The role of the gut microbiome and bile acid metabolism in chronic liver diseases

Abstract

Chronic hepatitis B virus (HBV) infection and metabolic dysfunction-associated fatty liver disease (MAFLD) are two of the most common chronic liver diseases globally. The gut microbiota and bile acid are implicated in HBV and MAFLD; however, the relationship among them is not well characterized. This thesis investigated the potential roles of the gut microbiome and bile acid metabolism for the two chronic liver diseases in different studies.

The first study investigated the role of the intestinal virome in a human microbiota-associated (HMA) mouse model. The intestinal virome of the human stool donors accounted for the variance in the intestinal bacterial communities of the mice receiving fecal microbiota transplantation (FMT) from human donors, highlighting the role of donor gut virome in re-shaping the gut microbial structure of the recipients. Moreover, Phapecoctavirus, a virulent Enterobacteriaceae bacteriophage, was identified as a potential biomarker depleted in the gut viral community of human FMT donors with MAFLD and the HMA mice received FMT from MAFLD donors.

The following two studies delineated the associations of gut microbiota and the gut microbial-derived metabolite bile acid with chronic HBV infection. A distinct gut bacterial signature c-Bacteroides, which was enriched in Bacteroides, Flavonifractor, Ruminococcus gnavus and Lachnoclostridium, was associated with higher odds of undetectable HBV DNA (<4.4 IU/mL) in on-treatment chronic HBV patients, suggesting that the distinct gut microbial signature could be related with the nucleos(t)ide analogue treatment response in chronic HBV patients. In addition, the patients with c-Bacteroides gut microbial signature possessed a characteristic circulating bile acid profile. They had a significantly elevated relative abundance of ursodeoxycholic acids (UDCAs) and a reduced level of glycolithocholic acid (GLCA) when compared with those with other gut microbial signatures. The two bile acids are secondary bile acids, so their alteration would probably be originated from the distinct composition of gut microbiota.

The gut microbiota and bile acid profile in the concomitance of MAFLD and HBV were examined in the last study. In chronic HBV patients undergoing nucleoside analogue therapy with undetectable (<4.4 IU/mL) HBV DNA, MAFLD-associated dysbiosis and alteration in the bile acid composition were consistent with those in non-HBV populations, including less diverse gut bacterial community, increased Enterobacteriaceae relative abundance, reduced Firmicutes and 6-hydroxy bile acid levels. In contrast, MAFLD was not associated with alteration in gut microbial structure and bile acid profile in on-treatment chronic HBV patients with detectable HBV DNA (≥4.4 IU/mL). The amount of differential bacterial taxa between MAFLD and non-MAFLD was limited, and there was no significant difference in circulating bile acid composition between MAFLD and non-MAFLD in patients with detectable HBV DNA. The results suggested that MAFLD in successfully-treated chronic HBV patients with undetectable HBV DNA is similar to that in the non-HBV population from the perspective of gut microbiota and bile acid metabolism.

These studies together characterized the role of the gut microbiome and bile acid metabolism in HBV and MAFLD, suggesting their usage as biomarkers and offering insights into the development of therapeutic options for these chronic liver diseases.