2022+亚太共识：胃肠道疾病中的小肠细菌过度生长.pdf

ASIAN-PACIFIC CONSENSUSAsian-Pacific consensus on small intestinal bacterial overgrowthin gastrointestinal disorders:An initiative of the IndianNeurogastroenterology and Motility AssociationUday C.Ghoshal1&Sanjeev Sachdeva2&Ujjala Ghoshal3&Asha Misra1&Amarender Singh Puri2&Nitesh Pratap4&AyeshaShah5&M.MasudurRahman6&KokAnnGwee7,8&VictoriaPYTan9&TahmeedAhmed10&YeongYehLee11,12&B S Ramakrishna13&Rupjyoti Talukdar14&S V Rana15&Saroj K Sinha16&Minhu Chen17&Nayoung Kim18&Gerald Holtmann5Received:20 June 2022/Accepted:2 August 2022#The Author(s)2022AbstractIn the clinical setting,small intestinal bacterial overgrowth(SIBO)is a frequent,but under-diagnosed entity.SIBO is linked tovarious gastrointestinal(GI)and non-GI disorders with potentially significant morbidity.The optimal management of SIBO isundefined while there is a lack of published consensus guidelines.Against this background,under the auspices of the IndianNeurogastroenterology and Motility Association(INMA),formerly known as the Indian Motility and Functional DiseasesAssociation(IMFDA),experts from the Asian-Pacific region with extensive research and clinical experience in the field ofgutdysbiosisincludingSIBOdevelopedthisevidence-basedpracticeguideline forthe managementofSIBOutilizingamodifiedDelphi process based upon 37 consensus statements,involving an electronic voting process as well as face-to-face meetings andreview of relevant supporting literature.These statements include 6 statements on definition and epidemiology;11 onetiopathogenesis and pathophysiology;5 on clinical manifestations,differential diagnosis,and predictors;and 15 on investiga-tions and treatment.When the proportion of those who voted either to accept completely or with minor reservations was 80%orhigher,the statement was regarded as accepted.The members of the consensus team consider that this guideline would bevaluable to inform clinical practice,teaching,and research on SIBO in the Asian-Pacific region as well as in other countries.Keywords Breathmethane.Disordersofgut-braininteraction.Dysbiosis.FODMAP.Gutmicrobiota.Hydrogenbreathtest.Irritablebowelsyndrome.RifaximinIntroductionThe human gut is inhabited by an intricate population of mi-crobes,collectively known as microbiota.The composition ofmicrobiota in the proximal gut differs qualitatively as well asquantitatively from that in the colon 1.Usually,the smallintestine isdevoidofcoliformbacteria,and evenifpresent thenumber is little.Small intestinal bacterial overgrowth(SIBO)is characterized by the presence of an excessive amount ofbacteria within the small intestine,which may result in a con-stellation of gastrointestinal(GI)symptoms 2,3.Studies utilizing molecular techniques suggest that com-pared to the true prevalence,SIBO remains in the clinicalsetting frequently undiagnosed 4.Etiopathogenesis ofSIBO is multifactorial 1 and it is linked to several GIand non-GI disorders with significant morbidity includingirritable bowel syndrome(IBS),non-alcoholic fatty liverdisease(NAFLD),chronic pancreatitis,celiac disease,obe-sity,and inflammatory bowel disease(IBD)5.Contrasting the prevalence,research into SIBO has juststarted and this condition remains worldwide largely un-der-researched.While diagnostic modalities for SIBO are still evolving,itsmanagement also remains a challenge with the limited dataand the absence of consensus-based clinical guidelines.Uday C Ghoshal and Sanjeev Sachdeva contributed equally to the workand are joint first authors of the paper.*Uday C.GExtended author information available on the last page of the articleIndian Journal of Gastroenterologyhttps:/doi.org/10.1007/s12664-022-01292-xAgainst this background and under the auspices of the IndianNeurogastroenterology and Motility Association(INMA),formerly known as the Indian Motility and FunctionalDiseases Association(IMFDA),experts from the Asian-Pacific Region with clinical and research experience in thefield of SIBO and gut dysbiosis collaborated with the aim todevelop evidence-based practice guideline for the manage-ment of patients with SIBO.The consensus team aimed toprovide valid guidance for clinical practice,teaching,and fu-ture research on SIBO across the globe with the firstconsensus-based guideline that utilized a rigorous Delphiprocess.MethodsThe members of the consensus team were selected from Asian-Pacific countries based on their interest and experience in thefield of gut dysbiosis including SIBO as evidenced by an elec-tronic literature search on PubMed.The members included ex-perts from India,Bangladesh,China,South Korea,Singapore,Hong Kong,Malaysia,and Australia.A core group of fourmembers was selected from among the consensus team mem-bers who made the first set of 37 statements on definition,epidemiology,etiopathogenesis,pathophysiology,clinicalmanifestations,differentialdiagnosis,predictors,investigations,andtreatment.The membersofthecoreteam hada preliminaryface-to-face meeting in