Fecal Microbiota Transplantation For Acute And Chronic Graft-versus-host Disease:A Pilot Study And Systematic Review

Chapter One:Research backgroundGraft-versus-host disease(GVHD)is one major cause of poor prognosis after hematopoietic stem cell transplantation(HSCT),especially in patients with GI acute(a)GVHD and only half of patients respond to the first-line therapy steroid.Increasing evidence reveals that dysbiosis of intestinal flora is associated with GVHD patients,which is manifested in the decrease of bacterial diversity and the change of bacterial structure.Basic research has demonstrated the effectiveness of GVHD intervention using microflora.Fecal microbiota transplantation is a new treatment method in recent years,which aims to reshape the intestinal microecology by transplanting the intestinal flora of healthy donors into the intestines of patients.The treatment of GVHD by fecal microbiota transplantation may be a promising therapy.Chapter Two:Efficacy and safety of fecal microbiota transplantation for graft-versus-host disease after hematopoietic stem cell transplantation:a systematic reviewObjective:It has been confirmed that intestinal microecology plays an important role in GVHD,and FMT,as a treatment to interfere with flora,has become a research hotspot in the treatment of GVHD.This part collects data from individual feasibility studies for systematic evaluation to explore the efficacy and safety of FMT in the treatment of GVHD.Methods:A Systematic research of CNKI,WANFANG DATA,CBM,VIP Cochrane Library,PubMed and OVID LWW was performed.All date on FMT in patients who developed GVHD after HSCT were included.Efficacy and adverse events were integrated,and meta analysis of high quality literature was attempted using the Stata.15 software.Results:A total of 15 literatures,including 5 single-arm trials,4 case series,6 case reports were included.A total of 67 aGVHD patients,all of which were either steroid resistant or steroid dependent,reported FMT outcome.13(19.4%)patients were of grade ?-? GVHD while 35(71.6%)of grade ?-? GVHD.Overall complete response rate of 67.2%was observed,with 35(52.2%)reporting a complete response and 10(14.9%)reporting a partial response.Terms of adverse events,a total of 70 adverse events were reported,with minor adverse events including abdominal discomfort and mild elevation of body temperature.No serious adverse events which can be attributable to FMT with certainty was observed.A meta analysis including the 8 literatures(5 single-arm studies and 3 case series)was carried out,showing that the overall response rate was 62%and the overall complete response rate was 52%.Subgroup analysis was conducted according to GVHD grade,FMT routes and FMT frequency,and no statistically significant difference was found.Though,there was general trend that patients with lower GVHD grade were more likely to achieve remission than those with higher GVHD grade,and patients accepting FMT via upper or lower gastrointestinal tract were more likely to achieve remission than those via oral capsules,and patients receiving at least 2 times of FMT are more likely to achieve remission.Conclusion:Based on current limited data,FMT appears to be an effective and safe treatment for refractory GVHD,which needs to be further validated by larger sample-size,prospective,and placebo-controlled clinical trials.Chapter Three:Efficacy and safety of fecal microbiota transplantation for graft-versus-host disease after hematopoietic stem cell transplantation:a pilot studyObjective:To evaluate the efficacy and safety of FMT in patients with clinically refractory GVHD treated by fecal bacteria transplantation.Methods:This is a small pilot study that enrolled patients diagnosed with graft-versus-host disease after hematopoietic stem cell transplantation in the hematology department and pediatric department of Nanfang hospital.These patients were treated with FMT.In this study,FMTs were conducted through endoscopy,nasojejunal tube or colonoscopy,while FMT material was provided from unrelated healthy donor.The efficacy was evaluated 14 days after the last FMT,and all the adverse events were recorded within 14 days after the FMT.In addition,related cytokines,fecal microbiota analysis(culture method)and propotion of cocci and bacilli were detected and analyzed.Results:A total of 25 patients(age range 2-61 years)were enrolled.A total of 47 FMTs were performed.Among them,12 patients were acute GVHD,mainly with gastrointestinal(GI)GVHD symptoms,while 13 patients were chronic GVHD(9 mainly with gastrointestinal GVHD symptoms,1 mainly with liver GVHD symptoms,2 mainly with pulmonary GVHD symptoms and 1 mainly with oral GVHD symptoms).All these patients were clinically refractory GVHD(steroid refractory or dependence,and/or failure to respond to conventional clinical treatment such as ruxotinib).All received 1-4 fecal microbiota transplantations.1.Among the 12 patients with acute GI-GVHD,5 patients achieved complete response(CR),3 partial response(PR)and 4 non-response(NR)14 days after the last FMT.And the overall response rate was 66.7%(8/12).It was observed that abdominal pain was alleviated in 50%(4/8)of the patients,while diarrhea was alleviated in 83.3%(10/12),bloody stool in 66.6%(2/3),and feces occult blood turned negative in 40%(4/10).2.Among the 9 patients with GI-cGVHD,4 patients achieved complete response(CR),3 partial response(PR)and 2 no response(NR)14 days after the last FMT.2 patient mainly with lung-GVHD achieved partial response,1 patient mainly with liver-GVHD achieved partial response while 1 mouth-GVHD patients had no response.Long-term follow-up showed that the total bilirubin of the liver-GVHD patient decreased steadily,and decreased to the normal level at the 10th month after FMT,with a decrease of 91.4%(256 mol/L).3.There were 26 adverse events,and there were 14 cases that may be related to FMT,including 7 cases of fever,2 cases of sinus tachycardia,2 cases of constipation,2 cases of vomiting,and 1 case of bloody stool.There were no serious adverse event definitely associated with FMT.4.Microbial sequencing analysis showed that FMT changed the diversity and community composition of intestinal flora in GVHD patients,and Blautia,Faecalibacterium and unclassified_f_Lachnospiraceae increased significantly after FMT,which might be the key genus of FMT intervention.Conclusion:FMT may be a potentially valuable treatment for graft-versus-host disease after hematopoietic stem cell transplantation.This study is the first to observe that FMT may improve liver-cGVHD and lung-cGVHD besides GI-GVHD.FMT was of good safety and no serious adverse events attributed to FMT were observed.