The Role of Zonulin as a Prognostic Biomarker in Liver Diseases: A Systematic Review

Kourosh Ghanadi, Nasrollah Naghdi

Abstract


Liver diseases have become a serious concern in the health care systems worldwide. There is an association between gut permeability and several liver diseases. Zonulin is recognized as a marker of intestinal permeability. Hence, this study summarizes the current knowledge about the role of zonulin as a prognostic biomarker in liver diseases. The present systematic review was performed according to the guidelines of the 2015 Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statements. Until May 2022, PubMed/Medline, Science Direct, Scopus, and Google Scholar as well as Google databases were searched using the relevant keywords including “Zonulin” and “Liver Diseases”, “Fatty Liver”, “Hepatitis”, “Cirrhosis”, “Carcinoma”, “Liver Steatosis”. Of 279 identified records through database searching, 37 articles were included in this systematic review. The evidence of this review revealed that the level of zonulin as the major biomarker of intestinal permeability increased in various types of liver diseases. Overall, we found that increased level of zonulin is associated with inflammatory responses in liver tissue and development of liver diseases. However, further studies could indicate the diagnostic and therapeutic role of zonulin in liver diseases including non-alcoholic fatty liver disease (NAFLD), Hepatitis, cirrhosis and hepatocellular carcinoma (HCC).


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Falih B, Mohammed S, Mohammed N. Effects of the silver nanoparticle synthesis from the leaves of the Capparis spinosa plant on the liver of mice infected with visceral leishmaniasis. Caspian Journal of Environmental Sciences, (2022); 20(4): 785-791.

Jain P. Liver Disease Detection from CT scan images using Deep Learning and Transfer Learning: Dublin, National College of Ireland; (2020); 2(5): 154-171.

Xu E, Zhang L, Yang H, Shen L, Feng Y, Ren M, et al. Transcriptome profiling of the liver among the prenatal and postnatal stages in chickens. Poultry Science, (2019); 98(12): 7030-40.

Zhang S, Yang X, Wang W. Associations of genetic polymorphisms in CTLA-4 and IL-18 with chronic liver diseases: Evidence from a meta-analysis. Genomics, (2020); 112(2): 1889-96.

Falih B, Mohammed S, Mohammed N. Effects of the silver nanoparticle synthesis from the leaves of the Capparis spinosa plant on the liver of mice infected with visceral leishmaniasis. Caspian Journal of Environmental Sciences, 2022; 20(4): 785-791. doi: 10.22124/cjes.2022.5765

Cheemerla S, Balakrishnan M. Global epidemiology of chronic liver disease. Clinical Liver Disease, (2021); 17(5): 365.

Asrani SK, Devarbhavi H, Eaton J, Kamath PS. Burden of liver diseases in the world. Journal of Hepatology, (2019); 70(1): 151-71.

Aishwarya V, Solaipriya S, Sivaramakrishnan V. Role of ellagic acid for the prevention and treatment of liver diseases. Phytotherapy Research, (2021);35(6):2925-44.

Nicoletti A, Ponziani FR, Biolato M, Valenza V, Marrone G, Sganga G, et al. Intestinal permeability in the pathogenesis of liver damage: From non-alcoholic fatty liver disease to liver transplantation. World journal of Gastroenterology, (2019); 25(33): 4814-4831.

Albillos A, De Gottardi A, Rescigno M. The gut-liver axis in liver disease: Pathophysiological basis for therapy. Journal of Hepatology, (2020); 72(3): 558-77.

Wood Heickman LK, DeBoer MD, Fasano A. Zonulin as a potential putative biomarker of risk for shared type 1 diabetes and celiac disease autoimmunity. Diabetes/Metabolism Research and Reviews, (2020); 36(5): 3309-3321.

Szymanska E, Wierzbicka A, Dadalski M, Kierkus J. Fecal Zonulin as a noninvasive biomarker of intestinal permeability in pediatric patients with inflammatory bowel diseases—correlation with disease activity and fecal calprotectin. Journal of Clinical Medicine, (2021); 10(17): 3905-3919.

Caviglia GP, Rosso C, Ribaldone DG, Dughera F, Fagoonee S, Astegiano M, et al. Physiopathology of intestinal barrier and the role of zonulin, Minerva Biotecnologica, (2019); 31(3): 83-92

Fasano A. Zonulin, regulation of tight junctions, and autoimmune diseases. Annals of the New York Academy of Sciences, (2012); 1258(1): 25-33.

Loffredo L, Zicari AM, Perri L, Carnevale R, Nocella C, Angelico F, et al. Does Nox2 overactivate in children with nonalcoholic fatty liver disease? Mary Ann Liebert, Inc., publishers 140 Huguenot Street, 3rd Floor New,(2019).

