Multi-Omics Characteristics Of Intestinal Microbiota Signature Associated With HBeAg Seroconversion

Background:To characterize gut microbiome in patients with hepatitis B e antigen(HBeAg)seroconversion and evaluate the potential of microbiome as non-invasive biomarkers for HBeAg seroconversion.Methods:In this case-control study,we prospectively collected fecal samples at baseline from the patients with HBeAg positive chronic hepatitis B(CHB)who would have oral antiviral therapy.Fecal microbiota was analyzed using 16S ribosomal DNA sequencing while fecal metabolite was determined by metabolomics.The HBeAg and anti-HBeAg levels were measured for each subject.Enrolled patients were randomly divided into training set and test set.We identified microbial signature and constructed classifier for HBeAg seroconversion using training set while validated the results using test set.Results:Thirty-seven of these subjects achieved HBeAg seroconversion within 156 weeks after the initiation of oral antiviral therapy,while 41 subjects remained HBeAg positive even after over 156 weeks of therapy.Using classical approaches,no differences were found between the microbiota from patients with and without HBeAg seroconversion.However,a computational statistical and machine learning approach allowed us to identify a microbial signature for HBeAg seroconversion.Using random forest method,we further constructed a classifier based on the microbial signature,with area under curve being 0.803 for the test set.Patients who achieved HBeAg seroconversion tended to have lower abundance of certain fecal metabolites such as essential amino acids,and several dipeptides,which had positive correlation with the relative abundance of Genus Christensenella.Conclusions:By analyzing the fecal microbiota from the patients with and without HBeAg seroconversion,we identified intestinal microbial signature that is associated with HBeAg seroconversion after oral antiviral therapy.