the implications of maternal lipids on fetal metabolism and growth between gestational diabetes mellitus and control pregnancies. Diabet. Med. 28, 1053–1059 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Lawlor, D. A., Relton, C., Sattar, N. & Nelson, S. M. Maternal adiposity—a determinant of perinatal and offspring outcomes? Nat. Rev. Endocrinol. 8, 679–688 (2012).

    Article  PubMed  Google Scholar 

  44. Aye, I. L., Rosario, F. J., Powell, T. L. & Jansson, T. Adiponectin supplementation in pregnant mice prevents the adverse effects of maternal obesity on placental function and fetal growth. Proc. Natl. Acad. Sci. USA 112, 12858–12863 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Shapiro, A. L. et al. Testing the fuel-mediated hypothesis: maternal insulin resistance and glucose mediate the association between maternal and neonatal adiposity, the Healthy Start study. Diabetologia 58, 937–941 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Isganaitis, E. et al. Developmental programming by maternal insulin resistance: hyperinsulinemia, glucose intolerance, and dysregulated lipid metabolism in male offspring of insulin-resistant mice. Diabetes 63, 688–700 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Challier, J. C. et al. Obesity in pregnancy stimulates macrophage accumulation and inflammation in the placenta. Placenta 29, 274–281 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Dimasuay, K. G., Boeuf, P., Powell, T. L. & Jansson, T. Placental responses to changes in the maternal environment determine fetal growth. Front. Physiol. 7, 12 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Roberts, V. H. et al. Beneficial and cautionary outcomes of resveratrol supplementation in pregnant nonhuman primates. FASEB J. 28, 2466–2477 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Frias, A. E. et al. Maternal high-fat diet disturbs uteroplacental hemodynamics and increases the frequency of stillbirth in a nonhuman primate model of excess nutrition. Endocrinology 152, 2456–2464 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Radaelli, T., Varastehpour, A., Catalano, P. & Hauguel-de Mouzon, S. Gestational diabetes induces placental genes for chronic stress and inflammatory pathways. Diabetes 52, 2951–2958 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Frias, A. E. & Grove, K. L. Obesity: a transgenerational problem linked to nutrition during pregnancy. Semin. Reprod. Med. 30, 472–478 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Li, H. P., Chen, X. & Li, M. Q. Gestational diabetes induces chronic hypoxia stress and excessive inflammatory response in murine placenta. Int. J. Clin. Exp. Pathol. 6, 650–659 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Aye, I. L., Jansson, T. & Powell, T. L. Interleukin-1β inhibits insulin signaling and prevents insulin-stimulated system A amino acid transport in primary human trophoblasts. Mol. Cell. Endocrinol. 381, 46–55 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Martin, U., Davies, C., Hayavi, S., Hartland, A. & Dunne, F. Is normal pregnancy atherogenic? Clin. Sci. (Lond.) 96, 421–425 (1999).

    Article  CAS  Google Scholar 

  56. Montelongo, A., Lasunción, M. A., Pallardo, L. F. & Herrera, E. Longitudinal study of plasma lipoproteins and hormones during pregnancy in normal and diabetic women. Diabetes 41, 1651–1659 (1992).

    Article  CAS  PubMed  Google Scholar 

  57. Averna, M. R. et al. Lipids, lipoproteins and apolipoproteins AI, AII, B, CII, CIII and E in newborns. Biol. Neonate 60, 187–192 (1991).

    Article  CAS  PubMed  Google Scholar 

  58. Neary, R. H. et al. Fetal and maternal lipoprotein metabolism in human pregnancy. Clin. Sci. (Lond.) 88, 311–318 (1995).

    Article  CAS  Google Scholar 

  59. McIntyre, H. D. et al. Hormonal and metabolic factors associated with variations in insulin sensitivity in human pregnancy. Diabetes Care 33, 356–360 (2010).

    Article  CAS  PubMed  Google Scholar 

  60. Radaelli, T. et al. Differential regulation of genes for fetoplacental lipid pathways in pregnancy with gestational and type 1 diabetes mellitus. Am. J. Obstet. Gynecol. 201, 209.e1–209.10 (2009).

    Article  CAS  Google Scholar 

  61. Díaz, P., Harris, J., Rosario, F. J., Powell, T. L. & Jansson, T. Increased placental fatty acid transporter 6 and binding protein 3 expression and fetal liver lipid accumulation in a mouse model of obesity in pregnancy. Am. J. Physiol. Regul. Integr. Comp. Physiol. 309, R1569–R1577 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. López-Luna, P., Ortega-Senovilla, H., López-Soldado, I. & Herrera, E. Fate of orally administered radioactive fatty acids in the late-pregnant rat. Am. J. Physiol. Endocrinol. Metab. 310, E367–E377 (2016).

    Article  PubMed  Google Scholar 

  63. Lager, S., Jansson, T. & Powell, T. L. Differential regulation of placental amino acid transport by saturated and unsaturated fatty acids. Am. J. Physiol. Cell Physiol. 307, C738–C744 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lager, S. et al. Oleic acid stimulates system A amino acid transport in primary human trophoblast cells mediated by toll-like receptor 4. J. Lipid Res. 54, 725–733 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Beijar, E. C., Mallard, C. & Powell, T. L. Expression and subcellular localization of TLR-4 in term and first trimester human placenta. Placenta 27, 322–326 (2006).

    Article  CAS  PubMed  Google Scholar 

  66. Musso, G. et al. Association of obstructive sleep apnoea with the presence and severity of non-alcoholic fatty liver disease. A systematic review and meta-analysis. Obes. Rev. 14, 417–431 (2013).

    Article  CAS  PubMed  Google Scholar 

  67. Taricco, E. et al. Effects of gestational diabetes on fetal oxygen and glucose levels in vivo. BJOG 116, 1729–1735 (2009).

    Article  CAS  PubMed  Google Scholar 

  68. Hayes, E. K. et al. Adverse fetal and neonatal outcomes associated with a life-long high fat diet: role of altered development of the placental vasculature. PLoS ONE 7, e33370 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Higgins, M., Felle, P., Mooney, E. E., Bannigan, J. & McAuliffe, F. M. Stereology of the placenta in type 1 and type 2 diabetes. Placenta 32, 564–569 (2011).

    Article  CAS  PubMed  Google Scholar 

  70. Li, Y. et al. GDM-associated insulin deficiency hinders the dissociation of SERT from ERp44 and down-regulates placental 5-HT uptake. Proc. Natl. Acad. Sci. USA 111, E5697–E5705 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Cao, L. et al. Hepatic insulin signaling changes: possible mechanism in prenatal hypoxia-increased susceptibility of fatty liver in adulthood. Endocrinology 153, 4955–4965 (2012).