Lucknow(India)on 10th November2017 to develop preliminary statements for further refinementand discussion by the full consensus group.The consensus process involved a modified Delphi method6.Before the first round of voting on the statements,an elec-tronic library was created in the Digital Medical Education sec-tion of the Shanti Public Educational and Development Societywebsite(www.spreadhealth.in).The first round of online votingwasheldinJuly2019.Thevotingwasconductedinanelectroniconline anonymous voting system developed in the Research andInnovation initiative menu in the www.spreadhealth.in and theresults were analyzed electronically.The result of the first roundofvotingwaspresentedtotheentireconsensusteaminaface-to-facemeetingheldinKolkata(India)on13thDecember2019,onthesidelinesoftheAsian-PacificDigestiveWeek-2019(APDW-2019)Conference.Duringthisface-to-facemeetingatKolkata,adiscussion was held on the modification of five statements,which could not reach 80%acceptance during the first roundof voting.Also,the formulation of an algorithm for the manage-mentofSIBOwasdiscussed.Thesecondroundofonlinevotingwas subsequently held in January 2020 in which the five modi-fied statements were put to voting.Method of Grading ofRecommendations,Assessment,Development and Evaluation(GRADE)Working group was used for deriving at the level ofagreement,level of evidence,and grade of recommendation(Table 1)7.When the proportion of those who voted eitherto accept completely or with some reservation was 80%orhigher,the statement was regarded as accepted.Finally,a con-sensus was achieved on all 37 statements,which included thefive modifiedstatements.Analgorithm ofmanagementof SIBOwas finalized as per suggestions of the consensus team.However,due to the pandemic of Corona Virus Disease-19(COVID-19)that devastated the whole world,further works onthisconsensusgotstalledforthenext2years.On7thMay2022,the core group members of the consensus team physically metduring the 5th Annual Congress of the Indian Motility andFunctional Diseases Association(now named as INMA)inLucknow,India,to finalize the manuscript for publication.Theconsensus was presented on the same day to all the delegates ofthe 5th INMA Congress.Consensus statementsDefinition and epidemiologyStatement 1:Small intestinal bacterial overgrowth(SIBO)isdefined as the growth of bacteria 105colony-forming unit(CFU)/mL or 103CFU/mL(particularly if coliforms arepresent)on a quantitative culture of upper gut aspirate.Voting summary:Accepted completely 57.9%,acceptedwithsomereservation36.8%,acceptedwithmajorreservation5.3%.Level of evidence:II-2.Grade of recommendation:B.SIBO is a clinical condition caused by the presence of anexcessive amount of bacteria within the small intestine.It isdefined asthe growthofbacteria105CFU/mLor103CFU/mL(particularly if coliforms are present)on a quantitativeculture of upper gut aspirate 1,814.Healthy controls havegenerally 103CFU/mL forSIBO correlated well with clinical symptoms,breath test re-sults,and sequencing 20.Indian Journal of GastroenterologyStatement 2:SIBO can be high-or low-threshold dependingupon the bacterial counts.Voting summary:Accepted completely 100%.Level of evidence:III.Grade of recommendation:C.The culture-based threshold for SIBO has been conten-tious,both as per published data as well as the opinion ofthe concerned experts.Several investigators have put forwardtheir viewpoint of the low-or high-threshold for SIBO basedupon the bacterial counts in the small bowel aspirate 13,1517.Low threshold is mostly taken as counts 103CFU/mL,while a high-threshold implies counts 105CFU/mL.The use of varying thresholds has yielded different rates ofprevalence of SIBO in several studies.It is quite understand-able that the use of a lower threshold often results in a higherfrequency of SIBO in the clinical studies reported to date.A study from Sweden reported a SIBO prevalence of 4%inboth IBS patients and controls while using the conventionalthreshold of 105CFU/mL,but the prevalence was found to besignificantlydifferent(43%inIBSvs.12%incontrols)whenthelower threshold was used 15.In a vital study from India on 80subjectswithIBS,15/80(19%)hadSIBOaspertheconvention-al threshold of 105CFU/mL,while 19/80(23.8%)additionalpatients had low-grade or low-threshold SIBO(bacterial countsof 103to 105CFU/mL)13.In a study from the USA on 139patients with unexplained gas,bloating and diarrhea,the preva-lence of SIBO using low-and high-thresholds was 44.6%and18%,respectively 16.In a study from India in patients withnon-alcoholic steatohepatitis(NASH),jejunal aspirate culture on35 subjects yielded SIBO in 14/35(40%)when a low-thresholdwas used,but the prevalence was only 5/35(14.3%)when thehigh-threshold was used 17.A recent North American consen-sus on breath testing and American College of Gastroenterologyguideline document on SIBO proposed using a lower threshold,i.e.103CFU/mL in upper gut aspirate culture for diagnosis ofSIBO 18,19.Statement 