研发新型抗乙肝病毒药物和寻找新的抗乙肝病毒作用靶点仍是世界性难题。HBV的PreS1与肝细胞的HBV受体及胆汁酸转运受体NTCP结合而进入细胞内，影响肝脏胆汁酸代谢以及肠道内菌群稳态。类法尼醇X受体激动剂促进下游靶基因SHP的表达，抑制STAT3的磷酸化及核转位，也抑制NTCP和胆汁酸合成关键酶CYP7A1的表达。STAT3活性对于HBV的病毒转录和复制至关重要。因此，我们提出“FXR受体激动剂一可调节胆汁酸代谢及肠道菌群稳态，抑制NTCP表达并阻止HBV入侵肝细胞；二可激活下游SHP靶基因，阻止STAT3的磷酸化及入核，抑制HBV基因组复制”的假说。本项目拟研究HBV病毒入侵和复制与胆汁酸代谢及肠道菌群的关系，进一步采用临床试验和人源化小鼠模型确定FXR激动剂对HBV病毒复制、胆汁酸代谢和肠道菌群构成的影响及其具体机制，为新型抗乙肝病毒药物的研发进行理论探索。

Developing new anti-HBV drugs and finding new drug targets is still a word problem .NTCP is a HBV specific receptor ,binding with PreS1 protein of HBV to mediate HBV into cell for replication , which may affects bile acid and intestinal flora homeostasis. Farnesoid X receptor agonists can promote the expression of downstream target gene called SHP, inhibiting the expression of the key enzyme of cholesterol in bile acid synthesis called 7α-hydroxylase and bile acid receptor called NTCP. It also can infect the activity of STAT3. STAT3 is essential to the transcription of HBV cccDNA. Based on this ,we propose that FXR receptor agonist participate in HBV replication through two mechanisms .One is to inhibit HBV binding with NTCP and invading hepatocytes, the other is to prevent STAT3 phosphorylation and suppress HBV genome replication by activating downstream target genes SHP. We determine the abnormal bile acid metabolism in patients with hepatitis B and intestinal flora composition by comparing the metabolic indexes of hepatitis B patients and normal people . We plan to explore the mechanism that FXR agonists inhibit HBV replication by clinical trials and humanization mouse model, providing theoretical basis for new antiviral drugs.