The role of the intestinal permeability in the progression of nonalcoholic fatty liver disease in obese children




intestinal permeability, non-alcoholic fatty liver disease, obesity, children, review


Many studies in recent years have revealed increased intestinal permeability in the non-alcoholic fatty liver disease (NAFLD) development and progression to nonalcoholic steatohepatitis (NASH) and liver fibrosis. The prevalence, course, and diagnostic criteria of pediatric NAFLD were considered in the article. The role of increased intestinal permeability in the pathogenesis of NAFLD has been demonstrated. Attention was paid to the structure of the intestinal barrier and possible methods for its permeability examination. Current studies of intestinal permeability in NAFLD in adults and children, which confirm its key role in the progression of NAFLD, were reviewed. A literature search was conducted in electronic databases Scopus, MedLine, EMBASE, Pubmed, Google Scholar, etc.


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Rehm JL, Connor EL, Wolfgram PM, Eickhoff JC, Reeder SB, Allen DB. Predicting hepatic steatosis in a racially and ethnically diverse cohort of adolescent girls. J Pediatr. 2014;165(2):319-325.e1. doi:10.1016/j.jpeds.2014.04.019.

Anderson EL, Howe LD, Jones HE, Higgins JP, Lawlor DA, Fraser A. The Prevalence of Non-Alcoholic Fatty Liver Disease in Children and Adolescents: A Systematic Review and Meta-Analysis. PLoS One. 2015;10(10):e0140908. doi:10.1371/journal.pone.0140908.

Yu EL, Golshan S, Harlow KE, et al. Prevalence of Nonalcoholic Fatty Liver Disease in Children with Obesity. J Pediatr. 2019;207:64-70. doi:10.1016/j.jpeds.2018.11.021.

Tricò D, Caprio S, Rosaria Umano G, et al. Metabolic Features of Nonalcoholic Fatty Liver (NAFL) in Obese Adolescents: Findings From a Multiethnic Cohort. Hepatology. 2018 Oct;68(4):1376-1390. doi: 10.1002/hep.30035.

Younossi Z, Anstee QM, Marietti M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15(1):11-20. doi: 10.1038/nrgastro.2017.109.

Mandala A, Janssen RC, Palle S, Short KR, Friedman JE. Pediatric Non-Alcoholic Fatty Liver Disease: Nutritional Origins and Potential Molecular Mechanisms. Nutrients. 2020;12(10):3166. doi:10.3390/nu12103166.

Vos MB, Abrams SH, Barlow SE, et al. NASPGHAN Clinical Practice Guideline for the Diagnosis and Treatment of Nonalcoholic Fatty Liver Disease in Children: Recommendations from the Expert Committee on NAFLD (ECON) and the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN). J Pediatr Gastroenterol Nutr. 2017;64(2):319-334. doi:10.1097/MPG.0000000000001482.

D'Adamo E, Castorani V, Nobili V. The Liver in Children With Metabolic Syndrome. Front Endocrinol (Lausanne). 2019 Aug 2;10:514. doi: 10.3389/fendo.2019.00514.

Jennison E, Byrne CD. The role of the gut microbiome and diet in the pathogenesis of non-alcoholic fatty liver disease. Clin Mol Hepatol. 2021;27(1):22-43. doi:10.3350/cmh.2020.0129.

Schwimmer JB, Zepeda A, Newton KP, et al. Longitudinal assessment of high blood pressure in children with nonalcoholic fatty liver disease. PLoS One. 2014;9(11):e112569. doi:10.1371/journal.pone.0112569.

Holterman AX, Guzman G, Fantuzzi G, et al. Nonalcoholic fatty liver disease in severely obese adolescent and adult patients. Obesity (Silver Spring). 2013 Mar;21(3):591-7. doi: 10.1002/oby.20174.

Nier A, Brandt A, Conzelmann IB, Özel Y, Bergheim I. Non-Alcoholic Fatty Liver Disease in Overweight Children: Role of Fructose Intake and Dietary Pattern. Nutrients. 2018;10(9):1329. doi:10.3390/nu10091329.

Pendyala S, Walker JM, Holt PR. A high-fat diet is associated with endotoxemia that originates from the gut. Gastroenterology. 2012;142(5):1100-1101.e2. doi:10.1053/j.gastro.2012.01.034.