Cakir M, ISBILEN A, Eyupoglu I, Sag E, ÖREM A, SEN T, et al. Effects of long-term synbiotic supplementation in addition to lifestyle changes in children with obesity-related non-alcoholic fatty liver disease. Turkish Journal of Gastroenterology, (2017); 28(5).

Baumann A, Nier A, Hernández-Arriaga A, Brandt A, Lorenzo Pisarello MJ, Jin CJ, et al. Toll-like receptor 1 as a possible target in non-alcoholic fatty liver disease. Scientific Reports, (2021); 11(1): 1-15.

Hendy OM, Elsabaawy MM, Aref MM, Khalaf FA, Oda AMA, El Shazly HM. Evaluation of circulating zonulin as a potential marker in the pathogenesis of non-alcoholic fatty liver disease. Bulletin of Egyptian Society for Physiological Sciences, (2016); 36(1): 20-9.

Carpino G, Del Ben M, Pastori D, Carnevale R, Baratta F, Overi D, et al. Increased liver localization of lipopolysaccharides in human and experimental NAFLD. Hepatology, (2020); 72(2): 470-85.

Hosseini M, Naderi M, Gholami S, Hadipour M. Toxic metals in the muscle and liver of five main commercially-important fishes from the Persian Gulf, Southern Iran. Caspian Journal of Environmental Sciences, 2018; 16(2): 191-198. doi: 10.22124/cjes.2018.2960

Krawczyk M, Maciejewska D, Ryterska K, Czerwińka-Rogowska M, Jamioł-Milc D, Skonieczna-Żydecka K, et al. Gut permeability might be improved by dietary fiber in individuals with nonalcoholic fatty liver disease (NAFLD) undergoing weight reduction. Nutrients, (2018); 10(11): 1793-1809.

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. Polish Archives of Internal Medicine, (2014); 124(12): 704-12.

Rosso C, Caviglia GP, Younes R, Foglia B, Blanco MJ, Ribaldone DG, et al. Circulating Zonulin is related to hepatic necroinflammation in patients with non alcoholic fatty liver disease. Clinical Laboratory, (2020); 66(4): 1-13.

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 Journal of Gastroenterology: Wourld Journal of gastrology, (2014); 20(45): 1710-1729.

Parkhomenko LK, Strashok LA, Khomenko MA. The role of zonoulin in the devolopement of liver fibrosis in obese Adolescents. Wiadomości Lekarskie. 2021; 74(1): 77-82.

Vitaglione P, Mazzone G, Lembo V, D'Argenio G, Rossi A, Guido M, et al. Coffee prevents fatty liver disease induced by a high-fat diet by modulating pathways of the gut–liver axis. Journal of Nutritional Science. (2019); 8(11): 198-211.

Lang S, Duan Y, Liu J, Torralba MG, Kuelbs C, Ventura‐Cots M, et al. Intestinal fungal dysbiosis and systemic immune response to fungi in patients with alcoholic hepatitis. Hepatology, (2020); 71(2): 522-38.

Horvath A, Durdevic M, Leber B, di Vora K, Rainer F, Krones E, et al. Changes in the intestinal microbiome during a multispecies probiotic intervention in compensated cirrhosis. Nutrients, (2020); 12(6): 1874.

Horvath A, Rainer F, Bashir M, Leber B, Schmerboeck B, Klymiuk I, et al. Biomarkers for oralization during long-term proton pump inhibitor therapy predict survival in cirrhosis. Scientific Reports. (2019); 9(1): 1-9.

Pietrukaniec M, Migacz M, Żak-Gołąb A, Olszanecka-Glinianowicz M, Chudek J, Duława J, et al. Zonulin Family Peptide Levels in Ascites and Serum in Patients with Liver Cirrhosis: A Preliminary Study. Disease Markers, (2019); 20(9): 2804-2819.

Wang X, Li M-m, Niu Y, Zhang X, Yin J-b, Zhao C-j, et al. Serum zonulin in HBV-associated chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Disease Markers. (2019); 19(2): 5945-5961.

Ponziani FR, Bhoori S, Castelli C, Putignani L, Rivoltini L, Del Chierico F, et al. Hepatocellular carcinoma is associated with gut microbiota profile and inflammation in nonalcoholic fatty liver disease. Hepatology, (2019); 69(1): 107-20.

Raparelli V, Basili S, Carnevale R, Napoleone L, Del Ben M, Nocella C, et al. Low‐grade endotoxemia and platelet activation in cirrhosis. Hepatology, (2017); 65(2): 571-81.

Hsu C-F, Lin M-W, Huang C-C, Li T-H, Liu C-W, Huang S-F, et al. Roles and mechanisms of circulating CEACAM1 in the cirrhosis-related intestinal hyperpermeability: in vitro approach. Journal of the Chinese Medical Association, (2021); 84(9): 851-9.

