Efficacy And Safety Of Facal Microbiota Transplantation In The Treatment Of HBV-related Chronic Liver Diseases

ObjectiveIn this study,gut microbiota and "Intestinal liver axis" as the starting point to study gut microbiota in patients with HBV-related chronic liver disease in the development of the disease.Facal Microbiota Transplantation can be used to determine whether Facal Microbiota Transplantation can reconstruct gut microbiota in patients with HBV infection;To clarify the effect of Facal Microbiota Transplantation on liver function,related complications,related inflammatory factors(IL-6,TNF-?)and intestinal mucosal barrier(DAO,D-lactate)in patients with Hepatitis B cirrhosis.The effect of Facal Microbiota Transplantation on liver function,HBV markers(HBeAg,HBV-DNA quantification)and liver fibrosis in patients with HBV infection was determined.The purpose of this study was to evaluate the efficacy and safety of Facal Microbiota Transplantation in HBV-related chronic liver disease,and to elucidate the possible mechanism of improving the progress and prognosis of HBV-related chronic liver disease by improving gut microecology.MethodsThis study is divided into two parts.The first part of patients with hepatitis B cirrhosis as the object of study,by observing the possible adverse reactions of patients with cirrhosis after Facal Microbiota Transplantation treatment,clear Facal Microbiota Transplantation on the safety of cirrhosis treatment.Followed by the observation and comparison of 17 cases of hepatitis B cirrhosis patients before and after treatment of Facal Microbiota Transplantation after digestive tract symptoms and general mental status;liver function changes;Cirrhosis-related complications(upper gastrointestinal bleeding,ascites,hepatic encephalopathy,etc.)and other comprehensive evaluation of the efficacy of Facal Microbiota Transplantation in the treatment of cirrhosis.Subsequently,the contents of DAO,D-lactate,IL-6 and TNF-? in serum of patients before and after Facal Microbiota Transplantation were detected by ELISA.The second part of the study of patients with chronic HBV infection,by observing all possible adverse reactions after treatment,clear Facal Microbiota Transplantation inpatients with chronic HBV infection safety.Followed by the observation and comparison of 18 cases of hepatitis B patients before and after treatment of Facal Microbiota Transplantation of digestive tract symptoms and general mental status improvement;changes in liver function indicators;HBV-DNA quantification,Negative HBe Ag situation;hepatitis B related complications(cirrhosis,liver failure,liver cancer,etc.)and so on to explore the efficacy of Facal Microbiota Transplantation in the treatment of hepatitis B patients.Finally,the 16 S rRNA method was used to detect and analyze all the stool samples before and after treatment.Results1,Baseline conditions of the subjects in this studyA total of 35 patients were enrolled in this study.Seventeen patients with Hepatitis B cirrhosis,including 12 males and 5 females,were aged 41-82 years,with an average age of 54.59 ± 11.09 years.There were 8 cases of Child-Pugh A grade,8 cases of B grade and 1 case of C grade.A total of 18 patients with chronic HBV infection,including 14 males and 4 females;were aged 24-71 years,with an average age of 44.83± 12.24 years;There were 10 cases of HBV carriers,8 cases of CHB patients.Significantly more males than females,and patients with cirrhosis were significantly older than patients with chronic HBV infection(P <0.05).2,Facal Microbiota Transplantation can improve liver function in patients with HBV-related chronic liver diseaseAfter treatment with Facal Microbiota Transplantation,the levels of GGT and TBA in Child-pugh grade A patients with Hepatitis B cirrhosis decreased,and the levels of ALB and CHE increased.The levels of ALT,AST,GGT and TPA in Child-pugh B / C patients were decreased,and the levels of PA and ALB increased,especially the TBIL and Child-Pugh scores decreased significantly(P <0.05).After the treatment of HBV carriers by Facal Microbiota Transplantation,the indicators of liver function changes little,all indicators before and after treatment in the clinical normal reference range.However,the levels of ALT,AST,GGT and ALP in CHB patients decreased significantly after treatment with Facal Microbiota Transplantation.In particular,thelevels of ALT,AST and GGT decreased significantly before and after treatment(P<0.05).3,Facal Microbiota Transplantation can control hepatitis B virus replication,reduce HBV-DNA quantitative,make HBeAg negativeAmong the 35 investigators,E antigen was negative in 4(2 long-term antiviral therapy and 2 non-antiviral