Netto Candido TL, Bressan J, Alfenas RCG. Dysbiosis and metabolic endotoxemia induced by high-fat diet. Nutr Hosp. 2018 Dec 3;35(6):1432-1440. English. doi: 10.20960/nh.1792.

Plaza-Díaz J, Solís-Urra P, Rodríguez-Rodríguez F, et al. The Gut Barrier, Intestinal Microbiota, and Liver Disease: Molecular Mechanisms and Strategies to Manage. Int J Mol Sci. 2020;21(21):8351. doi:10.3390/ijms21218351.

Di Ciaula A, Baj J, Garruti G, et al. Liver Steatosis, Gut-Liver Axis, Microbiome and Environmental Factors. A Never-Ending Bidirectional Cross-Talk. J Clin Med. 2020 Aug 14;9(8):2648. doi: 10.3390/jcm9082648.

Nighot M, Al-Sadi R, Guo S, et al. Lipopolysaccharide-Induced Increase in Intestinal Epithelial Tight Permeability Is Mediated by Toll-Like Receptor 4/Myeloid Differentiation Primary Response 88 (MyD88) Activation of Myosin Light Chain Kinase Expression. Am J Pathol. 2017 Dec;187(12):2698-2710. doi: 10.1016/j.ajpath.2017.08.005.

Guo S, Nighot M, Al-Sadi R, Alhmoud T, Nighot P, Ma TY. Lipopolysaccharide Regulation of Intestinal Tight Junction Permeability Is Mediated by TLR4 Signal Transduction Pathway Activation of FAK and MyD88. J Immunol. 2015;195(10):4999-5010. doi:10.4049/jimmunol.1402598.

Sharifnia T, Antoun J, Verriere TG, et al. Hepatic TLR4 signaling in obese NAFLD. Am J Physiol Gastrointest Liver Physiol. 2015;309(4):G270-G278. doi:10.1152/ajpgi.00304.2014.

Liu J, Zhuang ZJ, Bian DX, et al. Toll-like receptor-4 signalling in the progression of non-alcoholic fatty liver disease induced by high-fat and high-fructose diet in mice. Clin Exp Pharmacol Physiol. 2014 Jul;41(7):482-8. doi: 10.1111/1440-1681.12241.

Mouzaki M, Loomba R. Insights into the evolving role of the gut microbiome in nonalcoholic fatty liver disease: rationale and prospects for therapeutic intervention. Therap Adv Gastroenterol. 2019;12:1756284819858470. doi:10.1177/1756284819858470.

Kisseleva T, Brenner DA. Hepatic stellate cells and the reversal of fibrosis. J Gastroenterol Hepatol. 2006 Oct;21 Suppl 3:S84-7. doi: 10.1111/j.1440-1746.2006.04584.x.

Giorgio V, Miele L, Principessa L, et al. Intestinal permeability is increased in children with non-alcoholic fatty liver disease, and correlates with liver disease severity. Dig Liver Dis. 2014 Jun;46(6):556-60. doi: 10.1016/j.dld.2014.02.010.

Imajo K, Fujita K, Yoneda M, et al. Hyperresponsivity to low-dose endotoxin during progression to nonalcoholic steatohepatitis is regulated by leptin-mediated signaling. Cell Metab. 2012 Jul 3;16(1):44-54. doi: 10.1016/j.cmet.2012.05.012.

Mouries J, Brescia P, Silvestri A, et al. Microbiota-driven gut vascular barrier disruption is a prerequisite for non-alcoholic steatohepatitis development. J Hepatol. 2019;71(6):1216-1228. doi:10.1016/j.jhep.2019.08.005.

Zhou J, Tripathi M, Sinha RA, Singh BK, Yen PM. Gut microbiota and their metabolites in the progression of non-alcoholic fatty liver disease. Hepatoma Res. 2021 Jan 13;7:11. doi: 10.20517/2394-5079.2020.134.

Kirpich IA, Marsano LS, McClain CJ. Gut-liver axis, nutrition, and non-alcoholic fatty liver disease. Clin Biochem. 2015;48(13-14):923-930. doi:10.1016/j.clinbiochem.2015.06.023.

Poeta M, Pierri L, Vajro P. Gut-Liver Axis Derangement in Non-Alcoholic Fatty Liver Disease. Children (Basel). 2017;4(8):66. doi:10.3390/children4080066.

Mohammad S, Thiemermann C. Role of Metabolic Endotoxemia in Systemic Inflammation and Potential Interventions. Front Immunol. 2021;11:594150. doi:10.3389/fimmu.2020.594150.