    Article  CAS  PubMed  Google Scholar 

  72. Sun, Z. & Lazar, M. A. Dissociating fatty liver and diabetes. Trends Endocrinol. Metab. 24, 4–12 (2013).

    Article  CAS  PubMed  Google Scholar 

  73. Hashimoto, K. et al. Protective effect of N-acetylcysteine on liver damage during chronic intrauterine hypoxia in fetal guinea pig. Reprod. Sci. 19, 1001–1009 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Magee, T. R. et al. Down-regulation of transcription factor peroxisome proliferator-activated receptor in programmed hepatic lipid dysregulation and inflammation in intrauterine growth-restricted offspring. Am. J. Obstet. Gynecol. 199, 271.e1–271.e5 (2008).

    Article  CAS  Google Scholar 

  75. Rueda-Clausen, C. F. et al. Hypoxia-induced intrauterine growth restriction increases the susceptibility of rats to high-fat diet-induced metabolic syndrome. Diabetes 60, 507–516 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Bell, R. M. & Coleman, R. A. Enzymes of glycerolipid synthesis in eukaryotes. Annu. Rev. Biochem. 49, 459–487 (1980).

    Article  CAS  PubMed  Google Scholar 

  77. Suter, M. A. et al. A maternal high-fat diet modulates fetal SIRT1 histone and protein deacetylase activity in nonhuman primates. FASEB J. 26, 5106–5114 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Bernstein, I. M., Goran, M. I., Amini, S. B. & Catalano, P. M. Differential growth of fetal tissues during the second half of pregnancy. Am. J. Obstet. Gynecol. 176, 28–32 (1997).

    Article  CAS  PubMed  Google Scholar 

  79. Satapati, S. et al. Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver. J. Lipid Res. 53, 1080–1092 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Sunny, N. E., Parks, E. J., Browning, J. D. & Burgess, S. C. Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease. Cell Metab. 14, 804–810 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Koliaki, C. & Roden, M. Hepatic energy metabolism in human diabetes mellitus, obesity and non-alcoholic fatty liver disease. Mol. Cell. Endocrinol. 379, 35–42 (2013).

    Article  CAS  PubMed  Google Scholar 

  82. Alkhouri, N., Carter-Kent, C. & Feldstein, A. E. Apoptosis in nonalcoholic fatty liver disease: diagnostic and therapeutic implications. Expert Rev. Gastroenterol. Hepatol. 5, 201–212 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Thompson, L. P. & Al-Hasan, Y. Impact of oxidative stress in fetal programming. J. Pregnancy 2012, 582748 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  84. McCoin, C. S., Knotts, T. A., Ono-Moore, K. D., Oort, P. J. & Adams, S. H. Long-chain acylcarnitines activate cell stress and myokine release in C2C12 myotubes: calcium-dependent and -independent effects. Am. J. Physiol. Endocrinol. Metab. 308, E990–E1000 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Kaochar, S. & Tu, B. P. Gatekeepers of chromatin: small metabolites elicit big changes in gene expression. Trends Biochem. Sci. 37, 477–483 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. McCurdy, C. E. et al. Maternal obesity reduces fetal skeletal muscle oxidative capacity in Japanese macaques. JCI Insight, 1, e86612 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Borengasser, S. J. et al. Maternal obesity during gestation impairs fatty acid oxidation and mitochondrial SIRT3 expression in rat offspring at weaning. PLoS ONE 6, e24068 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Burgueño, A. L., Cabrerizo, R., Gonzales Mansilla, N., Sookoian, S. & Pirola, C. J. Maternal high-fat intake during pregnancy programs metabolic-syndrome-related phenotypes through liver mitochondrial DNA copy number and transcriptional activity of liver PPARGC1A. J. Nutr. Biochem. 24, 6–13 (2013).

    Article  CAS  PubMed  Google Scholar 

  89. Sookoian, S. et al. Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: impact of liver methylation of the peroxisome proliferator-activated receptor γ coactivator 1α promoter. Hepatology 52, 1992–2000 (2010).

    Article  CAS  PubMed  Google Scholar 

  90. Gallego-Durán, R. & Romero-Gómez, M. Epigenetic mechanisms in non-alcoholic fatty liver disease: an emerging field. World J. Hepatol. 7, 2497–2502 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Sookoian, S., Gianotti, T. F., Burgueño, A. L. & Pirola, C. J. Fetal metabolic programming and epigenetic modifications: a systems biology approach. Pediatr. Res. 73, 531–542 (2013).

    Article  CAS  PubMed  Google Scholar 

  92. Suter, M. A., Takahashi, D., Grove, K. L. & Aagaard, K. M. Postweaning exposure to a high-fat diet is associated with alterations to the hepatic histone code in Japanese macaques. Pediatr. Res. 74, 252–258 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Gemma, C. et al. Maternal pregestational BMI is associated with methylation of the PPARGC1A promoter in newborns. Obesity (Silver Spring) 17, 1032–1039 (2009).

    Article  CAS  Google Scholar 

  94. Igosheva, N. et al. Maternal diet-induced obesity alters mitochondrial activity and redox status in mouse oocytes and zygotes. PLoS ONE 5, e10074 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Jungheim, E. S. et al. Diet-induced obesity model: abnormal oocytes and persistent growth abnormalities in the offspring. Endocrinology 151, 4039–4046 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Harley, I. T. et al. IL-17 signaling accelerates the progression of nonalcoholic fatty liver disease in mice. Hepatology 59, 1830–1839 (2014).

    Article  CAS  PubMed  Google Scholar 

  98. Boursier, J. et al. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology 63, 764–775 (2016).

    Article  CAS  PubMed  Google Scholar 

  99. Wieland, A., Frank, D. N., Harnke, B. & Bambha, K. Systematic review: microbial dysbiosis and nonalcoholic fatty liver disease. Aliment. Pharmacol. Ther. 42, 1051–1063 (2015).

    Article  CAS  PubMed  Google Scholar 

  100. Schnabl, B. & Brenner, D. A. Interactions between the intestinal microbiome and liver diseases. Gastroenterology 146, 1513–1524 (2014).

