肠道菌群介导巨噬细胞极化充当慢性乙型肝炎免疫调控开关的分子机制

Late complications of chronic hepatitis B (CHB) are a serious threat to human health. Recent studies have shown that the clinical outcome of hepatitis B virus (HBV) infection is closely related to the intestinal flora, but its mechanism needs to be further explored. Studies have shown that lipopolysaccharide (LPS) produced by the intestinal flora binds to its receptor Toll-like receptor 4 (TLR4) to trigger macrophage polarization and participate in the regulation of intrahepatic inflammation. Recently, our study has shown that macrophage M1 polarization is significantly correlated with HBeAg seroconversion after oral antiviral therapy for CHB. It is speculated that intestinal flora may trigger macrophage M1 polarization and promote the immune control on CHB through LPS-TLR4 pathway. In this project, we will explore the correlation between intestinal flora and macrophage M1 polarization from clinical samples, and reveal the regulation of macrophage M1 polarization on CHB immune status, and clarify the molecular mechanism of the genesis of immune control on CHB based on intestinal microflora. This study will provide a theoretical basis for the prevention and treatment of CHB based on intestinal bacteria, and provide new ideas to improve the efficacy of CHB and enhance the immune control on CHB.

慢性乙型肝炎(CHB)晚期并发症严重威胁到着人类健康。近年研究表明乙肝病毒(HBV)感染的临床结局与肠道菌群有着密切关系，但其机制还有待深入探索。研究发现肠道菌群产生的脂多糖(LPS)与其受体Toll样受体4(TLR4)结合可诱导巨噬细胞极化，参与肝内炎症调控。最近，我们的研究表明巨噬细胞M1型极化与CHB口服抗病毒治疗后HBeAg血清学转换有着明显相关性，推测肠道菌群可能通过LPS-TLR4通路诱导巨噬细胞M1型极化促进CHB免疫控制。在本项目中，我们将从临床样本出发，探索肠道菌群与巨噬细胞M1型极化的相关性，揭示巨噬细胞M1型极化对CHB免疫状态的调控作用，阐明基于肠道菌群的CHB免疫控制发生的分子机制。本研究将为基于肠道细菌的慢性乙型肝炎防治提供一定的理论依据，并提供新思路以改善CHB疗效、提高CHB免疫控制率。

慢性乙型肝炎（CHB）晚期并发症严重威胁到着人类健康。近年研究表明乙肝病毒（HBV）感染的临床结局与肠道菌群有着密切关系，但其机制还有待深入探索。研究发现肠道菌群产生的脂多糖（LPS）与其受体Toll样受体4（TLR4）结合可诱导巨噬细胞极化，参与肝内炎症调控。前期研究表明巨噬细胞M1型极化与CHB口服抗病毒治疗后HBeAg血清学转换有着明显相关性，推测肠道菌群可能通过LPS-TLR4通路诱导巨噬细胞M1型极化促进CHB免疫控制。项目组以持续表达HBV的C57BL/6J小鼠为研究对象，以健脾补肾中药颗粒剂灌胃，研究发现肠道菌群Alloprevotella丰度显著增加，肝内巨噬细胞M1极化增强，小鼠对HBV清除速度加快。项目组以利福昔明处理表达HBV小鼠模型，分析肠道微生物群、肝脏代谢组学和转录组学。发现小鼠肠道菌群中乳酸杆菌和阿克曼氏菌丰度、肝内谷氨酰胺代谢和氨基酸代谢以及肝内炎症途径（趋化因子信号通路、NF-κB信号通路等）与HBsAg血清学清除有关。项目组通过分析比较口服抗病毒治疗获得HBeAg血清转换患者和非HBeAg血清转换患者的肠道菌群及其代谢产物，结果表明肠道菌群及其代谢产物在口服抗病毒治疗诱导的HBeAg血清转换中起着关键作用。本研究将为基于肠道细菌的慢性乙型肝炎防治提供一定的理论依据，并提供新思路以改善CHB疗效、提高CHB免疫控制率。