A novel therapy targeting the gut–liver axis for chronic hepatitis B: Ursodeoxycholic acid plus Bifidobacterium
Zhen Xun, Xiaobao Yao, Caorui Lin, Xinyao Yang, Yanfang Zhang, Xin Yang, Yujue He, Renquan Jiang, Yanping Lan, Yuchen Ye, D. Ye, Shanjian Chen, Ke Ma, Wennan Wu, Siyi Xu, Bin Yang, Can Liu, Jing Chen, Qi Zheng, Qishui Ou
Abstract
Background & Aims Targeting the gut–liver axis is a promising approach to treat liver diseases. We aimed to assess the therapeutic efficacy of targeting the gut microbiota–bile acids (BAs) axis with ursodesoxycholic acid (UDCA) plus the probiotic Bifidobacterium to treat chronic hepatitis B (CHB). Methods BA profiles were characterized by mass spectrometry and gut microbiota by 16S rRNA sequencing in patients with CHB and healthy controls (HCs). UDCA and Bifidobacterium treatment was assessed in a preclinical model and in a 2-month clinical trial of 22 participants with CHB treated by the clinically approved oral dose of UDCA (250 mg twice per day, n =6), or Bifidobacterium (2 g twice per day, n =6), or UDCA plus Bifidobacterium ( n =10). Results UDCA was the most significantly decreased serum BA in patients with CHB compared to HCs ( p <0.001), and had the anti-HBV effect in vitro and in vivo . In the gut, the Bifidobacterium abundance was the most dramatically decreased fecal microbiomes in patients with CHB ( p =0.018), and had the anti-HBV effect in vivo . Finally, combined treatment with UDCA and Bifidobacterium reduced serum alanine aminotransferase ( p =0.008), HBV DNA (77% reduction; p <0.001), pregenomic RNA (59% reduction; p <0.001), and hepatitis B surface antigen (15% reduction; p =0.002) levels; reduced NKG2A expression on natural killer (NK) cells and PD-1 expression on CD8 + T cells by about half ( p <0.01); and increased secretion of granzyme B, perforin, and interferon-γ expression by CD8 + T cells and NK cells ( p <0.05), which were better than UDCA or Bifidobacterium monotherapy in participants. Conclusions UDCA plus Bifidobacterium treatment ameliorates CHB by promoting CD8 + T and NK cell function and could be a complementary therapy deserving further investigations for CHB disease. Clinical Trial Number ChiCTR2200062861.