| Objective:1.To systematically appraise the efficacy and security of fecal microbiota transplantation in the treatment on chronic constipation;2.To search the factors affecting effectiveness of fecal microbiota transplantation in the treatment on chronic constipation,and to offer evidence-based reference to the clinical therapeutics of chronic constipation.Methods:1.Basic methods:Through systematic review and meta-analysis,the relevant results and influencing factors of the efficacy and security of fecal microbiota transplantation in the treatment of patients with chronic constipation are integrated.2.Document retrieval:Computer search Web of Science database,PubMed,Science Direct,Cochrane Library,Sino Med database,Wanfang database,VIP database and CNKI database.The search time is set to be since the establishment of each database until September 7,2022.Chinese keywords:fecal microbiota transplantation and its synonym,and constipation.English keywords:Fecal microbiota transplantation,FMT,constipation etc.Export the retrieved literatures to the Endnote X9 software and manage them.3.Literature screening:After removing duplicate literatures,read all the titles and abstracts of literatures for initial screening based on inclusion and exclusion criteria.Read the whole text of the remaining literatures for re-screening,and the randomized controlled trials meeting the requirements are finally included.4.Data extraction:The pre-designed table is used to extract the basic data of all randomized controlled trials,including the basic information of the literatures and the researches,the intervening measures and the outcome indicators.5.Quality assessment:The bias risk assessment tool recommended by the Cochrane Reviewer’s Handbook and the Jadad scale are selected to assess the quality of all literatures included.6.Combined effect size analysis:The software Review Manager 5.4 is used to process the sorted data,perform meta analysis on the combined variables and draw the forest map.Continues variables are analyzed by means difference,standardized mean difference and 95%confidence interval.The dichotomous variables are analyzed by relative risk and 95%CI.The combined effect size is tested by Z(u)test and P value is calculated.7.Heterogeneity test:Cochrane Q test is used to calculate P value and I~2 is combined to analyze the heterogeneity of each indicator.If P≥0.1 or I~2<50%,it is believed that there is small heterogeneity,and fixed effects model is selected for analysis;whereas significant heterogeneity is considered to exist,and random effects model is adopted.If there is significant heterogeneity,sensitivity analysis is used to remove studies one by one and the remaining results are combined.8.Subgroup analysis:Subgroup analysis is conducted according to the type of patients,dose,frequency and route of fecal microbiota transplantation,preparation before transplantation,storage temperature of fecal bacteria solution and combined therapy to further explore the source of heterogeneity and factors affecting the efficacy of fecal microbiota transplantation.9.Publication bias detection:If more than eight studies are included according to the research indicators,funnel plots are drawn using the software Revman 5.4.The software R4.2.0is used to Egger’s test and Trim-and-fill method to assess the publication bias of results.Results:1.Basic information of included researches:A total of eleven literatures meeting the criteria were included,including one English paper and ten Chinese papers.There were 925patients in total,including 725 patients with functional constipation,130 patients with slow transit constipation and 70 patients with irritable bowel syndrome with predominant constipation.Control group included 457 patients and experimental group included 468 patients.Patients in the control group only accepted tranditional treatment(such as laxative,tranditional Chinese medicine,education and behavioral strategies),while patients in the experimental group received fecal microbiota transplantation in addition to the control group.2.Review of literature quality:Based on the Cochrane bias risk assessment tool,one randomized controlled trial was fully consistent with low risk,and the remaining ten studies did not report the method of hiding random assignment sequences and the blindness of investigators and subjects.The five studies did not describe whether or not follow-up was conducted and the specific conditions.According to Jadad scale,there were six high quality studies and five low quality.3.The results of meta analysis:3.1Effective rate:A total of six studies reported the effective rate of patients,and there was statistical heterogeneity among all researches(P=0.08).Meta-analysis