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

Review Article

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

Kourosh Ghanadi1, Nasrollah Naghdi2*

Adv. life sci., vol. 9, no. 3, pp. 277-283, October 2022
*- Corresponding Author: Nasrollah Naghdi (Email: nasrollah.naghdi1357@gmail.com)
Authors' Affiliations

 1. Department of Internal Medicine, School of Medicine, Lorestan, University of Medical Science, Khorramabad – Iran
2. Biotechnology and Medicinal Plants Research Centre, Ilam University of Medical Sciences, Ilam – Iran
 [Date Received: 16/07/2021; Date Revised: 21/08/2022; Date Published: 31/10/2022]

Abstractaa download_button
Introduction
Methods
Discussion
Conclusion
References 

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).

Keywords: Zonulin; Liver Diseases; Fatty Liver; Hepatitis; Cirrhosis 

Introduction6th button-01

The liver is one of the most important organs in the body that performs various physiological functions [1]. The main function of the liver is to purify the blood of the gastrointestinal tract before transferring it to the rest of the body [2]. Detoxification, protein synthesis, production of biochemical compounds, metabolic function and hormone production are other important functions of the liver [3]. Hence, liver dysfunction can lead to a health threatening condition. Mortality and disability due to liver diseases have raised concerns all over the world [4]. Liver diseases impose health and economic burden on the health care system around the world [5]. The number of cases of the liver diseases is estimated at approximately 1.5 billion worldwide [6]. Globally, recent epidemiological data represents that around 2 million deaths per year occur due to the liver diseases [7]. The most common liver diseases are non-alcoholic fatty liver disease (NAFLD), Hepatitis B, Hepatitis C, alcohol-related liver disease (ALD), cirrhosis and hepatocellular carcinoma (HCC) [6]. Cirrhosis and HCC together account for the death of two million people [7]. There is currently no way to compensate for the lack of liver function other than liver transplantation [8]. Several genetic and environmental factors play role in the progression of liver diseases. Emerging data have shown the association between development of the liver diseases and changes in intestinal permeability [9]. Evidence supports the role of the liver– gut axis in the pathogenesis of some of liver diseases including NAFLD [10]. Due to the connection between the gut and the liver through the portal circulation, changes in intestinal permeability can facilitate the entrance of harmful substances to the liver and disrupt metabolic pathways. On the other hand, the interaction between these substances and liver immune cells can lead to inflammation and eventually development of liver disease [9]. Zonulin is a biomarker related to the intestinal barrier integrity of the small intestine [11]. Zonulin is a 47-kDa protein which is identified as the only physiological biomarker for the intestinal permeability [12]. It is known for the reverse regulation of intestinal permeability through disassembling intercellular tight junctions [13]. It has been shown that one of the most important functions of zenolin in the body is controlling the intercellular tight junctions between the intestinal enterocytes and as a result, helping the absorption of nutrients in the body. Furthermore, there are several pieces of evidence about the biological properties of zonulin in activation of EGFR and subsequently the effect of zonulin on transepithelial electrical resistance (TEER) [14]. In fact, zonulin can be considered as a biomarker of gut barrier dysfunction for several diseases including autoimmune, neurodegenerative and liver diseases because of the connection between the liver and the gut means liver– gut axis. Zonulin can also be proposed as a promising therapeutic target for the treatment of various diseases [14]. Hence, this systematic review summarizes the current knowledge about the role of Zonulin as a prognostic biomarker in liver diseases.

Methods6th button-01

Search strategy

The present systematic review was carried out according to the guidelines of the 2015 Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statements. Electronic databases such as PubMed/Medline, Science Direct, Scopus, and Google Scholar as well as Google were searched using the following keywords: “Zonulin” and “Liver Diseases”, “Fatty Liver”, “Hepatitis”, “Cirrhosis”, “Carcinoma”, “Liver Steatosis”.

Eligibility criteria

All relevant studies published in the English language until May 2022 were eligible in the current study. The present systematic review included all articles that evaluated the role of zonulin in liver diseases. Articles with insufficient information were not included in this study.

Data extraction and quality assessment

Title/abstract of the studies first were retrieved independently by two reviewers for choosing eligible articles. The studies that could not meet the eligibility criteria were excluded. Then, the extraction of data was carried out by reading the full text of the screened articles. In controversial cases, the debate articles were discussed by the authors and finally decided accordingly.. 

Discussion6th button-01

As shown in Figure-1, 279 studies were initially identified after our search. After removal of duplicate articles, 181 were retrieved. Of these, 130 studies that did not meet the inclusion criteria of the study were excluded. Then, 51 studies were chosen based on the research topic. Finally, 37 articles were included in the current systematic review after critical analysis. Table-1 displays the main features of the selected studies. As zonulin is associated with liver diseases, changes in the zonulin level considered as outcome.

Free radicals are toxic products of oxygen metabolism that contain at least one unpaired electron. Excessive production of free radicals during a process called oxidative stress causes damage to different parts of the cell such as proteins, DNA and cell membrane [52-58]. These irreversible damages lead to changes in cell function or cell death. Oxidative damage to vital molecules ultimately leads to chronic diseases such as heart disease, cancer, diabetes, Alzheimer’s, Parkinson’s, arthritis and infertility (59-64). The human body needs both types of oxidants (free radicals) and antioxidants for normal metabolism, signal transmission, and regulation of cellular activities [65-69]. Zonulin has been identified as the main indicator of intestinal permeability. It is a protein that participates in the regulation of tight junction of the small intestine through increasing its permeability by disconnection of the zonula occludens-1 protein from tight junctions. Zonulin also involves in the development of intestinal innate immunity [30, 44]. Hepatocytes, enterocytes, adipose tissue, and immune cells are known as the main cells which produce zonulin and small intestine is recognized as only site of zonulin performance [31, 44]. Zonulin could affect intestinal permeability by controlling the binding between the intestinal epithelial cells ([46]. Furthermore, this protein participates in the transmission of biomolecules and immune cells between the intestinal lumen and blood [43]. Zonulin also plays role in the inhibition of the entry of wide range of pathogens including bacteria, antigens, toxins, and other pathogens. This is while facilitating the entry of necessary nutrients [30]. It has been shown that increased plasma levels of zonulin is associated with various types of diseases such as celiac disease, autoimmune diseases, type 1diabetes, fatty liver as well as obesity-associated insulin resistance [18, 43].