therapy)of 11 HBeAg-positive patients after the treatment of Facal Microbiota Transplantation,with a negative conversion rate of 36.4%.In 15HBV-DNA positive patients not treated with antiviral therapy,HBV achieved a virological response in 8 patients with a response rate of 53.3% after the treatment of Facal Microbiota Transplantation.The other two patients had decreased levels of HBV-DNA titers.4,Facal Microbiota Transplantation can improve intestinal mucosal barrier function in patients with Hepatitis B cirrhosisThe levels of serum TNF-?,IL-6,DAO and D-lactic acid in patients with Hepatitis B cirrhosis were decreased after treatment with Facal Microbiota Transplantation,but the indexes of different grades of cirrhosis were different.For Child A patients,the three indexes of TNF-?,DAO and D-lactate decreased significantly(P <0.05),for Child B / C patients,the two indexes of IL-6 and D-lactate decreased significantly(P <0.05).5,Facal Microbiota Transplantation can improve the degree of liver fibrosis in patients with chronic HBV infectionThe serum levels of COL ?,HA,P?P and LN in patients with chronic HBV infection after Facal Microbiota Transplantation treatment decreased,especially before and after treatment with COL ?(P <0.05).However,the changes of the indicators in patients with different stages of HBV infection were different.For hepatitis B carriers,the indexes of COL ?and HA decreased significantly(P <0.05),while those of CHB patients LN decreased significantly(P <0.05).6,Facal Microbiota Transplantation can prevent the onset of complications related to cirrhosis,control of hepatitis B disease progressionThe number of related complications of 17 patients with cirrhosis decreased from13 to 3,among them,the number of peritonitis was reduced from 3 to 1,ascites wasreduced from 6 to 1,hepatic encephalopathy was reduced from 4 to 0,no patient developed liver failure or liver cancer.18 patients with chronic HBV infection after Facal Microbiota Transplantation treatment,did not appear of liver failure,cirrhosis,liver cancer and other hepatitis B-related complications during the follow-up of 6months.7,Differences in gut microbiota in patients with HBV-related chronic liver diseaseThe two parts of the study yielded 4,477,089 and 4,577,262 high-quality sequences,respectively,resulting in 9780 and 9692 OTU.There was a significant difference in the bacterial structure of each group of stool samples.1)Relative abundance of gut microbiota at the phylum and genus leve:Analysis of the donor gut microbiota showed that at the level of phylum and genus,the composition of donor gut microbiota was relatively stable and diversity was good.In all samples,the firmicutes and bacteroidetes constitute the two most important categories accounted for 43.0% and 49.3% of the total sequence,respectively.At the genera level,Bacteroides(Bacteroidetes),Prevotella(Bacteroidetes),Ruminococcaceae(Firmicutes)are the most important genus in all samples.After the patients was treated with Facal Microbiota Transplantation,the individual bacteria phylum and bacteria genus gradually closer to the donor's gut microbiota.2)Venn map analysis showed that the donor fecal sample contained more OTUs than the patients,indicates that the relative abundance of gut microbiota of the donor is relatively high.The number of specific OTUs in fecal samples before and after treatment was 381,287,223,and 93 respectively in patients with hepatitis B cirrhosis.The number of specific OTUs before and after treatment in patients with chronic HBV infection was383,290,563,and 49,respectively,showing a gradually decreasing trend.It was shown that the relative abundance of specific gut microbiota in the feces of patients gradually decreased after Facal Microbiota Transplantation treatment.3)LEfSe analysis showed that there were as many as 107 different bacteria genuses in the feces samples of healthy donors compared with patients with hepatitis B cirrhosis.Compared with chronic HBV-infected patients,there were 7 different bacteria genuses in the feces samples of healthy donors.After Facal Microbiota Transplantation treatment in patients with hepatitis B cirrhosis and patients with chronic HBV infection,the genus Prevotella(Bacteroidetes)was found to be a differential microbiota with an LDA value close to 5,much higher than other groups.ConclusionFacal Microbiota Transplantation in the treatment of HBV-related chronic liver disease is relatively safe.Continuous Facal Microbiota Transplantation treatment can control hepatitis B virus replication,improve liver function and control the progress of liver disease,which is a new mode of treatment for patients with HBV-related chronic liver disease.