Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease

Abstract

The role played by the gut in nonalcoholic fatty liver disease (NAFLD) is still a matter of debate, although animal and human studies suggest that gut-derived endotoxin may be important. We investigated intestinal permeability in patients with NAFLD and evaluated the correlations between this phenomenon and the stage of the disease, the integrity of tight junctions within the small intestine, and prevalence of small intestinal bacterial overgrowth (SIBO). We examined 35 consecutive patients with biopsy-proven NAFLD, 27 with untreated celiac disease (as a model of intestinal hyperpermeability) and 24 healthy volunteers. We assessed the presence of SIBO by glucose breath testing (GBT), intestinal permeability by means of urinary excretion of 51 Cr-ethylene diamine tetraacetate ( 51 Cr-EDTA) test, and the integrity of tight junctions within the gut by immunohistochemical analysis of zona occludens-1 (ZO-1) expression in duodenal biopsy specimens. Patients with NAFLD had significantly increased gut permeability (compared with healthy subjects; P < 0.001) and a higher prevalence of SIBO, although both were lower than in the untreated celiac patients. In patients with NAFLD, both gut permeability and the prevalence of SIBO correlated with the severity of steatosis but not with presence of NASH. Conclusions: Our results provide the first evidence that NAFLD in humans is associated with increased gut permeability and that this abnormality is related to the increased prevalence of SIBO in these patients. The increased permeability appears to be caused by disruption of intercellular tight junctions in the intestine, and it may play an important role in the pathogenesis of hepatic fat deposition.

A case–control study on the effect of metabolic gene polymorphisms, nutrition, and their interaction on the risk of non-alcoholic fatty liver disease

“…Moderate alcohol drinking might have a protective role on the risk of developing NAFLD in view of the (Dunn et al 2008) or through the beneficial effect of high-density lipoprotein (HDL) cholesterol increased levels as for cardiovascular disease (CVD) (Djousse et al 2009). Additional studies, however (Abdelmalek et al 2010;Abid et al 2009), suggested that a high intake of soft drinks which are rich of fructose, might have a detrimental effect on the risk of NAFLD (Miele et al 2009). In our study, the information on alcohol, however, was limited to wine and spirits consumption, thus did not include information on soft drinks consumption.…”

Nonalcoholic fatty liver disease and bariatric surgery: a comprehensive review

“…Furthermore, there is evidence that hepatic inflammation can be reduced by means of changes to the gut microbiota induced by antibiotics and probiotics. [47][48][49][50][51][52][53][54][55][56] Under high levels of oxidative stress, which is a feature usu- …”

Nonalcoholic fatty liver disease as trigger of cardiovascular and metabolic complication in metabolic syndrome

“…On the other hand, the components of MS, such as hypertriacylglycerolaemia, hyperglycaemia and hyperinsulinaemia, are hypothesized to contribute to endotoxaemia through altering jejunal motility and gastrointestinal transit time, conditions that may favor bacterial overgrowth, and leak endotoxins into the intestinal mucosa [71]. This might also explain the increased prevalence of SIBO in NAFLD patients, as reported by our group [25]. Other studies also find that obese individuals have significantly higher LBP levels compared with their normal-weight counterparts [72].…”

“…In in vitro and animal models of NAFLD, increased IP, and alterations of gut microbiota have been shown to increase the exposure of the liver to gut-derived bacterial products [such as lipopolysaccharides (LPS)], which may cause low-grade endotoxemia in the portal system [24]. Both IP and the prevalence of SIBO appear to be correlated with the severity of steatosis [25]. Bacterial products belong to distinct classes of endogenous signals, triggering the host immune response by the activation of Toll-Like Receptors (TLRs) [26].…”

“…While immune cell recruitment exerts a containment action against pathogens, it can also result in host tissue damage through cytokines, such as TNF-a, which mediate the inflammatory responses. A wide range of data demonstrate that LPS is elevated in experimental models of hepatic fibrosis and in patients with cirrhosis [25,26]. There is evidence that alterations of the intestinal microbiota, and a failure of the intestinal mucosal barrier, cause increases in bacterial translocation and LPS levels, especially in the later stages of hepatic fibrosis and cirrhosis [27,29].…”