using the random effects model indicated that fecal microbiota transplantation could improve the effective rate of patients[RR=0.70,95%CI(0.60,0.82)].3.2Constipation related scale scores:BSFS score and PAC-QOL score before and after treatment were reported in six studies,Wexner score and KESS score were reported in three studies.Statistical heterogeneity was found among all the indicators(all P<0.1).Random effects model was selected to analyze the combined effect size.Fecal microbiota transplantation could increase BSFS score[MD=0.78,95%CI(0.47,1.10)],decrease Wexner score[MD=-2.83,95%CI(-3.62,-2.03)],PAC-QOL score[MD=-13.81,95%CI(-15.22,-12.39)]and KESS score[MD=-6.65,95%CI(-11.21,-2.09)].3.3Intestinal flora levels:Three studies reported the level of oxygen flora of yeast,bifidobacterium and lactobacillus of anaerobic bacteria before and after treatment between the two groups,and two studies reported the level of enterobacterium.Among them,there was statistical heterogeneity among the studies of lactobacillus of anaerobic bacteria and bifidobacterium(all P<0.1),and random effects model was selected.There was no statistical heterogeneity among the other two indexes(all P>0.1),and fixed effects model was adopted.The results indicated that fecal microbiota transplantation could cut down the level of oxygen flora of yeast[MD=-1.14,95%CI(-1.19,-1.09)]and enterobacterium[MD=-0.87,95%CI(-0.95,-0.78)]of patients.It can increase the level of bifidobacterium[MD=1.11,95%CI(1.02,1.20)]and lactobacillus of anaerobic bacteria[MD=0.95,95%CI(0.85,1.05)].3.4Mental status score:Two studies reported SAS score and SDS score of the two groups before and after the treatment,and there was no statistical heterogeneity among all indicators(all P>0.1).Fixed effects model was selected for meta-analysis.The results showed that fecal microbiota transplantation could reduce SAS score[MD=-4.98,95%CI(-6.69,-3.27)]and SDS score[MD=-6.51,95%CI(-8.08,-4.93)]in patients.3.5Gastrointestinal hormone level:Four studies reported the contents of SP,and MTL before and after the treatment in two groups,and three studies reported the contents of VIP.There was statistical heterogeneity among the studies of SP and MTL(all P<0.1),and random effects model was selected to analyze the results.There was no heterogeneity among VIP studies(P=0.51),and fixed effects model was adopted.The results indicated that fecal microbiota transplantation could improve the contents of SP[MD=7.29,95%CI(5.12,9.46)]in patients,reduce the contents of VIP[MD=-3.86,95%CI(-3.98,-3.75)],while could not change the level of MTL[MD=4.82,95%CI(-26.08,35.71)].3.6Gastrointestinal recovery:Two studies compared the impact of FMT and traditional therapy on first anal exhaust time,bowel sound recovert time and first spontaneous defecation time in patients with chronic constipation.There was no statistical heterogeneity among all indicators(all P>0.1),and fixed effects model was used to sum up the results.The results indicated that fecal microbiota transplantation could cut down the time of gastrointestinal motility recovery:first anal exhaust time[MD=-12.47,95%CI(-13.19,-11.74)],bowel sound recovert time[SMD=-2.80,95%CI(-3.19,-2.40)]and first spontaneous defecation time[SMD=-2.59,95%CI(-2.96,-2.21)].3.7Adverse reaction:Seven studies reported the adverse reaction of the two groups of patients,among which one study used the total number of occurrence for statistics,and the remaining six studies used the number of occurrence cases for statistics,so the former was not included in the analysis of total results.There was no statistical heterogeneity among the studies(P=0.66),and fixed effects model was used for meta-analysis.Results indicated that there was no significant difference between FMT and traditional treatment in patients with chronic constipation[RR=2.15,95%CI(0.92,5.05)].4.Subgroup analysis:4.1Different patients:There were three studies on patients with functional constipation,two studies on patients with slow transit constipation and one study with irritable bowel syndrome with predominant constipation.The combined results were 0.76(95%CI:0.67,0.87),0.51(95%CI:0.29,0.90)and 0.77(95%CI:0.60,1.00),respectively.Fecal microbiota transplantation was effective in improving fecal morphology of the first two types of patients,and the combined results were[MD=0.68,95%CI(0.31,1.05)]and[MD=1.10,95%CI(0.35,1.86)]respectively.4.2Different transplantation dose:The dose of fecal microbiota transplantation could be divided into 100ml,300ml and 400ml according to the index effective rate,and there were two studies on different subgroups.The combined result of 100ml dose was 0.51(95%CI:0.29,0.90).The same index of 300ml was 0.75(95%CI:0.63,0.91),and that of 400ml