| Background:In recent years,the global prevalence of chronic kidney disease(CKD)has been increasing year by year,which reached 10.8% in China and was associated with huge economic and social burden to Chinese people and the society.IgA nephropathy(IgAN)is the most common type of CKD in China.About 45.2% of renal biopsy patients were diagnosed with IgAN,and 25-50% of them progress to the end-stage renal disease(ESRD)within 10-20 years.Therefore,study on the pathogenesis and the strategy of prevention and treatment is of great importance to improve the prognosis of IgAN.Previous studies suggested that gut microbiota was associated with immune regulation,metabolism,neuroendocrine regulation,and other physiological and pathological processes,and was hailed as the new "organ" and "gene pool" of human beings.At present,studies have confirmed that gut dysbiosis was involved in the occurrence and progression of some immune-related and metabolism-related diseases such as inflammatory bowel disease and colon cancer.Disorders in immune regulation and metabolism play an important role on the development of IgAN and other CKD.Exploring the characteristics of gut microbiota of IgAN patients could furtherly reveal the pathogenesis and provide new targets for the prevention and treatment of IgAN.Recently,a number of studies have preliminarily explored the characteristics of gut microbiota in patients with CKD.Among them,four studies explored the alteration of intestinal flora between IgAN patients and healthy people,but the results of these studies were quite different and did not form a consistent conclusion.In addition,these studies did not explore the relationship between the characteristics of the gut microbiota and clinical efficacy,nor the association between the changes of the bacterial flora during treatment and the clinical efficacy,as well as the effect of therapeutic regimens on gut microbiota in IgAN patients.Exploring the association between characteristics of gut microbiota at baseline and prognosis can provide new biomarkers for pre-judgment of the prognosis of IgAN.The analysis of the changes of intestinal flora during treatment and the relationship between these changes and clinical efficacy can provide important evidence to clarify the role of gut microbiota on the pathogenesis of IgAN and to guide clinical practice.Many studies have proved that faecal microbiota transplantation(FMT)can safely and effectively reconstruct the intestinal microecology and could effectively treat clostridium difficile infection,inflammatory bowel disease,and other diseases.Scholars hypothesized that the repairment of intestinal mucosal immune system and the improvement of intestinal epithelial barrier function may be the potential mechanism of FMT to exert clinical efficacy.Some studies have shown that intestinal immune disorder was closely related to the production of galactose-deficient IgA1,a key molecule of in the pathogenesis of IgAN.Theoretically,the reconstruction of intestinal microecology can repair the intestinal mucosal immune system to reduce the production of galactose-deficient IgA1 and achieve the success treatment of IgAN.Therefore,the exploration of the efficacy,safety,and feasibility of FMT in refractory IgAN patients,which is expected to bring a breakthrough in the treatment of IgAN and provide the important basis for elucidating the role of gut dysbiosis in the pathogenesis of IgAN.Objective:To explore the characteristics of gut microbiota in IgAN patients,the association between the gut microbiota and clinical efficacy,and the influence of different therapeutic regimens on gut microbiota,and to evaluate the efficacy,safety,and feasibility of FMT for treating refractory IgAN by reconstructing intestinal microecology.Methods:In the first part,databases from their date of inception to March 31,2020 were systematically searched for case-control or cross-sectional studies comparing the gut microbial profiles in adult patients with IgAN and other CKD with those in healthy controls.Quantitative analysis of alterations of gut microbial parameters was conducted.In the second part,we included patients who were diagnosed with IgAN by renal biopsy in our hospital from July 2017 to October 2020 and had not received immunosuppressive therapy before.Baseline clinical data,treatment regimens,and 24 hours total urine protein(24h UP),renal function and other indicators for efficacy evaluation were recorded.Stool specimens of patients were collected before the