Chen D, Le TH, Shahidipour H, Read SA, Ahlenstiel G. The Role of Gut-Derived Microbial Antigens on Liver Fibrosis Initiation and Progression. Cells. 2019;8(11):1324. doi:10.3390/cells8111324.

Ilan Y. Leaky gut and the liver: a role for bacterial translocation in nonalcoholic steatohepatitis. World J Gastroenterol. 2012;18(21):2609-2618. doi:10.3748/wjg.v18.i21.2609.

Inzaugarat ME, Wree A, Feldstein AE. Hepatocyte mitochondrial DNA released in microparticles and toll-like receptor 9 activation: A link between lipotoxicity and inflammation during nonalcoholic steatohepatitis. Hepatology. 2016;64(2):669-671. doi:10.1002/hep.28666.

Alisi A, Manco M, Devito R, Piemonte F, Nobili V. Endotoxin and plasminogen activator inhibitor-1 serum levels associated with nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr. 2010 Jun;50(6):645-9. doi: 10.1097/MPG.0b013e3181c7bdf1.

Wong VW, Wong GL, Chan HY, et al. Bacterial endotoxin and non-alcoholic fatty liver disease in the general population: a prospective cohort study. Aliment Pharmacol Ther. 2015;42(6):731-40. doi: 10.1111/apt.13327.

Miele L, Valenza V, La Torre G, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology. 2009;49(6):1877-87. doi: 10.1002/hep.22848.

Luther J, Garber JJ, Khalili H, et al. Hepatic Injury in Nonalcoholic Steatohepatitis Contributes to Altered Intestinal Permeability. Cell Mol Gastroenterol Hepatol. 2015 Mar;1(2):222-232. doi: 10.1016/j.jcmgh.2015.01.001.

Schoultz I, Keita AV. The Intestinal Barrier and Current Techniques for the Assessment of Gut Permeability. Cells. 2020;9(8):1909. doi:10.3390/cells9081909.

Albillos A, de Gottardi A, Rescigno M. The gut-liver axis in liver disease: Pathophysiological basis for therapy. J Hepatol. 2020 Mar;72(3):558-577. doi: 10.1016/j.jhep.2019.10.003.

Dai X, Hou H, Zhang W, et al. Microbial Metabolites: Critical Regulators in NAFLD. Front Microbiol. 2020;11:567654. doi:10.3389/fmicb.2020.567654.

Chopyk DM, Grakoui A. Contribution of the Intestinal Microbiome and Gut Barrier to Hepatic Disorders. Gastroenterology. 2020;159(3):849-863. doi: 10.1053/j.gastro.2020.04.077.

Van Itallie CM, Anderson JM. Architecture of tight junctions and principles of molecular composition. Semin Cell Dev Biol. 2014;36:157-65. doi: 10.1016/j.semcdb.2014.08.011.

Guo S, Al-Sadi R, Said HM, Ma TY. Lipopolysaccharide causes an increase in intestinal tight junction permeability in vitro and in vivo by inducing enterocyte membrane expression and localization of TLR-4 and CD14. Am J Pathol. 2013 Feb;182(2):375-87. doi: 10.1016/j.ajpath.2012.10.014.

Plaza-Díaz J, Solis-Urra P, Aragón-Vela J, Rodríguez-Rodríguez F, Olivares-Arancibia J, Álvarez-Mercado AI. Insights into the Impact of Microbiota in the Treatment of NAFLD/NASH and Its Potential as a Biomarker for Prognosis and Diagnosis. Biomedicines. 2021;9(2):145. doi:10.3390/biomedicines9020145.

Nier A, Engstler AJ, Maier IB, Bergheim I. Markers of intestinal permeability are already altered in early stages of non-alcoholic fatty liver disease: Studies in children. PLoS One. 2017;12(9):e0183282. doi:10.1371/journal.pone.0183282.

De Munck TJI, Xu P, Verwijs HJA, et al. Intestinal permeability in human nonalcoholic fatty liver disease: A systematic review and meta-analysis. Liver Int. 2020;40(12):2906-2916. doi:10.1111/liv.14696.

Nobili V, Alisi A, Cutrera R, et al. Altered gut-liver axis and hepatic adiponectin expression in OSAS: novel mediators of liver injury in paediatric non-alcoholic fatty liver. Thorax. 2015 Aug;70(8):769-81. doi: 10.1136/thoraxjnl-2015-206782.