    Article  CAS  PubMed  Google Scholar 

  101. Singh, V. et al. Microbiota-dependent hepatic lipogenesis mediated by stearoyl CoA desaturase 1 (SCD1) promotes metabolic syndrome in TLR5-deficient mice. Cell Metab. 22, 983–996 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Ridlon, J. M., Kang, D. J., Hylemon, P. B. & Bajaj, J. S. Bile acids and the gut microbiome. Curr. Opin. Gastroenterol. 30, 332–338 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  103. den Besten, G. et al. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J. Lipid Res. 54, 2325–2340 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Leung, C., Rivera, L., Furness, J. B. & Angus, P. W. The role of the gut microbiota in NAFLD. Nat. Rev. Gastroenterol. Hepatol. 13, 412–425 (2016).

    Article  CAS  PubMed  Google Scholar 

  105. David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014).

    Article  CAS  PubMed  Google Scholar 

  106. Walker, A. W. et al. Dominant and diet-responsive groups of bacteria within the human colonic microbiota. ISME J. 5, 220–230 (2011).

    Article  CAS  PubMed  Google Scholar 

  107. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Ley, R. E. et al. Evolution of mammals and their gut microbes. Science 320, 1647–1651 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Muegge, B. D. et al. Diet drives convergence in gut microbiome functions across mammalian phylogeny and within humans. Science 332, 970–974 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. 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 

  111. Wu, G. D. et al. Comparative metabolomics in vegans and omnivores reveal constraints on diet-dependent gut microbiota metabolite production. Gut 65, 63–72 (2016).

    Article  CAS  PubMed  Google Scholar 

  112. Ma, J. et al. High-fat maternal diet during pregnancy persistently alters the offspring microbiome in a primate model. Nat. Commun. 5, 3889 (2014).

    Article  CAS  PubMed  Google Scholar 

  113. Chu, D. M. et al. The early infant gut microbiome varies in association with a maternal high-fat diet. Genome Med. 8, 77 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Myles, I. A. et al. Parental dietary fat intake alters offspring microbiome and immunity. J. Immunol. 191, 3200–3209 (2013).

    Article  CAS  PubMed  Google Scholar 

  115. Collado, M. C., Isolauri, E., Laitinen, K. & Salminen, S. Distinct composition of gut microbiota during pregnancy in overweight and normal-weight women. Am. J. Clin. Nutr. 88, 894–899 (2008).

    Article  CAS  PubMed  Google Scholar 

  116. Santacruz, A. et al. Gut microbiota composition is associated with body weight, weight gain and biochemical parameters in pregnant women. Br. J. Nutr. 104, 83–92 (2010).

    Article  CAS  PubMed  Google Scholar 

  117. Kalliomäki, M., Collado, M. C., Salminen, S. & Isolauri, E. Early differences in fecal microbiota composition in children may predict overweight. Am. J. Clin. Nutr. 87, 534–538 (2008).

    Article  PubMed  Google Scholar 

  118. Soderborg, T. K., Borengasser, S. J., Barbour, L. A. & Friedman, J. E. Microbial transmission from mothers with obesity or diabetes to infants: an innovative opportunity to interrupt a vicious cycle. Diabetologia 59, 895–906 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Donnet-Hughes, A. et al. Potential role of the intestinal microbiota of the mother in neonatal immune education. Proc. Nutr. Soc. 69, 407–415 (2010).

    Article  PubMed  Google Scholar 

  120. Van den Abbeele, P., Van de Wiele, T., Verstraete, W. & Possemiers, S. The host selects mucosal and luminal associations of coevolved gut microorganisms: a novel concept. FEMS Microbiol. Rev. 35, 681–704 (2011).

    Article  CAS  PubMed  Google Scholar 

  121. Maynard, C. L., Elson, C. O., Hatton, R. D. & Weaver, C. T. Reciprocal interactions of the intestinal microbiota and immune system. Nature 489, 231–241 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Khodayar-Pardo, P., Mira-Pascual, L., Collado, M. C. & Martinez-Costa, C. Impact of lactation stage, gestational age and mode of delivery on breast milk microbiota. J. Perinatol. 34, 599–605 (2014).

    Article  CAS  PubMed  Google Scholar 

  123. Cabrera-Rubio, R. et al. The human milk microbiome changes over lactation and is shaped by maternal weight and mode of delivery. Am. J. Clin. Nutr. 96, 544–551 (2012).

    Article  CAS  PubMed  Google Scholar 

  124. Latuga, M. S., Stuebe, A. & Seed, P. C. A review of the source and function of microbiota in breast milk. Semin. Reprod. Med. 32, 68–73 (2014).

    Article  PubMed  Google Scholar 

  125. Hunt, K. M. et al. Characterization of the diversity and temporal stability of bacterial communities in human milk. PLoS ONE 6, e21313 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Martín, R., Heilig, G. H., Zoetendal, E. G., Smidt, H. & Rodríguez, J. M. Diversity of the Lactobacillus group in breast milk and vagina of healthy women and potential role in the colonization of the infant gut. J. Appl. Microbiol. 103, 2638–2644 (2007).

    Article  CAS  PubMed  Google Scholar 

  127. Solís, G., de Los Reyes-Gavilan, C. G., Fernández, N., Margolles, A. & Gueimonde, M. Establishment and development of lactic acid bacteria and bifidobacteria microbiota in breast-milk and the infant gut. Anaerobe 16, 307–310 (2010).

    Article  PubMed  Google Scholar 

  128. Coppa, G. V., Bruni, S., Morelli, L., Soldi, S. & Gabrielli, O. The first prebiotics in humans: human milk oligosaccharides. J. Clin. Gastroenterol. 38, S80–S83 (2004).

    Article  CAS  PubMed  Google Scholar 

  129. Bode, L. Human milk oligosaccharides: prebiotics and beyond. Nutr. Rev. 67, S183–S191 (2009).

    Article  PubMed  Google Scholar 

  130. Azad, M. B. et al. Gut microbiota of healthy Canadian infants: profiles by mode of delivery and infant diet at 4 months. CMAJ 185, 385–394 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Houghteling, P. D. & Walker, W. A. Why is initial bacterial colonization of the intestine important to infants' and children's health? J. Pediatr. Gastroenterol. Nutr. 60, 294–307 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Giannone, P. J., Schanbacher, B. L., Bauer, J. A. & Reber, K. M. Effects of prenatal lipopolysaccharide exposure on epithelial development and function in newborn rat intestine. J. Pediatr. Gastroenterol. Nutr. 43, 284–290 (2006).

    Article  CAS  PubMed  Google Scholar 

  133. Mirpuri, J. et al. Proteobacteria-specific IgA regulates maturation of the intestinal microbiota. Gut Microbes 5, 28–39 (2014).

    Article  PubMed  Google Scholar 

  134. Wang, Y. & McCusker, C. Neonatal exposure with LPS and/or allergen prevents experimental allergic airways disease: development of tolerance using environmental antigens. J. Allergy Clin. Immunol. 118, 143–151 (2006).

