Abstract
BackgroundThe modification of gut microbiota is a potential strategy in the treatment of liver disease. The probiotic Lactobacillus rhamnosus GG (LGG) improves gut eubiosis, reduces bacterial translocation and bile acid homeostasis in alcoholic and non‐alcoholic liver diseases. In the current study, we aimed to examine the effect of LGG on gut microbiota alteration and hepatic and fecal bile acid composition, and to understand the mechanisms by which LGG protects liver of mice with bile duct ligation (BDL).MethodsLiver injury was induced in mice by BDL for 11 days. One group of mice received a daily dose of LGG at 109 CFU by oral gavage. Tissues, serum and fecal samples were collected. Intestinal microbiota were determined with pyrosequencing, and fecal bile salt hydrolase activity was determined. Hepatic, serum and fecal bile acid compositions were determined by LC‐MS‐based metabolomics analysis. Liver fibrosis and injury were assessed by Sirius Red and HE staining of liver section, serum AST, ALT levels and bilirubin analysis. Hepatic and intestinal bile acid synthesis and transport signaling was analyzed.ResultsBDL significantly increased serum levels of AST and ALT and liver fibrosis in the operation group compared to SHAM group, and these results were decreased by LGG treatment (n=8). Hepatic total bile acid concentration, and serum total and direct bilirubin levels were elevated in BDL mice and reduced in BDL‐LGG‐treated mice. Metabolomics profiling showed distinct bile acid compositions in serum and liver among SHAM, BDL and BDL‐LGG treatment groups. Hepatic concentrations of T‐αMCA and T‐βMCA, which are known FXR antagonists, were elevated in BDL mice and reduced in BDL‐LGG treated mice. In addition, the level of CDCA, which is known a potent FXR agonist, was significantly decreased in BDL mice and normalized in BDL‐LGG‐treated mice. These data indicates that LGG treatment might exert its function by activating intestinal and liver FXR signaling. Indeed, LGG treatment significantly decreased Cyp7A1 mRNA levels, which is a key enzyme in the bile acid synthesis and regulated by hepatic FXR activation, and increased intestinal expression of FGF15, a FXR target and a suppressor of hepatic bile acid synthesis through gut‐liver axis. Analysis of genes involved in the bile acid metabolism and transport, such as CYP27A1, CYP7B1, SHP, NTCP, BSEP, MRP3, MRP4 and OST‐β showed a positive regulation by LGG in BDL mice. Microbiota analysis showed an increase of bile salt hydrolase (BSH)‐producing bacteria in the fecal samples from the BDL mice receiving LGG treatment. Agreeing with microbiota analysis, LGG treatment increased fecal deconjugated bile acids and BSH activity (which is responsible for bile acid deconjugation favoring bile acid excretion).ConclusionLGG treatment ameliorates BDL‐induced microbiota change, hepatic bile acid accumulation and compositional change in the gut and liver, prevents liver injury and fibrosis in a mouse model of cholestatic liver disease. These results support the role of LGG in regulation of intestinal microbiota homeostasis, hepatic bile acid accumulation, and fecal bile acid excretion leading to the prevention of cholestatic liver injury. The underlying mechanism of this protective effect is likely through microbiota mediated‐FXR activation leading to a reduction of hepatic bile acid synthesis, and increase of bile acid excretion via deconjugation in the gut.Support or Funding InformationSupported by grants from NIH and Veterans AdministrationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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