Gut microbes associated with functional cure of chronic hepatitis B

Background and aims: Hepatitis B virus (HBV) is prevalent worldwide and is difficult to eradicate. Current treatment strategies for chronic hepatitis B ultimately seek to achieve functional cure (FC); however, the factors contributing to FC remain unclear. We aimed to investigate the gut microbiota profiles of patients with chronic hepatitis B who achieved FC. Methods: Among 105 HBeAg-negative patients with chronic hepatitis B, 70 were enrolled, after excluding patients with cirrhosis or hepatocellular carcinoma and those receiving nucleoside analogs. The gut microbiota of patients who achieved FC was assessed and compared with that of patients with high-titer of HBV DNA (HBV DNA ≥ 3.3 log IU/mL) or low-titer of HBV DNA (HBV DNA < 3.3 log IU/mL). Furthermore, we used cell culture-generated HBV (HBVcc) as a model for HBV infection to evaluate the effects of short-chain fatty acids (SCFAs) produced by the identified bacteria. Results: There was no difference in the alpha or beta diversity of the gut microbiota between the FC group and the other groups. However, compared with the other groups, the FC group presented a greater relative abundance of bacteria that produce SCFAs, especially butyrate. In vitro studies demonstrated that 1.0 mM butyrate reduces HBsAg production in HBVcc-infected cells. Furthermore, butyrate administration was most effective at the post-HBV infection stage. Conclusions: Our findings suggest that butyrate-producing bacteria contribute to FC in HBeAg-negative patients with chronic hepatitis B through butyrate-mediated inhibition of HBV production.