was0.77(95%CI:0.65,0.91).Transplantation doses were divided into 100ml,150ml and 300ml according to BSFS score,and there were two studies for each subgroup.The results showed that100ml and 150ml could improve fecal morphology of patients,and combined results were[MD=1.10,95%CI(0.35,1.86)]and[MD=0.97,95%CI(0.80,1.13)].4.3Different transplantation frequency:The frequency of fecal microbiota transplantation was divided into three times and six times,and there were three studies based on effective rate and two and three studies based on BSFS score.The consequence indicated that the combined result of three times transplantation was 0.74(95%CI:0.64,0.87),and the morphology of feces was changed[MD=0.88,95%CI(0.81,0.94)].The combined result of six times transplantation was 0.61(95%CI:0.40,0.92),while the morphology of feces did not change significantly[MD=0.72,95%CI(-0.15,1.60)].4.4Different transplantation route:The route of fecal microbiota transplantation according to the effective rate were divided into gastroscopy,nasointestinal tube and colonoscopy,including three studies,two studies and one study respectively.The consequence showed that the combined result of gastroscopy was 0.76(95%CI:0.67,0.87),the combined result of nasointestinal tube was 0.51(95%CI:0.29,0.90),and that of colonoscopy was0.77(95%CI:0.60,1.00).The route could be divided into gastroscopy and nasointestinal tube,including four studies and three studies respectively.The results showed that fecal morphology of patients could be improved by both approaches,and the combined results were[MD=0.68,95%CI(0.31,1.05)]and[MD=1.10,95%CI(0.35,1.86)].4.5Preparation before transplantation:According to preparation before fecal microbiota transplantation,the patients were divided into intestinal preparation group and non-preparation group.Four and two studies reported effective rate and BSFS score,respectively.The consequence showed that the group of intestinal prepared had an combined result of0.63(95%CI:0.47,0.84),and the unprepared group had an combined result of 0.77(95%CI:0.65,0.91).Fecal microbiota transplantation could improve fecal morphology in both groups,and the combined results were[MD=0.72,95%CI(0.04,1.39)]、[MD=0.97,95%CI(0.80,1.13)],respectively.4.6Different reservation temperature of bacterial solution:According to the preservation temperature of bacterial solution,studies were divided into above zero group and below zero group.There were three studies and one study according to the effective rate,and there were two studies and three studies according to BSFS score.The consequence showed that the combined result of above zero group was 0.76(95%CI:0.67,0.87),and that of below zero group was 0.37(95%CI:0.22,0.62).The fecal morphology of below zero group changed[MD=1.00,95%CI(0.83,1.17)],while there was no significant change in the group above zero group[MD=0.33,95%CI(-0.33,0.98)].4.7Combined therapy with different treatments:According to the effective rate,combined treatments could be divided into PEG group and lactulose group,including three studies respectively.The consequence showed that the combined result of PEG group was0.56(95%CI:0.41,0.78),and that of lactulose group was 0.78(95%CI:0.69,0.88).According to BSFS score,combined treatments could be divided into the group of laxative and traditional Chinese medicine group,including five studies and one study.The results showed that fecal morphology of patients in both groups was significantly improved,and the combined results were[MD=0.74,95%CI(0.23,1.26)]and[MD=1.05,95%CI(0.99,1.11)].Conclusions:1.Fecal microbiota transplantation is effective in the treatment of chronic constipation,which can improve clinical symptoms,quality of life,mental status,shorten the recovery time of gastrointestinal motility,and adjust gastrointestinal hormones and intestinal bacteria levels.2.Fecal microbiota transplantation is safe in the treatment of chronic constipation.There is no significant difference in adverse reactions compared with traditional treatment,but the number of cases is small and no serious adverse reactions occur.3.Fecal microbiota transplantation can improve the clinical symptoms and fecal morphology of patients with functional constipation and slow transit constipation.Clinical symptoms and fecal morphology of patients with chronic constipation can be improved by using 100ml dose,three times frequency,gastroscopy and nasointestinal tube,fecal bacteria liquid stored at below-zero temperature and the combined application of laxative.The efficacy of fecal microbiota transplantation in the treatment of chronic constipation is not significantly related to intestinal preparation before transplantation. |
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