| Objective: Inflammatory bowel disease(IBD)is a non-specific chronic inflammatory disease.Its etiology and pathogenesis still remain unclear.It can be mainly divided into ulcerative colitis(UC)and Crohn’s disease(CD).IBD is still incurable and tends to recur for whole life,so the disease monitoring is very important.At present,the commonly used methods are colonoscopy,CTE/MRE,enteroscopy,fecal calprotectin,etc.Although these examinations can reflex disease status and evaluate treatment effect,there are some limitations for these methods,for instance,the price is not cheap,the examination process is cumbersome,and some examinations are not carried out commonly.Therefore,to find a convenient,less invasive and more optimized detection method has attracted many attentions in clinical research.The microbiomes in human body are considered to be related to the pathogenesis of IBD.It is found that the intestinal and oral microbiota of IBD patients are different from normal people,and dysbiosis occurred in IBD patients.Some studies have shown that the intestinal microbiota can also reflect the condition and treatment effect of IBD,but the studies are few.Less studies focused on oral microbiota,and there are no literature reports on using oral bacteria to evaluate the treatment effect and the activity of the disease.Recently,some researches reported the correlation between the composite inflammatory indexes and gut,oral microbiota,and other studies have shown that these indexes can reflect the disease severity of IBD patients,and can also evaluate the effect of treatment.It’s easy to get the specimen of oral and gut microbiota,and calculation of composite indexes only needs routine blood test results.Could these indexes,gut and oral microbiota better reflect disease status and evaluate treatment effect when using these indicators alone or combined? The answer to this question may provide more methods in IBD monitoring and may provide more choices for patients.In the last few years,fecal microbiota transplantation(FMT)has drawn much attention from researchers,but these studies didn’t reach a conclusion.Some randomized controlled trials(RCT)have shown that FMT can help to achieve remission in IBD patients,while some studies got the opposite conclusion.Since there is no standard guideline about the use of FMT in IBD,and also the numbers of patients enrolled in the published RCTs were not large enough,it’s of great importance to make a comprehensive analysis about these RCTs.This study intends to first explore the the differences of bacteria in oral cavity and intestinal tract of IBD patients,to examine the correlation between oral and intestinal bacteria and disease severity scores,CRP and ESR,and to explore the role of oral and intestinal flora in reflecting the disease activity of IBD and evaluating the effect of infliximab treatment.And then we plan to explore the application of composite inflammatory indexes in reflecting the disease activity and treatment effect of IBD,and examine the correlation between microbiota and composite inflammatory indexes,and we’ll combine these indicators to establish a predictive model for the disease monitoring in CD.Finally,through the published RCTs of FMT,we made a meta-analysis and discussed the therapeutic effect of fecal bacteria transplantation on IBD from the aspects of clinical remission,clinical response and endoscopic remission,and used the method of network meta-analysis to compare the treatment efficacy with biological agents,so as to better evaluate the effect of FMT.Materials and Methods: 1.We enrolled IBD patients from West China Hospital of Sichuan University and other healthy people during 2020 to 2021.Saliva of IBD patients and healthy people were collected,DNA was extracted by kit,and v3-v4 region of 16 Sr DNA was amplified by PCR.The sequence information was analyzed by using Illumina platform.The α polymorphism and β polymorphism of oral bacteria were compared.KEGG functional pathway analysis was conducted.The abundance differences of bacteria in different groups under several states(such as disease activity and mitigation,anxiety or depression state,use of biological agents)were compared.Correlation between the abundance of bacteria and disease activity score,CRP and ESR were analyzed.ROC curve was used to judge the role of oral flora in reflecting disease activity and evaluating the efficacy of infliximab.2.We enrolled IBD patients from West China Hospital of Sichuan University and other healthy people during 2020 to 2021.Feces of IBD patients and healthy people were collected.DNA extraction,PCR amplification and sequencing were performed.The α polymorphism and β polymorphism of intestinal bacteria were compared,and the functional analysis was conducted.The abundance differences of bacteria in different groups under several states(such as disease activity and mitigation,anxiety or depression state,use of biological agents)were compared.The correlation analysis of abundance of bacteria and disease activity score,CRP and ESR was carried out.ROC curve was drawn to judge the role of intestinal flora in reflecting disease activity and evaluating the efficacy of infliximab,and co-occurrence network analysis was conducted to examine the mutual genera between oral and intestinal bacteria. 3.UC and CD patients admitted to gastroenterology department of West China Hospital of Sichuan University from April 2018 to February 2021 were screened and enrolled and their clinical data were collected.The following composite inflammatory indexeses were calculated by: NLR is the ratio of absolute value of neutrophil to absolute value of lymphocyte;PLR is the ratio of absolute value of platelet to lymphocyte;CRP/Alb is the ratio of C-reactive protein to albumin.LMR is the ratio of absolute value of lymphocyte to absolute value of monocyte,and SII is the ratio of absolute value of platelet count absolute value of neutrophil to absolute value of lymphocyte.The main outcome was as follows: 1)according to clinical score,patients were divided into clinical activity group and clinical remission group;according to endoscopic score,patients were divided into endoscopic activity group and endoscopic remission group,and the differences of five kinds of composite inflammatory indexes in different groups were discussed.Logistic regression analysis was used to evaluate independent risk factors of clinical and endoscopic active disease flares,and Spearman or Pearson correlation analysis was used to evaluate the correlation between the composite inflammatory indexes and clinical and endoscopic scores.ROC curve was used to explore the diagnostic value of composite inflammatory indexes in disease activity and remission;2)according to whether patients achieved clinical remission at 14 weeks