Intestinal Permeability in Human Nonalcoholic Fatty Liver Disease

A Systematic Review and Meta-analysis

Toon J. I. De Munck; Pan Xu; Harm J. A. Verwijs; Ad A. M. Masclee; Daisy Jonkers; Jef Verbeek; Ger H. Koek


Liver International. 2020;40(12):2906-2916. 

In This Article

Abstract and Introduction


Background: The gut-liver axis is considered to play a critical role in the development and progression of nonalcoholic fatty liver disease (NAFLD). The integrity of the epithelial barrier is crucial to protect the liver against the invasion of microbial products from the gut, although its exact role in NAFLD onset and progression is not clear.

Methods: We performed a systematic review and meta-analysis of studies that addressed the intestinal permeability (IP) in association with NAFLD presence or severity as defined by the presence of nonalcoholic steatohepatitis (NASH) and the degree of steatosis, hepatic inflammation or fibrosis. A total of 14 studies were eligible for inclusion.

Results: Studies investigating IP in adult (n = 6) and paediatric (n = 8) NAFLD showed similar results. Thirteen of the included studies focussed on small IP, two studies on whole gut permeability and none on colonic permeability. In the pooled analysis, NAFLD patients showed an increased small intestinal permeability compared to healthy controls based on dual sugar tests (standardized mean difference 0.79, 95% CI 0.49–1.08) and serum zonulin levels (standardized mean difference 1.04 ng/mL, 95% CI 0.40–1.68). No clear difference in IP was observed between simple steatosis and NASH patients. Furthermore, whole gut and small intestinal permeability increased with the degree of hepatic steatosis in 4/4 studies, while no association with hepatic inflammation or fibrosis was observed.

Conclusion: Based on the limited number of studies available, IP appears to be increased in NAFLD patients compared to healthy controls and is associated with the degree of hepatic steatosis.


Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world in both adults and children. NAFLD prevalence is approximately 25% in the adult population and 8% in the paediatric population.[1,2] The spectrum of NAFLD ranges from nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH) to liver fibrosis, cirrhosis and hepatocellular carcinoma.[1] To date, the exact pathophysiology of NAFLD has not completely been elucidated and it is not clear to what extent paediatric NAFLD differs from adult NAFLD.[3]

The interaction between the gut and the liver, the so-called 'gut-liver axis', is considered to play a critical role in development and progression of NAFLD in both children and adults.[4] Crosstalk between gut and liver is facilitated through the intestinal barrier. This intestinal barrier consists of structural elements (mucus and closely lined epithelial cells sealed by tight junctions), immune cells and soluble mediators (eg IgA, antimicrobial peptides).[4] An intact intestinal barrier is able to restrict translocation of bacterial products, while allowing active transport from nutrients across the tight junctions.[4] The epithelial integrity of the intestinal barrier can be assessed in vivo by measuring the intestinal permeability (IP). Increased IP can lead to translocation of microbial products from the gut to the liver through the portal system. Known factors that contribute to an increased IP include consumption of a Western diet (ie high fat intake), gut microbiome perturbations, pro-inflammatory cytokines, alcohol and use of antibiotics.[5,6]

Currently, a number of non-invasive tests to measure IP in humans are being used. Urinary recovery of orally administered sugars (ie sucrose, lactulose to mannitol ratio (L/M), lactulose to rhamnose ratio (L/R), sucralose to erythritol ratio (S/E) and sucralose) are widely accepted as markers for IP. Five hour (h) urinary sucrose levels are used as indicator for gastroduodenal permeability, 5–6 h L/M and L/R as indicators for small intestinal permeability, and 5–24 h or 0–24 h S/E as indicators for colon and whole gut permeability respectively. By using the ratio of two sugars with different size and therefore different transport mechanism (paracellularly versus transcellularly), correction for differences in renal function, intestinal transit time and gastric emptying is possible.[7] Urinary recovery of a single substance cannot correct for these factors, which can differ between patients and thereby affect the outcome. Other substances used to measure IP in vivo are various polymers of polyethylene glycol (PEG) and 51Cr-labelled ethylenediaminetetraacetic acid (51Cr-EDTA).[7] More recently, zonulin, a 47-kDa protein, has been introduced as a potentially useful systemic marker for small intestinal and gastroduodenal permeability, but not for colon permeability.[8] Serum zonulin has emerged as a relevant biomarker because it is an important factor to regulating IP by modulating intercellular tight junctions.[9,10] However, the specificity of serum zonulin as biomarker for small intestinal permeability remains uncertain.[11]

In both adults and paediatric NAFLD patients, several studies investigated IP and its role in the pathogenesis and progression from NAFL to NASH.[12–17] However, the exact association between IP and NAFLD severity (degree of steatosis, hepatic inflammation, fibrosis or presence of NASH) is not clear. The aim of this systematic review and meta-analysis was to summarize studies in humans on the association between in vivo IP alterations and NAFLD presence and/or severity. We hypothesize that IP is increased in NAFLD, being most pronounced in progressive disease as characterized by the presence of NASH, advanced steatosis, hepatic inflammation or hepatic fibrosis. Furthermore, in the included studies, we will summarize the clinical parameters (eg anthropometric data and blood biochemical variables), which have been observed to correlate with the degree of IP in NAFLD patients.