    Article  CAS  PubMed  Google Scholar 

  135. Lemas, D. J. et al. Alterations in human milk leptin and insulin are associated with early changes in the infant intestinal microbiome. Am. J. Clin. Nutr. 103, 1291–1300 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. 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 

  137. Henkel, A. & Green, R. M. The unfolded protein response in fatty liver disease. Semin. Liver Dis. 33, 321–329 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Puri, P. et al. Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology 134, 568–576 (2008).

    Article  CAS  PubMed  Google Scholar 

  139. Gregor, M. F. et al. Endoplasmic reticulum stress is reduced in tissues of obese subjects after weight loss. Diabetes 58, 693–700 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. 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 http://dx.doi.org/10.1002/hep.28709 (2016).

  141. Ridlon, J. M. & Bajaj, J. S. The human gut sterolbiome: bile acid-microbiome endocrine aspects and therapeutics. Acta Pharm. Sin. B 5, 99–105 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Inagaki, T. et al. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc. Natl. Acad. Sci. USA 103, 3920–3925 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Studer, E. et al. Conjugated bile acids activate the sphingosine-1-phosphate receptor 2 in primary rodent hepatocytes. Hepatology 55, 267–276 (2012).

    Article  CAS  PubMed  Google Scholar 

  144. Hylemon, P. B. et al. Bile acids as regulatory molecules. J. Lipid Res. 50, 1509–1520 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Kawamata, Y. et al. A G protein-coupled receptor responsive to bile acids. J. Biol. Chem. 278, 9435–9440 (2003).

    Article  CAS  PubMed  Google Scholar 

  146. Seok, S. et al. Transcriptional regulation of autophagy by an FXR-CREB axis. Nature 516, 108–111 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Perino, A. & Schoonjans, K. TGR5 and immunometabolism: insights from physiology and pharmacology. Trends Pharmacol. Sci. 36, 847–857 (2015).

    Article  CAS  PubMed  Google Scholar 

  148. Yao, J. et al. FXR agonist GW4064 alleviates endotoxin-induced hepatic inflammation by repressing macrophage activation. World J. Gastroenterol. 20, 14430–14441 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Sayin, S. I. et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-β-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 17, 225–235 (2013).

    Article  CAS  PubMed  Google Scholar 

  150. Papacleovoulou, G. et al. Maternal cholestasis during pregnancy programs metabolic disease in offspring. J. Clin. Invest. 123, 3172–3181 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Fiorucci, S. & Distrutti, E. Bile acid-activated receptors, intestinal microbiota, and the treatment of metabolic disorders. Trends Mol. Med. 21, 702–714 (2015).

    Article  CAS  PubMed  Google Scholar 

  152. McMahan, R. H. et al. Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease. J. Biol. Chem. 288, 11761–11770 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Calmus, Y. & Poupon, R. Shaping macrophages function and innate immunity by bile acids: mechanisms and implication in cholestatic liver diseases. Clin. Res. Hepatol. Gastroenterol. 38, 550–556 (2014).

    Article  CAS  PubMed  Google Scholar 

  154. Koenig, J. E. et al. Succession of microbial consortia in the developing infant gut microbiome. Proc. Natl Acad. Sci. USA 108, 4578–4585 (2011).

    Article  PubMed  Google Scholar 

  155. Bäckhed, F. et al. Dynamics and stabilization of the human gut microbiome during the first year of life. Cell Host Microbe 17, 690–703 (2015).

    Article  CAS  PubMed  Google Scholar 

  156. Giorgio, V. et al. Intestinal permeability is increased in children with non-alcoholic fatty liver disease, and correlates with liver disease severity. Dig. Liver Dis. 46, 556–560 (2014).

    Article  PubMed  Google Scholar 

  157. Weaver, L. T., Laker, M. F. & Nelson, R. Intestinal permeability in the newborn. Arch. Dis. Child 59, 236–241 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Jakobsdottir, G., Xu, J., Molin, G., Ahrné, S. & Nyman, M. High-fat diet reduces the formation of butyrate, but increases succinate, inflammation, liver fat and cholesterol in rats, while dietary fibre counteracts these effects. PLoS ONE 8, e80476 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Dawiskiba, T. et al. Serum and urine metabolomic fingerprinting in diagnostics of inflammatory bowel diseases. World J. Gastroenterol. 20, 163–174 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Kotas, M. E. & Medzhitov, R. Homeostasis, inflammation, and disease susceptibility. Cell 160, 816–827 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Okabe, Y. & Medzhitov, R. Tissue biology perspective on macrophages. Nat. Immunol. 17, 9–17 (2016).

    Article  CAS  PubMed  Google Scholar 

  162. Wynn, T. A., Chawla, A. & Pollard, J. W. Macrophage biology in development, homeostasis and disease. Nature 496, 445–455 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Okabe, Y. & Medzhitov, R. Tissue-specific signals control reversible program of localization and functional polarization of macrophages. Cell 157, 832–844 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Xue, J. et al. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 40, 274–288 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Duffield, J. S. et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J. Clin. Invest. 115, 56–65 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Ramachandran, P. et al. Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc. Natl. Acad. Sci. USA 109, E3186–E3195 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  167. Tacke, F. & Zimmermann, H. W. Macrophage heterogeneity in liver injury and fibrosis. J. Hepatol. 60, 1090–1096 (2014).

    Article  CAS  PubMed  Google Scholar 

  168. Karlmark, K. R. et al. Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 50, 261–274 (2009).

    Article  CAS  PubMed  Google Scholar 

  169. Karlmark, K. R. et al. The fractalkine receptor CX3CR1 protects against liver fibrosis by controlling differentiation and survival of infiltrating hepatic monocytes. Hepatology 52, 1769–1782 (2010).

    Article  CAS  PubMed  Google Scholar 

  170. Seki, E. et al. CCR2 promotes hepatic fibrosis in mice. Hepatology 50, 185–197 (2009).

    Article  CAS  PubMed  Google Scholar 

  171. Ensan, S. et al. Self-renewing resident arterial macrophages arise from embryonic CX3CR1+ precursors and circulating monocytes immediately after birth. Nat. Immunol. 17, 159–168 (2016).

    Article  CAS  PubMed  Google Scholar 

  172. Brenner, D. A., Paik, Y. H. & Schnabl, B. Role of gut microbiota in liver disease. J. Clin. Gastroenterol. 49 (Suppl. 1), S25–S27 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Ganz, M. & Szabo, G. Immune and inflammatory pathways in NASH. Hepatol. Int. 7 (Suppl. 2), 771–781 (2013).