Hendy OM, Elsabaawy MM, Aref MM, Khalaf FM, Oda AMA, El Shazly HM. Evaluation of circulating zonulin as a potential marker in the pathogenesis of nonalcoholic fatty liver disease. APMIS. 2017 Jul;125(7):607-613. doi: 10.1111/apm.12696.

Chwist A, Hartleb M, Lekstan A, Kukla M, Gutkowski K, Kajor M. A composite model including visfatin, tissue polypeptide-specific antigen, hyaluronic acid, and hematological variables for the diagnosis of moderate-to-severe fibrosis in nonalcoholic fatty liver disease: a preliminary study. Pol Arch Med Wewn. 2014;124(12):704-12. doi: 10.20452/pamw.2558.

Volynets V, Küper MA, Strahl S, et al. Nutrition, intestinal permeability, and blood ethanol levels are altered in patients with nonalcoholic fatty liver disease (NAFLD). Dig Dis Sci. 2012 Jul;57(7):1932-41. doi: 10.1007/s10620-012-2112-9.

Troisi J, Pierri L, Landolfi A, et al. Urinary Metabolomics in Pediatric Obesity and NAFLD Identifies Metabolic Pathways/Metabolites Related to Dietary Habits and Gut-Liver Axis Perturbations. Nutrients. 2017;9(5):485. Published 2017 May 11. doi:10.3390/nu9050485.

Guercio Nuzio S, Di Stasi M, Pierri L, et al. Multiple gut-liver axis abnormalities in children with obesity with and without hepatic involvement. Pediatr Obes. 2017 Dec;12(6):446-452. doi: 10.1111/ijpo.12164.

Pacifico L, Bonci E, Marandola L, Romaggioli S, Bascetta S, Chiesa C. Increased circulating zonulin in children with biopsy-proven nonalcoholic fatty liver disease. World J Gastroenterol. 2014;20(45):17107-17114. doi:10.3748/wjg.v20.i45.17107.

Jin R, Willment A, Patel SS, et al. Fructose induced endotoxemia in pediatric nonalcoholic Fatty liver disease. Int J Hepatol. 2014;2014:560620. doi:10.1155/2014/560620.

Çakır M, Aksel İşbilen A, Eyüpoğlu İ, et al. Effects of long-term synbiotic supplementation in addition to lifestyle changes in children with obesity-related non-alcoholic fatty liver disease. Turk J Gastroenterol. 2017 Sep;28(5):377-383. doi: 10.5152/tjg.2017.17084.

Loffredo L, Zicari AM, Perri L, et al. Does Nox2 Overactivate in Children with Nonalcoholic Fatty Liver Disease? Antioxid Redox Signal. 2019 Apr 1;30(10):1325-1330. doi: 10.1089/ars.2018.7596.

Rosso C, Caviglia GP, Younes R, et al. Circulating Zonulin is Related to Hepatic Necroinflammation in Patients with Non Alcoholic Fatty Liver Disease. Clin Lab. 2020 Apr 1;66(4). doi: 10.7754/Clin.Lab.2019.190922.

Guercio Nuzio S, Di Stasi M, Pierri L, et al. Multiple gut-liver axis abnormalities in children with obesity with and without hepatic involvement. Pediatr Obes. 2017 Dec;12(6):446-452. doi: 10.1111/ijpo.12164.

Zhou X, Han D, Xu R, et al. A model of metabolic syndrome and related diseases with intestinal endotoxemia in rats fed a high fat and high sucrose diet. PLoS One. 2014;9(12):e115148. doi:10.1371/journal.pone.0115148.

Grootjans J, Thuijls G, Verdam F, Derikx JP, Lenaerts K, Buurman WA. Non-invasive assessment of barrier integrity and function of the human gut. World J Gastrointest Surg. 2010;2(3):61-69. doi:10.4240/wjgs.v2.i3.61.

Kolodziejczyk AA, Zheng D, Shibolet O, Elinav E. The role of the microbiome in NAFLD and NASH. EMBO Mol Med. 2019;11(2):e9302. doi:10.15252/emmm.201809302.




How to Cite

Stepanov, Y., Zavhorodnia, N., & Zhyhyr, N. (2022). The role of the intestinal permeability in the progression of nonalcoholic fatty liver disease in obese children. GASTROENTEROLOGY, 56(1), 20–28.



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