Aims
Gut-vascular barrier (GVB) dysfunction has been shown to be a prerequisite for nonalcoholic fatty liver disease (NAFLD) development. However, the causes of GVB disruption and the underlying mechanisms are still elusive. Here, we explored whether and how Escherichia coli (E. coli) NF73-1, a pathogenic E. coli strain isolated from nonalcoholic steatohepatitis patients, contributes to NAFLD by modulating the GVB.
Background & aims
Gut-vascular barrier (GVB) dysfunction has been shown to be a prerequisite for nonalcoholic fatty liver disease (NAFLD) development. However, the causes of GVB disruption and the underlying mechanisms are still elusive. Here, we explored whether and how Escherichia coli (E. coli) NF73-1, a pathogenic E. coli strain isolated from nonalcoholic steatohepatitis patients, contributes to NAFLD by modulating the GVB.
Conclusions
E. coli NF73-1 disrupts GVB and aggravates NAFLD via inhibiting the Wnt/β-catenin signalling pathway. Targeting E. coli NF73-1 or selectively enhancing the GVB may act as potential avenues for the prevention and treatment of NAFLD.
Methods
C57BL/6J mice were fed with high-fat diet (HFD) or normal diet in the presence or absence of E. coli NF73-1 for the indicated time periods. Intestinal barrier function and infiltration of immune cells were evaluated in these mice. Endothelial cells were exposed to E. coli NF73-1 for barrier integrity analysis.
Results
HFD-induced GVB disruption preceded the damage of intestinal epithelial barrier (IEB) as well as intestinal and hepatic inflammatory changes and can be reversed by vascular endothelial growth factor A blockade. Antibiotic treatment prevented mice from HFD-induced liver steatosis by restoration of the GVB. Notably, E. coli NF73-1 caused a more conspicuous damage of GVB than that of the IEB and contributed to NAFLD development. Mechanistically, E. coli NF73-1 dismantled the GVB by inhibiting the Wnt/β-catenin signalling pathway. Activation of Wnt/β-catenin improved the GVB and impeded the translocation of E. coli NF73-1 into the liver in vitro and in vivo. Conclusions: E. coli NF73-1 disrupts GVB and aggravates NAFLD via inhibiting the Wnt/β-catenin signalling pathway. Targeting E. coli NF73-1 or selectively enhancing the GVB may act as potential avenues for the prevention and treatment of NAFLD.