    Article  PubMed  Google Scholar 

  174. Szabo, G., Bala, S., Petrasek, J. & Gattu, A. Gut-liver axis and sensing microbes. Dig. Dis. 28, 737–744 (2010).

    Article  PubMed  Google Scholar 

  175. Ilan, Y. Leaky gut and the liver: a role for bacterial translocation in nonalcoholic steatohepatitis. World J. Gastroenterol. 18, 2609–2618 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  176. Mazagova, M. et al. Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice. FASEB J. 29, 1043–1055 (2015).

    Article  CAS  PubMed  Google Scholar 

  177. Hartmann, P., Haimerl, M., Mazagova, M., Brenner, D. A. & Schnabl, B. Toll-like receptor 2-mediated intestinal injury and enteric tumor necrosis factor receptor I contribute to liver fibrosis in mice. Gastroenterology 143, 1330–1340 (2012).

    Article  CAS  PubMed  Google Scholar 

  178. Fouts, D. E., Torralba, M., Nelson, K. E., Brenner, D. A. & Schnabl, B. Bacterial translocation and changes in the intestinal microbiome in mouse models of liver disease. J. Hepatol. 56, 1283–1292 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Miura, K., Seki, E., Ohnishi, H. & Brenner, D. A. Role of toll-like receptors and their downstream molecules in the development of nonalcoholic fatty liver disease. Gastroenterol. Res. Pract. 2010, 362847 (2010).

    Article  PubMed  Google Scholar 

  180. Seki, E. et al. TLR4 enhances TGF-β signaling and hepatic fibrosis. Nat. Med. 13, 1324–1332 (2007).

    Article  CAS  PubMed  Google Scholar 

  181. El Kasmi, K. C. et al. Toll-like receptor 4-dependent Kupffer cell activation and liver injury in a novel mouse model of parenteral nutrition and intestinal injury. Hepatology 55, 1518–1528 (2012).

    Article  CAS  PubMed  Google Scholar 

  182. Tilg, H., Moschen, A. R. & Szabo, G. Interleukin-1 and inflammasomes in alcoholic liver disease/acute alcoholic hepatitis and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology 64, 955–965 (2016).

    Article  CAS  PubMed  Google Scholar 

  183. Szabo, G. Gut-liver axis in alcoholic liver disease. Gastroenterology 148, 30–36 (2015).

    Article  CAS  PubMed  Google Scholar 

  184. Chen, P., Starkel, P., Turner, J. R., Ho, S. B. & Schnabl, B. Dysbiosis-induced intestinal inflammation activates tumor necrosis factor receptor I and mediates alcoholic liver disease in mice. Hepatology 61, 883–894 (2015).

    Article  CAS  PubMed  Google Scholar 

  185. Chen, P. et al. Supplementation of saturated long-chain fatty acids maintains intestinal eubiosis and reduces ethanol-induced liver injury in mice. Gastroenterology 148, 203–214 (2015).

    Article  CAS  PubMed  Google Scholar 

  186. Schnabl, B. Linking intestinal homeostasis and liver disease. Curr. Opin. Gastroenterol. 29, 264–270 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Miura, K. et al. Toll-like receptor 2 and palmitic acid cooperatively contribute to the development of nonalcoholic steatohepatitis through inflammasome activation in mice. Hepatology 57, 577–589 (2013).

    Article  CAS  PubMed  Google Scholar 

  188. Iraporda, C. et al. Lactate and short chain fatty acids produced by microbial fermentation downregulate proinflammatory responses in intestinal epithelial cells and myeloid cells. Immunobiology 220, 1161–1169 (2015).

    Article  CAS  PubMed  Google Scholar 

  189. Österreicher, C. H. et al. Fibroblast-specific protein 1 identifies an inflammatory subpopulation of macrophages in the liver. Proc. Natl Acad. Sci. USA 108, 308–313 (2011).

    Article  PubMed  Google Scholar 

  190. El Kasmi, K. C. & Stenmark, K. R. Contribution of metabolic reprogramming to macrophage plasticity and function. Semin. Immunol. 27, 267–275 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Ramachandran, P., Iredale, J. P. & Fallowfield, J. A. Resolution of liver fibrosis: basic mechanisms and clinical relevance. Semin. Liver Dis. 35, 119–131 (2015).

    Article  CAS  PubMed  Google Scholar 

  192. Pellicoro, A., Ramachandran, P., Iredale, J. P. & Fallowfield, J. A. Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat. Rev. Immunol. 14, 181–194 (2014).

    Article  CAS  PubMed  Google Scholar 

  193. El Kasmi, K. C. et al. Adventitial fibroblasts induce a distinct proinflammatory/profibrotic macrophage phenotype in pulmonary hypertension. J. Immunol. 193, 597–609 (2014).

    Article  CAS  PubMed  Google Scholar 

  194. Netea, M. G. et al. Trained immunity: a program of innate immune memory in health and disease. Science 352, http://dx.doi.org/10.1126/science.aaf1098 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Saeed, S. et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science 345, http://dx.doi.org/10.1126/science.1251086 (2014).

  196. Cheng, S. C. et al. mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. Science 345, http://dx.doi.org/10.1126/science.1250684 (2014).

  197. O'Neill, L. A. & Pearce, E. J. Immunometabolism governs dendritic cell and macrophage function. J. Exp. Med. 213, 15–23 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Foster, S. L., Hargreaves, D. C. & Medzhitov, R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447, 972–978 (2007).

    Article  CAS  PubMed  Google Scholar 

  199. Mills, E. L. & O'Neill, L. A. Reprogramming mitochondrial metabolism in macrophages as an anti-inflammatory signal. Eur. J. Immunol. 46, 13–21 (2016).

    Article  CAS  PubMed  Google Scholar 

  200. Ng, R. L. et al. Altered immunity and dendritic cell activity in the periphery of mice after long-term engraftment with bone marrow from ultraviolet-irradiated mice. J. Immunol. 190, 5471–5484 (2013).

    Article  CAS  PubMed  Google Scholar 

  201. Burgess, S. L. et al. Bone marrow dendritic cells from mice with an altered microbiota provide interleukin 17A-dependent protection against Entamoeba histolytica colitis. MBio 5, e01817 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Galván-Peña, S. & O'Neill, L. A. Metabolic reprograming in macrophage polarization. Front. Immunol. 5, 420 (2014).