and 54 weeks after treatment of infliximab,patients were divided into clinical remission and non-remission group,and the differences of composite inflammatory indexes were evaluated.Logistic regression analysis was used to evaluate the independent risk factors of active disease after infliximab treatment.ROC curve was used to investigate the role of compound inflammatory indexes in the evaluation of the efficacy of infliximab;3)Spearman correlation analysis was used to evaluate the correlation between oral,gut microbiota and composite inflammatory indexes;4)oral,gut microbiota and composite inflammatory indexes were used to establish a conjoint predictive model which is based on logistic regression analysis,ROC curve was drawn to judge the combined predictive ability of the three factors for disease activity and the efficacy of infliximab.4.The data of randomized controlled trials of FMT in UC were extracted from Pub Med,EMBASE and Cochrane library databases.The treatment effect of FMT in UC were analyzed by meta-analysis using Revman software.The results of the randomized controlled trials of biological agents such as adalimumab and vedolizumab were compared by network meta-analysis which was carried out using Stata software.And we evaluated the therapeutic effect of FMT and different biological agents on UC.Results: 1.In the study of oral microbiota,the α diversity in UC patients is higher than that in CD and healthy people.The β diversity of UC patients is different from that of healthy people.The composition of oral microbiota in UC,CD and healthy people are different,at the dominant level,the abundance of Bacteroidetes decreased and Firmicutes increased in UC and CD patients.The function of oral microbiota are also different,the oral bacteria of UC and CD patients have more genes in pathways of signal transduction,gene transcription and virus related infectious diseases,but less genes in pathways of multiple physiological functions and metabolism.Disease activity,infliximab and anxiety/depression state would affect the composition of bacterial flora to a certain extent.The abundance of oral bacteria is related to the clinical activity score,CRP and ESR.The of varied oral bacteria can be used to predict the disease activity of patients and the efficacy of 14 weeks and 54 weeks of infliximab treatment.2.In the study of intestinal microbiota,the α diversity of healthy people is higher than that of UC and CD patients.The β diversity of UC patients is different from that of healthy people.The composition of intestinal microbiota in UC,CD and healthy people are different,at the dominant level,the abundance of Actinobacteriota decreased and Proteobacteria increased in UC and CD patients.The function of intestinal microbiota are also different,the intestinal bacteria of UC and CD patients have more genes pathways of drug resistance,neurodegenerative diseases and tumor,which suggesting that they may be more pathogenic.Disease activity,infliximab and anxiety/depression state would affect the structure of bacterial flora to a certain extent.The abundance of intestinal bacteria is related to the clinical activity scores,CRP and ESR.The varied intestinal bacteria can be used to predict the disease activity and the efficacy of 14 weeks and 54 weeks of infliximab treatment.The mutual genera of oral and intestinal bacteria in UC and CD patients are more than those in healthy people,while disease activity,infliximab and anxiety/depression state could affect the mutual genera.3.The composite inflammatory indexes in UC and CD patients between clinical remission and active stage,endoscopic remission and active stage are different.In CD,CRP/Alb is the independent risk factor of clinical active stage and endoscopic active stage,while in UC,no indexes are the independent risk factors of disease active flares.All the indexes have strong correlation with clinical and endoscopic scores.In general,the levels of NLR,PLR,SII,CRP/Alb were positively correlated with disease severity,while LMR was negatively correlated.Composite inflammatory indexes can predict the disease activity of IBD patients.As for the evaluation of the curative effect of infliximab,there were differences in the values of composite inflammatory indexes between CD patients with different response to 14 weeks and 54 weeks of infliximab treatment.The levels of PLR,SII,CRP/Alb and LMR before infliximab treatment can predict the effect of 14 weeks of infliximab treatment,and the level of NLR,SII,LMR at 14 weeks of infliximab treatment can better predict the curative effect of 54 weeks of infliximab treatment in CD patients.Several oral and gut microbiota obviously correlated with inflammatory indexes.The conjoint predictive model which combined intestinal bacteria,oral bacteria and composite inflammatory indexes can better reflect the disease status and curative effect of 14 weeks of infliximab treatment.4.FMT was superior to placebo in inducing clinical remission and clinical response,and does not significantly increase serious adverse event,but it has no obvious advantage in endoscopic remission.In the network meta-analysis with ustekinumab,adalimumab,infliximab and vedolizumab,in terms of induction of clinical remission,ustekinumab was the most effective,followed by FMT,vedolizumab,infliximab and adalimumab;in terms of clinical response,infliximab was the most effective,followed by ustekinumab,FMT,vedolizumab and adalimumab;in terms of induction of endoscopic remission,the effect of infliximab was the best,followed by ustekinumab,vedolizumab and adalimumab.Conclusion: 1.Dysbiosis existed in IBD patients’ oral and intestinal microbiota,disease activity,anxiety/depression state,and the use of infliximab will affect the structure of bacterial flora to a certain extent.Some microflora has obvious correlation with clinical activity scores and inflammatory indicators.Oral and intestinal microflora can predict the severity of disease and the effect of infliximab.;2.The composite inflammatory indexes can reflect the clinical disease activity and endoscopic disease activity of UC and CD patients,and can predict the efficacy infliximab treatment in CD patients;Several oral and gut microbiota obviously correlated with composite inflammatory indexes;the conjoint predictive model which combined intestinal bacteria,oral bacteria and composite inflammatory indexes can better reflect the CD disease status and curative effect of infliximab;3.FMT can effectively induce clinical remission and clinical response,and in these two aspects,the effect of FMT is as the same as that of some biologics,but the effect of FMT is limited in inducing endoscopic remission.Ustekinumab and infliximab are more effect in UC patients. |
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