initial treatment and 6 months later.Healthy controls who were willing to donate stool specimens were recruited from community and physical examination centers of the Xijing hospital.The blood,urine,and stool routine test,and parameters of liver and kidney function of healthy controls were recorded.Faecal microbiota was analyzed by 16S-rRNA gene sequencing.In the third part,we screened refractory IgAN patients in our hospital from November2017 to October 2020,and recruited two healthy donors for stool donation.Fresh faecal bacterial suspension was administered to the refractory IgAN patients through transendoscopic enteral tubing(TET)placed with colonoscopy,once a day,each time200 ml,and continued for 40 days.24 h UP,renal function and other indicators for efficacy evaluation were recorded.Infection,bleeding,diarrhea,and other adverse events were monitored.Fresh faecal specimens were collected before the treatment and at 1-,3-,and 6-month after the treatment.The faecal microbiota before,during,and after FMT was analyzed by 16S-rRNA gene sequencing.Results:Twenty-six studies with a total of 1492 CKD patients and 948 healthy controls,including four studies focused on IgAN(n=161),were included in our systematic review.Compared to healthy controls,the abundance of phylum Proteobacteria and Fusobacterium,and genus Escherichia＿Shigella and Desulfovibrio were higher,and that of genus Roseburia,Faecalibacterium,Pyramidobacter,Prevotellaceae＿UCG-001 and Prevotella＿9 were lower in patients with CKD;the abundance of phylum Proteobacteria and Fusobacterium,and genus Streptococcus and Desulfovibrio were higher,while that of genus Prevotella,Coprococcus,Megamonas,Faecalibacterium and Prevotella＿9 were lower in patients with ESRD.In particular,the abundance of taxa in the bacterial chain,Proteobacteria – Gammaproteobacteria – Enterobacteriales – Enterobacteriaceae –Escherichia＿Shigella,were specifically higher in patients with CKD.Moreover,higher concentrations of trimethylamine-N-oxide(TMAO)and p-cresyl sulphate(PCS)and lower concentrations of short-chain fatty acids(SCFAs)were observed in advanced CKD patients.The gut permeability in patients with CKD was not determined due to the heterogeneity of the selected indicators.Two studies supported the higher abundance of Escherichia＿Shigella,and lower abundance of Bifidobacterium in IgAN patients compared to healthy controls,respectively.The results of other parameters of gut microbiota in IgAN patients were inconsistent,and no study focused on the relationship between the gut microbiota characteristics and clinical outcome.A total of 70 untreated and newly diagnosed primary IgAN patients and 30 healthy controls were included in the prospective cohort study.Twenty-three IgAN patients received supportive care therapy(SC)regimen dominated by RAS(renin-angiotensin system)inhibitors,34 patients received immunosuppressive regimen(IT).Among 34 patients,18 patients received corticosteroid plus cyclophosphamide(CS+CTX)regimen,and 16 patients received corticosteroid plus mycophenolate mofetil(CS+MMF)regimen.Case-control study suggested that,compared with healthy controls,the composition of the baseline gut microbiota of IgAN patients was significantly changed,and there were taxa with significant differences in abundance at different classification levels.At the phylum level,the abundance of Proteobacteria and Actinobacteria was high while that of Bacteroidetes and Synergistetes was low.At the genus level,the abundance of Escherichia＿Shigella and Eggerthella is relatively high,while that of Faecalibacterium,Roseburia and Lachnospira is relatively low.In particular,the bacrerial chain,Proteobacteria-Gammaproteobacteria-Enterobacteriales-Enterobacteriaceae-Escherichia＿S higella,were specifically expanded in patients with IgAN.Analysis of the baseline gut microbiota presented that there was no significant difference in the composition and Alpha diversity of the baseline gut microbiota between IgAN patients who did or did not obtain clinical remission within 6 months receiving the SC,IT,CS+CTX,CS+MMF regimen.Analysis of the changes of gut microbiota before and after treatment showed that IgAN patients,who achieved clinical remission after receiving the IT regimen for 6 months,experienced increased Alpha diversity and significant changes in the composition of the gut microbiota,accompanied with increased abundance of Actinobacteria and Candidate＿division＿TM7 and decreased abundance of Eschericha-Shigella.The above changes were