    PubMed  PubMed Central  Google Scholar 

  203. Palsson-McDermott, E. M. et al. Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the warburg effect in LPS-activated macrophages. Cell Metab. 21, 65–80 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Perdiguero, E. G. & Geissmann, F. The development and maintenance of resident macrophages. Nat. Immunol. 17, 2–8 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Kierdorf, K., Prinz, M., Geissmann, F. & Gomez Perdiguero, E. Development and function of tissue resident macrophages in mice. Semin. Immunol. 27, 369–378 (2016).

    Article  CAS  PubMed Central  Google Scholar 

  206. Hoeffel, G. et al. C-Myb+ erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity 42, 665–678 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Piccinini, A. M., Zuliani-Alvarez, L., Lim, J. M. P. & Midwood, K. S. Distinct microenvironmental cues stimulate divergent TLR4-mediated signaling pathways in macrophages. Sci. Signal. 9, ra86 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Harris, J. K. et al. Specific microbiome changes in a mouse model of parenteral nutrition associated liver injury and intestinal inflammation. PLoS ONE 9, e110396 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. El Kasmi, K. C. et al. Phytosterols promote liver injury and Kupffer cell activation in parenteral nutrition-associated liver disease. Sci. Transl. Med. 5, 206ra137 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Morris, M. W. Jr et al. Modulation of the inflammatory response by increasing fetal wound size or interleukin-10 overexpression determines wound phenotype and scar formation. Wound Repair Regen. 22, 406–414 (2014).

    Article  PubMed  Google Scholar 

  211. Godfrey, K. M., Gluckman, P. D. & Hanson, M. A. Developmental origins of metabolic disease: life course and intergenerational perspectives. Trends Endocrinol. Metab. 21, 199–205 (2010).

    Article  CAS  PubMed  Google Scholar 

  212. Syngelaki, A. et al. Metformin versus placebo in obese pregnant women without diabetes mellitus. N. Engl. J. Med. 374, 434–443 (2016).

    Article  CAS  PubMed  Google Scholar 

  213. Chiswick, C. et al. Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 3, 778–786 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Rowan, J. A., Hague, W. M., Gao, W., Battin, M. R. & Moore, M. P. Metformin versus insulin for the treatment of gestational diabetes. N. Engl. J. Med. 358, 2003–2015 (2008).

    Article  CAS  PubMed  Google Scholar 

  215. Rowan, J. A. et al. Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition at 2 years of age. Diabetes Care 34, 2279–2284 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Flynn, A. C. et al. Dietary interventions in overweight and obese pregnant women: a systematic review of the content, delivery, and outcomes of randomized controlled trials. Nutr. Rev. 74, 312–328 (2016).

    Article  PubMed  Google Scholar 

  217. Oteng-Ntim, E., Varma, R., Croker, H., Poston, L. & Doyle, P. Lifestyle interventions for overweight and obese pregnant women to improve pregnancy outcome: systematic review and meta-analysis. BMC Med. 10, 47 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  218. Hernandez, T. L. et al. Women with gestational diabetes randomized to a higher-complex carbohydrate/low-fat diet manifest lower adipose tissue insulin resistance, inflammation, glucose, and free fatty acids: a pilot study. Diabetes Care 39, 39–42 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Hernandez, T. L. et al. A higher-complex carbohydrate diet in gestational diabetes mellitus achieves glucose targets and lowers postprandial lipids: a randomized crossover study. Diabetes Care 37, 1254–1262 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Patterson, E. et al. Gut microbiota, obesity and diabetes. Postgrad. Med. J. 92, 286–300 (2016).

    Article  CAS  PubMed  Google Scholar 

  221. Cotillard, A. et al. Dietary intervention impact on gut microbial gene richness. Nature 500, 585–588 (2013).

    Article  CAS  PubMed  Google Scholar 

  222. Le Chatelier, E. et al. Richness of human gut microbiome correlates with metabolic markers. Nature 500, 541–546 (2013).

    Article  CAS  PubMed  Google Scholar 

  223. Remely, M. et al. Gut microbiota composition correlates with changes in body fat content due to weight loss. Benef. Microbes 6, 431–439 (2015).

    Article  CAS  PubMed  Google Scholar 

  224. Rautava, S., Collado, M. C., Salminen, S. & Isolauri, E. Probiotics modulate host-microbe interaction in the placenta and fetal gut: a randomized, double-blind, placebo-controlled trial. Neonatology 102, 178–184 (2012).

    Article  PubMed  Google Scholar 

  225. Ilmonen, J., Isolauri, E., Poussa, T. & Laitinen, K. Impact of dietary counselling and probiotic intervention on maternal anthropometric measurements during and after pregnancy: a randomized placebo-controlled trial. Clin. Nutr. 30, 156–164 (2011).

    Article  PubMed  Google Scholar 

  226. Luoto, R., Kalliomäki, M., Laitinen, K. & Isolauri, E. The impact of perinatal probiotic intervention on the development of overweight and obesity: follow-up study from birth to 10 years. Int. J. Obes. (Lond.) 34, 1531–1537 (2010).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  228. Savcheniuk, O. et al. Short-term periodic consumption of multiprobiotic from childhood improves insulin sensitivity, prevents development of non-alcoholic fatty liver disease and adiposity in adult rats with glutamate-induced obesity. BMC Complement. Altern. Med. 14, 247 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  229. Singh, A. K., Pandey, S. K. & Naresh Kumar, G. Pyrroloquinoline quinone-secreting probiotic Escherichia coli Nissle 1917 ameliorates ethanol-induced oxidative damage and hyperlipidemia in rats. Alcohol. Clin. Exp. Res. 38, 2127–2137 (2014).

    Article  CAS  PubMed  Google Scholar 

  230. Pham, V. T., Lacroix, C., Braegger, C. P. & Chassard, C. Early colonization of functional groups of microbes in the infant gut. Environ. Microbiol. 18, 2246–2258 (2016).

    Article  CAS  PubMed  Google Scholar 

  231. Mudaliar, S. et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 145, 574–582 (2013).

    Article  CAS  PubMed  Google Scholar 

  232. Neuschwander-Tetri, B. A. et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385, 956–965 (2015).

    Article  CAS  PubMed  Google Scholar 

  233. Carr, R. M. & Reid, A. E. FXR agonists as therapeutic agents for non-alcoholic fatty liver disease. Curr. Atheroscler. Rep. 17, http://dx.doi.org/10.1007/s11883-015-0500-2 (2015).

  234. Ferslew, B. C. et al. Altered bile acid metabolome in patients with nonalcoholic steatohepatitis. Dig. Dis. Sci. 60, 3318–3328 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Bernhard, W. et al. Choline supply of preterm infants: assessment of dietary intake and pathophysiological considerations. Eur. J. Nutr. 52, 1269–1278 (2013).