However, little knowledge is available regarding the association of zonulin levels with liver disorders. Hence, the aim of the present study was to review systematically the current knowledge about the role of zonulin as a prognostic biomarker in liver diseases. To our best knowledge, the present study for the first time investigated the role of zonulin as a prognostic biomarker in liver diseases through a systematic review of published literature. The findings in the present study suggested that the level of circulating zonulin increases in subjects with liver diseases such as NAFLD, cirrhosis, steatosis, fatty liver, hepatitis, HCC, and other types of liver diseases as mentioned above.  Over recent years, a significant correlation has been found between the level of zonulin and intestinal leakage related diseases [67]. Researchers have shown that many diseases originate from the gut. This applies more to liver diseases because of the close anatomical relationship between the liver and the gut. In fact, the intestine communicates with the liver through the portal circulation system, and blood first directly enters the liver from the intestines. The liver also affects the intestine by producing bile. On the other hand, the intestines are known as hosts of various species of bacteria called the intestine microbiota, and any changes in these bacteria have been associated with liver diseases such as fatty liver and cirrhosis [41].

Several studies have revealed the association between the level of zonulin and various types of liver diseases including NAFLD [20, 24]. Pacifico L et al. demonstrated that the level of circulating zonulin elevated in children and adolescents with NAFLD. They concluded that this increase in zonulin level was correlated to the severity of hepatic steatosis [24]. Furthermore, it has been shown that the concentration of zonulin increased in obese subjects which was associated with gut microbiota and total bacteria count. On the other hand, zonulin level could be related to diet fat percentage and fiber intake in association with daily energy consumption [68]. Obesity and NAFLD are closely related to each other. Obesity could induce insulin resistance and finally accumulate fat in the liver. Additionally, obesity is associated with zonulin level through increased intestinal permeability. A possible mechanism which could explain the association between level of zonulin and NAFLD is changes in the gut microbiota following development of obesity in obese subjects. This process has ability to increase intestinal permeability and finally induce high level of zonulin [46]. In line with the other studies, Hendy et al. showed that circulating zonulin could be propose as potential marker and therapeutic target of NAFLD. They understood that increased circulating IL-6 caused by obesity mediated relationship between insulin sensitivity and circulating zonulin. In fact, production of IL-6 and TNF-α, is the primary cause of liver damage in many liver diseases. Researcher have reported the linkage between concentration of zonulin and inflammatory markers in obese patients. This interrelation mediates the role of increased level of zonulin with various diseases including NAFLD, obesity and diabetes [20]. In addition to NAFLD, increased level of zonulin is also observed in other liver diseases such as cirrhosis. Raparelli et al. demonstrated that the level of zonulin has an elevation in cirrhotic patients compared to healthy subjects. They observed that increased gut permeability and subsequently level of zonulin induced enhancing levels of lipopolysaccharides (LPS) and finally liver injury [33]. In line with above study, Hsu et al. indicated that the level of zonulin increased in cirrhotic patients and was associated with carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) [34]. In another similar study, Voulgaris TA and colleagues found that high level of zonulin was associated with advanced cirrhosis by the presence of ascites [36].

Emerging data have shown conflicting results about the level of zonulin in different liver diseases. For example, Mustafa Kerem Calgin and colleagues showed that the levels of serum zonulin decreased in chronic Hepatitis-B patients. They explained that the possible mechanisms involved in this reduction in the level of zonulin may be associated with intestinal microbiota and viral load in hepatitis patients [41]. This is while an increase in the level of zonulin has been observed in many liver diseases, including biliary tract infection, and cholangitis [48, 49]. Increasing evidence shows that plasma zonulin levels increased in type 1 diabetes [69]. It has been reported that there is a link between zonulin and diabetes in liver disease. The linkage between serum levels of zonulin and diabetes in liver disease could be explain through the association between diabetes and obesity, obesity and alternations in gut microbiome and lately to NAFLD [20]. It seems that the lack of studies on the role of zonulin in liver diseases has caused such contradictory data. The main strength of the current study was that it reviewed the role of zonulin in liver diseases for the first time. The main limitation of the current study was heterogeneity and contradictions in various reports.

 

 

 

 

 

 

 

Conclusion6th button-01

Taking together, our findings indicate that changes in the level of zonulin are associated with intestinal permeability. Furthermore, we concluded that zonulin as the main biomarker of intestinal permeability increased in various types of liver diseases. Our results revealed that enhanced level of zonulin as a result of increased intestinal permeability released numerous pathogens, antigens and toxic metals from intestine to liver which trigger immune cells and cytokines and eventually inflammatory responses and subsequently tissue damage in the liver. In conclusion we showed that zonulin could propose as a reliable biomarker associated with liver injury and even a therapeutic marker. However, due to the lack of about the role of zonulin in liver diseases further research could improve information.

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Author Contributions

All the authors contributed equally to the writing of the manuscript.

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Conflict of Interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

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