Sapone A, de Magistris L, Fiandra R, Federico A, D'Auria M, Blanco CDC, et al. Intestinal permeability, zonulin and liver cirrhosis. Liver Cirrhosis (2006); 20(2): 1-9.

Voulgaris TA, Karagiannakis D, Hadziyannis E, Manolakopoulos S, Karamanolis GP, Papatheodoridis G, et al. Serum zonulin levels in patients with liver cirrhosis: Prognostic implications. World Journal of Hepatology, (2021); 13(10): 1394.

Wosiewicz P, Żorniak M, Hartleb M, Barański K, Hartleb M, Onyszczuk M, et al. Portal vein thrombosis in cirrhosis is not associated with intestinal barrier disruption or increased platelet aggregability. Clinics and Research in Hepatology and Gastroenterology, (2016); 40(6): 722-9.

Úbeda M, Lario M, Muñoz L, Borrero M-J, Rodríguez-Serrano M, Sánchez-Díaz A-M, et al. Obeticholic acid reduces bacterial translocation and inhibits intestinal inflammation in cirrhotic rats. Journal of Hepatology, (2016); 64(5):1049-57.

Blesl A, Jüngst C, Lammert F, Fauler G, Rainer F, Leber B, et al. Secondary Sclerosing Cholangitis in Critically Ill Patients Alters the Gut–Liver Axis: A Case Control Study. Nutrients, (2020); 12(9): 2728.

Gasimova K. Cytokine and Antimicrobial Peptide Levels in Cholelithiasis. Klinicheskaia khirurgiia, (2021);88(1-2):23-7.

Calgin MK, Cetinkol Y. Decreased levels of serum zonulin and copeptin in chronic Hepatitis-B patients. Pakistan Journal of Medical Sciences, (2019); 35(3): 847-860.

Damms-Machado A, Louis S, Schnitzer A, Volynets V, Rings A, Basrai M, et al. Gut permeability is related to body weight, fatty liver disease, and insulin resistance in obese individuals undergoing weight reduction. The American Journal of Clinical Nutrition, (2017); 105(1): 127-35.

Deniz CD, Ozler S, Sayın FK. Association of adverse outcomes of intrahepatic cholestasis of pregnancy with zonulin levels. Journal of Obstetrics and Gynaecology, (2021); 41(6): 904-9.

Güvey H, Çelik S, Çalışkan CS, Yılmaz Z, Yılmaz M, Erten Ö, et al. How Do Serum Zonulin Levels Change in Gestational Diabetes Mellitus, Pregnancy Cholestasis, and the Coexistence of Both Diseases? International Journal of Environmental Research and Public Health, (2021); 18(23): 12555-12571.

Dhillon AK, Kummen M, Trøseid M, Åkra S, Liaskou E, Moum B, et al. Circulating markers of gut barrier function associated with disease severity in primary sclerosing cholangitis. Liver International, (2019); 39(2): 371-81.

Kim A-S, Ko H-J. Plasma concentrations of zonulin are elevated in obese men with fatty liver disease. Diabetes, metabolic syndrome and obesity: Targets and Therapy, (2018); 11(19): 149-162.

Akao T, Morita A, Onji M, Miyake T, Watanabe R, Uehara T, et al. Low serum levels of zonulin in patients with HCV-infected chronic liver diseases. Euroasian Journal of Hepato-Gastroenterology, (2018); 8(2): 112-125.

Weng YC, Chen WT, Lee JC, Huang YN, Yang CK, Hsieh HS, et al. Intestinal fatty acid‐binding protein is a biomarker for diagnosis of biliary tract infection. JGH Open, (2021); 5(10): 1160-5.

Tawdrous M, Horvath A, Schmerböck B, Leber B, Hartl A, Spindelböck W, et al. Gut permeability and neutrophil function in secondary sclerosing cholangitis of critically ill patients. Zeitschrift für Gastroenterologie, (2016); 54(05): 48-59.

Jung F, Burger K, Staltner R, Brandt A, Mueller S, Bergheim I. Markers of intestinal permeability are rapidly improved by alcohol withdrawal in patients with alcohol-related liver disease. Nutrients, (2021); 13(5): 1659-1669.

Clemente MG, Musu MP, Counts D, De Virgiliis S, Fasano A. Seric Zonulin, a Modulator of Intestinal Tight Junctions Permeability, is Increased in Different Autoimmune Disorders. American Journal of Pathology, 2008; 173(5): 1243–1252.

Negahdari B, Darvishi M, Saeedi AA. Gold nanoparticles and hepatitis B virus. Artificial Cells, Nanomedicine, and Biotechnology, (2019); 47(1): 455-61.