    Article  CAS  PubMed  Google Scholar 

  236. Cai, D. et al. Maternal dietary betaine supplementation modifies hepatic expression of cholesterol metabolic genes via epigenetic mechanisms in newborn piglets. Br. J. Nutr. 112, 1459–1468 (2014).

    Article  CAS  PubMed  Google Scholar 

  237. Guy, C. D. et al. Hedgehog pathway activation parallels histologic severity of injury and fibrosis in human nonalcoholic fatty liver disease. Hepatology 55, 1711–1721 (2012).

    Article  CAS  PubMed  Google Scholar 

  238. Briscoe, J. & Thérond, P. P. The mechanisms of hedgehog signalling and its roles in development and disease. Nat. Rev. Mol. Cell Biol. 14, 416–429 (2013).

    Article  CAS  PubMed  Google Scholar 

  239. Kwon, H. et al. Inhibition of hedgehog signaling ameliorates hepatic inflammation in mice with nonalcoholic fatty liver disease. Hepatology 63, 1155–1169 (2016).

    Article  CAS  PubMed  Google Scholar 

  240. Guy, C. D., Suzuki, A., Abdelmalek, M. F., Burchette, J. L. & Diehl, A. M. Treatment response in the PIVENS trial is associated with decreased hedgehog pathway activity. Hepatology 61, 98–107 (2015).

    Article  CAS  PubMed  Google Scholar 

  241. West, C. E. et al. Associations between maternal antioxidant intakes in pregnancy and infant allergic outcomes. Nutrients 4, 1747–1758 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Greenough, A., Shaheen, S. O., Shennan, A., Seed, P. T. & Poston, L. Respiratory outcomes in early childhood following antenatal vitamin C and E supplementation. Thorax 65, 998–1003 (2010).

    Article  PubMed  Google Scholar 

  243. Infante, P., Alfonsi, R., Botta, B., Mori, M. & Di Marcotullio, L. Targeting GLI factors to inhibit the hedgehog pathway. Trends Pharmacol. Sci. 36, 547–558 (2015).

    Article  CAS  PubMed  Google Scholar 

  244. Magnusardottir, A. R., Steingrimsdottir, L., Thorgeirsdottir, H., Hauksson, A. & Skuladottir, G. V. Red blood cell n-3 polyunsaturated fatty acids in first trimester of pregnancy are inversely associated with placental weight. Acta Obstet. Gynecol. Scand. 88, 91–97 (2009).

    Article  CAS  PubMed  Google Scholar 

  245. Stene, L. C. & Joner, G. Use of cod liver oil during the first year of life is associated with lower risk of childhood-onset type 1 diabetes: a large, population-based, case-control study. Am. J. Clin. Nutr. 78, 1128–1134 (2003).

    Article  CAS  PubMed  Google Scholar 

  246. Oien, T., Storrø, O. & Johnsen, R. Do early intake of fish and fish oil protect against eczema and doctor-diagnosed asthma at 2 years of age? A cohort study. J. Epidemiol. Community Health 64, 124–129 (2010).

    Article  PubMed  Google Scholar 

  247. Loguercio, C. et al. Silybin combined with phosphatidylcholine and vitamin E in patients with nonalcoholic fatty liver disease: a randomized controlled trial. Free Radic. Biol. Med. 52, 1658–1665 (2012).

    Article  CAS  PubMed  Google Scholar 

  248. Sorrentino, G., Crispino, P., Coppola, D. & De Stefano, G. Efficacy of lifestyle changes in subjects with non-alcoholic liver steatosis and metabolic syndrome may be improved with an antioxidant nutraceutical: a controlled clinical study. Drugs R. D. 15, 21–25 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Sen, S. & Simmons, R. A. Maternal antioxidant supplementation prevents adiposity in the offspring of Western diet-fed rats. Diabetes 59, 3058–3065 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Chen, S. et al. Resveratrol improves insulin resistance, glucose and lipid metabolism in patients with non-alcoholic fatty liver disease: a randomized controlled trial. Dig. Liver Dis. 47, 226–232 (2015).

    Article  CAS  PubMed  Google Scholar 

  251. Vega, C. C. et al. Resveratrol partially prevents oxidative stress and metabolic dysfunction in pregnant rats fed a low protein diet and their offspring. J. Physiol. 594, 1483–1499 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Bourque, S. L., Dolinsky, V. W., Dyck, J. R. & Davidge, S. T. Maternal resveratrol treatment during pregnancy improves adverse fetal outcomes in a rat model of severe hypoxia. Placenta 33, 449–452 (2012).

    Article  CAS  PubMed  Google Scholar 

  253. Poudel, R. et al. Effects of resveratrol in pregnancy using murine models with reduced blood supply to the uterus. PLoS ONE 8, e64401 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Hassanzadeh, P., Arbabi, E., Atyabi, F. & Dinarvand, R. The endocannabinoid system and NGF are involved in the mechanism of action of resveratrol: a multi-target nutraceutical with therapeutic potential in neuropsychiatric disorders. Psychopharmacology (Berl.) 233, 1087–1096 (2016).

    Article  CAS  Google Scholar 

  255. Pacher, P. & Kunos, G. Modulating the endocannabinoid system in human health and disease—successes and failures. FEBS J. 280, 1918–1943 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Maccarrone, M. et al. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol. Sci. 36, 277–296 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Lipina, C., Rastedt, W., Irving, A. J. & Hundal, H. S. New vistas for treatment of obesity and diabetes? Endocannabinoid signalling and metabolism in the modulation of energy balance. Bioessays 34, 681–691 (2012).

    Article  CAS  PubMed  Google Scholar 

  258. Fezza, F. et al. Endocannabinoids, related compounds and their metabolic routes. Molecules 19, 17078–17106 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Pertwee, R. G. et al. International union of basic and clinical pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2 . Pharmacol. Rev. 62, 588–631 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. Cani, P. D., Everard, A. & Duparc, T. Gut microbiota, enteroendocrine functions and metabolism. Curr. Opin. Pharmacol. 13, 935–940 (2013).

    Article  CAS  PubMed  Google Scholar 

  261. Jourdan, T. et al. Antagonism of peripheral hepatic cannabinoid receptor-1 improves liver lipid metabolism in mice: evidence from cultured explants. Hepatology 55, 790–799 (2012).

    Article  CAS  PubMed  Google Scholar 

  262. Liu, J. et al. Hepatic cannabinoid receptor-1 mediates diet-induced insulin resistance via inhibition of insulin signaling and clearance in mice. Gastroenterology 142, 1218–1228 (2012).

