Honda Takashi, Ishigami Masatoshi, Ishizu Yoji, Imai Norihiro, Ito Takanori, Yamamoto Kenta, Yokoyama Shinya, Muto Hisanori, Inukai Yosuke, Kato Asuka, Murayama Asako, Yoshio Sachiyo, Ishikawa Tetsuya, Fujishiro Mitsuhiro, Kawashima Hiroki, Kato Takanobu
Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan.
Department of Virology II, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo, 162-8640, Japan.
Hepatol Int. 2025 Jun;19(3):519-528. doi: 10.1007/s12072-025-10776-9. Epub 2025 Jan 27.
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.
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.
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.
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.
乙型肝炎病毒（HBV）在全球广泛流行且难以根除。慢性乙型肝炎的当前治疗策略最终旨在实现功能性治愈（FC）；然而，促成功能性治愈的因素仍不清楚。我们旨在调查实现功能性治愈的慢性乙型肝炎患者的肠道微生物群概况。
在105例HBeAg阴性慢性乙型肝炎患者中，排除肝硬化或肝细胞癌患者以及接受核苷类似物治疗的患者后，纳入70例。对实现功能性治愈的患者的肠道微生物群进行评估，并与高滴度HBV DNA（HBV DNA≥3.3 log IU/mL）或低滴度HBV DNA（HBV DNA＜3.3 log IU/mL）的患者进行比较。此外，我们使用细胞培养产生的HBV（HBVcc）作为HBV感染模型，以评估已鉴定细菌产生的短链脂肪酸（SCFAs）的作用。
功能性治愈组与其他组之间肠道微生物群的α或β多样性没有差异。然而，与其他组相比，功能性治愈组中产SCFAs的细菌，尤其是丁酸盐产生菌的相对丰度更高。体外研究表明，1.0 mM丁酸盐可降低HBVcc感染细胞中HBsAg的产生。此外，丁酸盐给药在HBV感染后阶段最有效。
我们的研究结果表明，产丁酸盐的细菌通过丁酸盐介导的对HBV产生的抑制作用，有助于HBeAg阴性慢性乙型肝炎患者实现功能性治愈。
