Zonulin level, a marker of intestinal permeability, is increased in association with liver enzymes in young adolescents

Highlights

• Serum zonulin is a biomarker associated with hepatic metabolic disturbances in young adolescents with overweight or obesity.

• There may be a potentially relevant pathophysiological mechanism linking zonulin to hepatic metabolic dysfunction even in young adolescents.

Abstract

Background

Zonulin is acknowledged as the only physiological mediator established to reversibly regulate intestinal permeability through modulation of intercellular tight junctions. We aimed to determine whether there are differences in zonulin levels between 74 subjects with overweight or obesity and 76 with normal-weight and to assess correlations of circulating zonulin levels with anthropometric measures and obesity-related biomarkers.

Methods

We assessed anthropometric and laboratory measures, including body mass index (BMI) z-score, blood pressure, liver enzymes, lipid profiles, and insulin resistance. Serum zonulin levels were measured using an enzyme-linked immunosorbent assay.

Results

The mean age of the participants was 12.8 ± 1.5 years. Circulating serum zonulin levels were significantly increased in subjects with overweight/obesity compared with those of normal-weight (P = 0.03). Zonulin levels were significantly and positively associated with BMI z-score, alanine aminotransferase levels, triglyceride, fasting insulin, and insulin resistance as indicated by the homeostatic model assessment of insulin resistance (HOMA-IR) (all P < 0.05). In multivariate linear regression analysis, alanine aminotransferase was significantly and positively associated with circulating zonulin levels in adolescents with overweight or obesity (P < 0.01) after controlling for the effect of potential confounding factors. BMI z-score tended to be positively associated with serum zonulin levels in this subgroup analysis (P = 0.06).

Conclusions

Serum zonulin is a biomarker associated with hepatic metabolic disturbances in young adolescents with overweight or obesity. The positive relationship suggests a potentially relevant pathophysiological mechanism linking zonulin to hepatic metabolism in this age group of young adolescents with overweight or obesity.

Introduction

Child and adolescent obesity remains prevalent across the developed world, and its prevalence is increasing in most developing countries [1,2]. There is mounting evidence reporting that childhood overweight and obesity is associated with significantly increased risk of later cardiometabolic morbidity, such as diabetes, hypertension, ischemic heart disease, and stroke, and premature mortality in adulthood [3].

Research work in the pathogenesis of obesity suggests that it may be the end result of increased intestinal permeability and absorption [4] and is closely correlated with sudden increases in intestinal absorptive capacity by increasing in amounts of absorptive mucosa [4]. Recently, it has become apparent that intestinal permeability controls molecular trafficking between the intestinal lumen and the submucosa, inducing either tolerance or immune responses to foreign antigens such as food antigens [5,6]. It is the intercellular tight junctions (TJs) that regulate this paracellular antigen trafficking in a well-orchestrated manner. TJs are thought to be exceptionally effective structures operative in several main functions of the intestinal epithelium under both physiological and pathological circumstances [7]. Chronic high circulating levels of inflammatory cytokines, which are often observed in subjects with obesity, may be an important contributor to intestinal barrier dysfunction through alterations of structure and localization of TJs [8]. Furthermore, accumulating evidence links the intestinal microbiome and inflammation, the intestinal barrier integrity, and liver diseases [9].

Zonulin is the only physiological protein known to control intestinal permeability reversibly via modulation of intercellular TJs [10,11]. It is a 47-kDa protein that increases intestinal permeability in the small intestine, is actively engaged in intestinal innate immunity [12], and is overexpressed in autoimmune diseases where TJ dysfunction plays a pivotal role, such as celiac disease [13,14] and type 1 diabetes [15]. In this regard, circulating zonulin is considered a useful biomarker of intestinal permeability [11,16]. In humans, increased zonulin levels have been reported to be closely correlated with increased intestinal permeability caused by genetic overexpression of intestinal TJ proteins [15]. Recent evidence have demonstrated higher circulating zonulin concentrations in adults with obesity compared with controls [17] and in adults with glucose intolerance compared with those with normal glucose tolerance [18].

Despite increasing data that zonulin plays a key role in the pathophysiology of obesity [17] and insulin resistance [18], few studies have investigated its relationship with obesity-related clinical factors and/or laboratory biomarkers in adolescent populations [19,20]. Understanding these relationships in this age group may help advance our understanding of the pathophysiology of adolescent obesity and metabolic dysregulation.

Therefore, we aimed to determine whether there is a difference in serum zonulin levels between subjects with overweight/obesity and those of normal-weight and to assess the relationship between serum zonulin levels and anthropometric measures and obesity-related biomarkers, such as liver enzymes, lipid profiles, and insulin resistance in a population of young adolescents.