    Article  CAS  PubMed  Google Scholar 

  263. Jeong, W. I. et al. Paracrine activation of hepatic CB1 receptors by stellate cell-derived endocannabinoids mediates alcoholic fatty liver. Cell Metab. 7, 227–235 (2008).

    Article  CAS  PubMed  Google Scholar 

  264. Julien, B. et al. Antifibrogenic role of the cannabinoid receptor CB2 in the liver. Gastroenterology 128, 742–755 (2005).

    Article  CAS  PubMed  Google Scholar 

  265. Mallat, A., Teixeira-Clerc, F., Deveaux, V., Manin, S. & Lotersztajn, S. The endocannabinoid system as a key mediator during liver diseases: new insights and therapeutic openings. Br. J. Pharmacol. 163, 1432–1440 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Muñoz-Luque, J. et al. Regression of fibrosis after chronic stimulation of cannabinoid CB2 receptor in cirrhotic rats. J. Pharmacol. Exp. Ther. 324, 475–483 (2008).

    Article  CAS  PubMed  Google Scholar 

  267. Guillot, A. et al. Cannabinoid receptor 2 counteracts interleukin-17-induced immune and fibrogenic responses in mouse liver. Hepatology 59, 296–306 (2014).

    Article  CAS  PubMed  Google Scholar 

  268. Louvet, A. et al. Cannabinoid CB2 receptors protect against alcoholic liver disease by regulating Kupffer cell polarization in mice. Hepatology 54, 1217–1226 (2011).

    Article  CAS  PubMed  Google Scholar 

  269. Bátkai, S. et al. Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury. FASEB J. 21, 1788–1800 (2007).

    Article  CAS  PubMed  Google Scholar 

  270. Cao, Z. et al. Monoacylglycerol lipase controls endocannabinoid and eicosanoid signaling and hepatic injury in mice. Gastroenterology 144, 808–817 (2013).

    Article  CAS  PubMed  Google Scholar 

  271. Tanvig, M. et al. Anthropometrics and body composition by dual energy X-ray in children of obese women: a follow-up of a randomized controlled trial (the Lifestyle in Pregnancy and Offspring [LiPO] study). PLoS ONE 9, e89590 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. Gillman, M. W. et al. Effect of treatment of gestational diabetes mellitus on obesity in the next generation. Diabetes Care 33, 964–968 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  273. Martin, R. M. et al. Effects of promoting longer-term and exclusive breastfeeding on cardiometabolic risk factors at age 11.5 years: a cluster-randomized, controlled trial. Circulation 129, 321–329 (2014).

    Article  CAS  PubMed  Google Scholar 

  274. Kramer, M. S. et al. Effects of prolonged and exclusive breastfeeding on child height, weight, adiposity, and blood pressure at age 6.5 y: evidence from a large randomized trial. Am. J. Clin. Nutr. 86, 1717–1721 (2007).

    Article  CAS  PubMed  Google Scholar 

  275. Wen, L. M. et al. Effectiveness of home based early intervention on children's BMI at age 2: randomised controlled trial. BMJ 344, e3732 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  276. Navarro, J. I., Sigulem, D. M., Ferraro, A. A., Polanco, J. J. & Barros, A. J. The double task of preventing malnutrition and overweight: a quasi-experimental community-based trial. BMC Public Health 13, 212 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  277. Hauner, H. et al. Effect of reducing the n-6:n-3 long-chain PUFA ratio during pregnancy and lactation on infant adipose tissue growth within the first year of life: an open-label randomized controlled trial. Am. J. Clin. Nutr. 95, 383–394 (2012).

    Article  CAS  PubMed  Google Scholar 

  278. Much, D. et al. Effect of dietary intervention to reduce the n-6/n-3 fatty acid ratio on maternal and fetal fatty acid profile and its relation to offspring growth and body composition at 1 year of age. Eur. J. Clin. Nutr. 67, 282–288 (2013).

    Article  CAS  PubMed  Google Scholar 

  279. Lauritzen, L., Hoppe, C., Straarup, E. M. & Michaelsen, K. F. Maternal fish oil supplementation in lactation and growth during the first 2.5 years of life. Pediatr. Res. 58, 235–242 (2005).

    Article  CAS  PubMed  Google Scholar 

  280. Asserhøj, M., Nehammer, S., Matthiessen, J., Michaelsen, K. F. & Lauritzen, L. Maternal fish oil supplementation during lactation may adversely affect long-term blood pressure, energy intake, and physical activity of 7-year-old boys. J. Nutr. 139, 298–304 (2009).

    Article  CAS  PubMed  Google Scholar 

  281. Andersen, A. D., Michaelsen, K. F., Hellgren, L. I., Trolle, E. & Lauritzen, L. A randomized controlled intervention with fish oil versus sunflower oil from 9 to 18 months of age: exploring changes in growth and skinfold thicknesses. Pediatr. Res. 70, 368–374 (2011).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are supported by the NIH–National Institute of Diabetes and Digestive and Kidney Diseases (R24 DK090964), the American Diabetes Association (ADA 1-13-GSK-13), and the Colorado NIH Nutrition and Obesity Research Center (NORC; P30 DK048520). We thank R. C. Janssen for help with editing the manuscript.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Section of Neonatology, University of Colorado, Anschutz Medical Campus, 12801 East 17th Avenue, MS 8106, Aurora, 80045, Colorado, USA

    Stephanie R. Wesolowski & Jacob E. Friedman

  2. Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, University of Colorado, Anschutz Medical Campus, 12801 East 17th Avenue, MS 8106, Aurora, 80045, Colorado, USA

    Karim C. El Kasmi

  3. Department of Anesthesiology, University of Colorado, Anschutz Medical Campus, 12801 East 17th Avenue, MS 8106, Aurora, 80045, Colorado, USA

    Karen R. Jonscher

  4. Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado, Anschutz Medical Campus, 12801 East 17th Avenue, MS 8106, Aurora, 80045, Colorado, USA

    Jacob E. Friedman

Authors
  1. Stephanie R. Wesolowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karim C. El Kasmi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Karen R. Jonscher
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jacob E. Friedman
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched data for the article, provided a substantial contribution to discussion of content, wrote the article, and reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Jacob E. Friedman.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wesolowski, S., Kasmi, K., Jonscher, K. et al. Developmental origins of NAFLD: a womb with a clue. Nat Rev Gastroenterol Hepatol 14, 81–96 (2017). https://doi.org/10.1038/nrgastro.2016.160

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrgastro.2016.160

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