contrary to some of the major features of baseline gut microbiota in IgAN patients.However,the composition and Alpha diversity of gut microbiota did not change in patients who did not achieve clinical remission.Therefore,these results suggested that the occurrence of change in gut microbiota may be one of the crucial factors for the clinical remission of IgAN.Analysis of the effects of different therapeutic regimens revealed that the CS+CTX regimen had a great impact on the gut microbiota of the IgAN patients.The change of gut microbiota in the patients who received the CS+CTX regimen was mainly attributed to the increased abundance of Actinobacteria and the decreased abundance of Pseudomonas.The CS+MMF regimen did not affect the composition and Alpha diversity of gut microbiota of IgAN patients.However,after treatment,the abundance of Peptostreptococcaceae increased while that of Negativicutes decreased.The SC regimen also did not affect the composition and Alpha diversity of gut microbiota in the patients,but the abundance of Lachnospiraceae,Lachnospiraceae＿Incertae＿Sedis,and Lactobacillus increased.Therefore,the above results indicate that different therapeutic regimens may exert different effects on the gut microbiota of IgAN patients.In the third part,6 patients with refractory IgAN were included in the clinical trial.No serious adverse events were observed during and after FMT.Two patients dropped out of the trial due to transient serum creatinine elevation and insignificant urinary protein decline,respectively.Four patients completed treatment and were followed up for 6months.During the trial period,the proteinuria of 75%(3/4)the patients reduced to less than half of the baseline level,achieving partial clinical remission.Although the other patient did not achieve clinical remission during the trial period,she gradually achieved partial clinical remission during the follow-up period.Thus,all four patients(4/4)who completed the trial achieved partial clinical remission during the treatment or follow-up period.At the same time,serum albumin concentrations increased gradually during the trial and follow-up periods.Analysis of gut microbiota before,during,and after FMT showed that the Alpha diversity of gut microbiota increased,and the composition of gut microbiota changed,similar to that of healthy donors.Meanwhile,the abundance of Proteobacteria gradually decreased,while that of Prevotella increased.Of note,as mentioned in the first and second parts,compared with healthy controls,the abundance of Proteobacteria in CKD or IgAN patients was significantly increased,while that of Prevotella decreased.These results suggested that FMT could be able to treat IgAN by changing the diversity of gut microbiota and the abundance of some key flora.Conclusion:Firstly,compared with healthy controls,the composition of gut microbiota in patients with CKD or ESRD may be changed.There were significant alterations in the abundance of intestinal flora at different classification levels in patients with CKD or ESRD.Meanwhile,the concentration of TMAO and PCS derived from intestinal flora was higher,while that of SCFAs was lower in CKD patients at stage 4 and 5.Of note,few studies focused on IgAN,and the results of parameters of gut microbiota in IgAN patients were inconsistent.Secondly,compared with healthy controls,the composition of the baseline gut microbiota of IgAN patients was significantly changed,and there were taxa with significant differences in abundance at different classification levels.In particular,the abundance of taxa in the chain,Proteobacteria – Gammaproteobacteria – Enterobacteriales –Enterobacteriaceae – Escherichia＿Shigella,increased.Thirdly,after 6 months of immunosuppressive therapy,IgAN patients who achieved clinical remission had changed bacterial composition and increased bacterial diversity,accompanied by depleted or expanded abundance of some specific taxa,compared to that before treatment.However,IgAN patients who did not achieve clinical remission did not experience the above changes.Different therapeutic regimens may have certain influence on the gut microbiota of IgAN patients,among which the CS+CTX regimen had the substantial influence,which needs further exploration.Finally,FMT may be used to treat refractory IgAN by reconstructing gut microbiota.At a later stage,randomized controlled trials are needed to further assess the safety and efficacy of FMT in treating refractory IgAN. |
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