Introduction
Nonalcoholic fatty liver disease (NAFLD) has emerged as the major cause of chronic liver disease worldwide, and its global prevalence is estimated to be 25% [1, 2]. NAFLD encompasses a spectrum of pathological changes, ranging from steatosis and nonalcoholic steatohepatitis (NASH), to liver cirrhosis and even hepatocellular carcinoma [3]. Considerable progress has been made toward understanding the pathogenesis of NAFLD, including the contributions of insulin resistance, inflammation, and oxidative stress [4-6]; however, the factors contributing to disease severity and progression have not been completely clarified.
There is evidence for a close interaction between the gut and the liver, known as the “gut-liver axis” [7, 8], and gut microbiota, microbial metabolites, and immune responses are associated with NAFLD pathogenesis [8-10]. Further, recent studies have suggested a role for intestinal barrier dysfunction in the progression of NAFLD [11-13]. In animal studies, increased intestinal permeability can be detected in mice with NAFLD induced by high-fat or choline-deficient diets [13, 14]. In addition, clinical studies have demonstrated increased intestinal permeability in patients with NAFLD relative to healthy controls [12, 13]. Moreover, a previous study reported a correlation between the lactulose/mannitol ratio and pathologic severity of NAFLD, indicating that intestinal permeability might correlate with the severity of NAFLD [12]. However, another investigation detected no significant differences in liver transaminases or triglycerides between NAFLD patients with normal and increased intestinal permeability [15]. Hence, further investigation is needed to fully understand whether intestinal permeability is associated with disease severity in NAFLD patients, especially with respect to liver test parameters and blood lipid levels. Further, recent studies have shown that some therapies can ameliorate NAFLD by improving the gut barrier permeability, indicating a potential role for addressing intestinal permeability in NAFLD treatment approaches [16, 17]. Nonetheless, it is still not known whether the treatment effect of NAFLD is affected by intestinal permeability.
Polyethylene glycol, 51Cr-labelled ethylene diamine tetraacetate acid (51Cr-EDTA), and a number of non-invasive tests (i.e., urinary recovery of orally administered sugars) are widely used to measure intestinal permeability in humans [18]. More recently, D-lactate, which is only produced by intestinal bacteria, has been also introduced as a convenient and well-accepted biomarker for intestinal permeability [19, 20]. Given that this compound is found in small concentrations in human blood, elevated level of serum D-lactate indicates increased intestinal permeability.
This study was designed to investigate the association between intestinal permeability and severity of NAFLD and the value of intestinal permeability for predicting the efficacy of metabolic therapy for NAFLD with the use of serum D-lactate.