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.