Darvishi M, Ziari K, Mohebbi H, Alizadeh K. Association between iron deficiency anemia and Helicobacter pylori infection among children under six years in Iran. Acta Medica Iranica, (2015); 92(16): 220-4.

Jalalmanesh S, Darvishi M, Rahimi M, Akhlaghdoust M. Contamination of senior medical students’ cell phones by nosocomial infections: a survey in a university-affiliated Hospital in Tehran. Shiraz E-Medical Journal, (2017);18(4): 231-249.

Bahmani M., Jalilian A, Salimikia I, Shahsavari S, Abbasi N.

Phytochemical screening of two Ilam native plants Ziziphus nummularia (Burm.f.) Wight & Arn. And Ziziphus spina-christi (Mill.) Georgi using HS-SPME and GC-MS spectroscopy. Plant Science Today, (2020); 7(2): 275-280.

Solati K, Karimi M, Rafieian-Kopaei M, Abbasi N, Abbaszadeh S, Bahmani M. Phytotherapy for wound healing: The most important herbal plants in wound healing based on iranian ethnobotanical documents. Mini-Reviews in Medicinal Chemistry, (2021); 21(4): 500-519.

Abbasi N, Khalighi Z, Eftekhari Z, Bahmani M. Extraction and phytoanalysis of chemical compounds of Eucalyptus globulus leaf native to Dehloran, Ilam province, Iran by HS-SPME and GC-MS. Advances in Animal and Veterinary Sciences, (2020); 8(6): 647-652.

Darvishi M, Forootan M, Nazer MR, Karimi E, Noori M. Nosocomial Infections, Challenges and Threats: A Review Article. Iranian Journal of Medical Microbiology, (2020); 14(2): 162-81.

Sedighi M, Namdari M, Mahmoudi P, Khani A, Manouchehri A, Anvari M. An Overview of Angiogenesis and Chemical and Physiological Angiogenic Factors: Short Review. Journal of Chemical Health Risks, (2022); 22(8): 1-12.

Forootan M, Tabatabaeefar M, Mosaffa N, Ashkalak HR, Darvishi M. Investigating esophageal stent-placement outcomes in patients with inoperable non-cervical esophageal cancer. Journal of Cancer, (2018); 9(1): 213-221.

Darvishi M. Antibiotic resistance pattern of uropathogenic methicillin-resistant staphylococcus aureus isolated from immunosuppressive patients with pyelonephritis. Journal of Pure and Applied Microbiology, (2016); 10(4): 2663-8.

Tavakolpour S, Darvishi M, Mirsafaei HS, Ghasemiadl M. Nucleoside/nucleotide analogues in the treatment of chronic hepatitis B infection during pregnancy: a systematic review. Infectious Diseases, (2018); 50(2): 95-106.

Darvishi M, Sadeghi SS. Evaluation of association of Helicobacter pylori infection and coronary heart disease (CHD) among CCU patients. Journal of Pure and Applied Microbiology, (2016) ;10(4): 2621-6.

Manouchehri A, Pirhadi M, Shokri S, Khaniki GJ. The possible effects of heavy metals in honey as toxic and carsinogenic substances on human health: A systematic review. Uludağ Arıcılık Dergisi, (2021); 21(2): 237-46.

Jafari H, Nemati M, Haddad Molayan P, Khaleghi Rostamkolaie L, Hamidi Nejat H. Scolicidal activity of Mesobuthus eupeus venom against the protoscolices of Echinococcus granulosus. Archives of Razi Institute, (2019); 74(2): 183-9.

Salah Najim A, Bahry Al_Sadoon M, Salem Sheet M. Effect of Caraway Seed Extract on the Blood Biochemistry and Antioxidant Capacity among the Hyperoxidative Stress-Induced Rats. Archives of Razi Institute, (2022); 77(2): 553-63.

Fasano A. Intestinal permeability and its regulation by zonulin: diagnostic and therapeutic implications. Clinical Gastroenterology and Hepatology, (2012); 10(10): 1096-100.

Żak-Gołąb A, Kocełak P, Aptekorz M, Zientara M, Juszczyk Ł, Martirosian G, et al. Gut microbiota, microinflammation, metabolic profile, and zonulin concentration in obese and normal weight subjects. International Journal of Endocrinology, (2013); 13(1): 171-185.

Moreno-Navarrete JM, Sabater M, Ortega F, Ricart W, Fernandez-Real JM. Circulating zonulin, a marker of intestinal permeability, is increased in association with obesity-associated insulin resistance. PloS one, (2012); 7(5): e37160.




DOI: http://dx.doi.org/10.62940/als.v9i3.1496

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