3:Microbiological spectrum in SIBO may varybased on the underlying causes.Voting summary:Accepted completely 68.3%,acceptedwithsomereservation21.1%,acceptedwithmajorreservation5.3%,rejected with reservation 5.3%.Level of evidence:II-2.Grade of recommendation:B.Based on the type of microflora,the cultured bacteria in sub-jects with SIBO can be broadly classified as Gram-positive floraand coliform flora 21,22.Isolated Gram-positive flora mayinclude Streptococcus,Staphylococcus,Enterococcus,Micrococcus,Lactobacillus,Corynebacterium,Fusobacterium,and Peptostreptococcus,while predominant among Gram-negative flora are Escherichia coli(E.coli),Klebsiella,Proteus,Acinetobacter,Enterobacter,Citrobacter,Neisseria,Bacteroides,andClostridia.There maybe a mixof Gram-positive andGram-negative populations,as well as aerobic and anaerobic bacteria16,23.The type of isolated bacterial species may vary dependingupon the underlying pathophysiology 21,2426.While de-pletion of the gastric acid barrier due to hypochlorhydria,useof proton pump inhibitors(PPIs),or other causes may predis-pose to SIBO with Gram-positive flora 24,25,pathophysi-ological mechanisms like small bowel anatomical alterationsand sub-optimal intestinal clearance function predisposes toSIBO with predominantly Gram-negative flora 26.Table 1 Level of the agreement,level of evidence,and grade ofrecommendation used in thisconsensus(method of Grading ofRecommendations,Assessment,Development and EvaluationGRADE working group)Level of agreementIAccepted completelyIIAccepted with some reservationIIIAccepted with major reservationIVRejected with reservationVRejected completelyLevel of evidenceIEvidence obtained from at least one randomized controlled trialII-1Evidence obtained from well-designed controlled trials without randomizationII-2Evidence obtained from well-designed cohort or case-controlled studyII-3Evidence obtained from the comparison between time and places with or without interventionIIIThe opinion of respected authorities,based on experience or expert committeesRecommendation(based on the quality of evidence)AThere is good evidence to support the statementBThere is fair evidence to support the statementCThere is poor evidence to support the statement but recommendation made on other groundsDThere is fair evidence to refute the statementEThere is good evidence to refute the statementIndian Journal of GastroenterologyInastudyfromNorway24onfifteenhealthysubjectswitha mean age of 84 years,12(80%)were found to havehypochlorhydria with mean pH of 6.6 and a mean bacterialcount of 108CFU/mL in fasting gastric aspirate.Normochlorhydric individuals had counts of 101CFU/mL.Predominant microflora detected included Streptococcusviridans,coagulase-negative staphylococci,and Haemophilusspecies.E.coli and Klebsiella were found in only one individ-ual.No subject had strict anaerobes in culture of aspirate.Similarly,data from Switzerland 25,utilizing duodenalaspirate culture performed on 25 patients with peptic ulcerdisease taking omeprazole for more than 5 weeks,and 15control subjects who were outpatients referred for upper GIendoscopy but with no exposure to PPIs found SIBO in 56%of subjects on PPI and 0%of controls.Hemolytic and non-hemolytic streptococci were the most commonly isolatedbacteria.Various etiologies of malabsorption syndrome(MAS)areassociated with intestinal stasis that may result in SIBO 27,28.In a study from Lucknow(India)26,jejunal aspiratecultures of 50 patients with MAS were analyzed.The cultureshowed growthofbacteriain34/50(68%)subjects withMASwith 21/50(42%)having counts 105CFU/mL.Thecommonest isolated bacteria were Streptococcus species andE.coli.Statement 4:The frequency of SIBO is low among healthysubjects but is higher in the elderly.Voting summary:Accepted completely 84.1%,acceptedwith some reservation 5.3%,accepted with major reservation5.3%,rejected with reservation 5.3%.Level of evidence:II-2.Grade of recommendation:B.As per different published studies with an evaluation ofsmall sets of healthy subjects as controls,SIBO has been re-ported in 0%to 22%depending primarily on the type of di-agnostictestused29,30.FrequencyofSIBOishigherintheelderlyrangingfrom14.5%to56%31,32.Across-sectionalsurveyfromGermanyrevealedSIBOin15.6%inolderadults,compared with 5.9%in subjects aged 24 to 59 years 33.Several studies on SIBO in GI disorders have found olderage to be an independent risk factor for the occurrence ofSIBO 3436.Elderly subjects are expected to be more prone to SIBObecause of several factors like reduced gastric acid 24,re-duced GI motility,anatomic factors like diverticula,co-morbidities like diabetes mellitus,and use of various medica-tions,which may predispose to SIBO.A study from the UK37 found that factors predictive of a positive glucose hydro-gen breath test(GHBT)in the elderly included increasing age(75 years),low serum vitamin B12,low serum albumin,pre-vious partial gastrectomy,previous right hemicolectomy,presence of small bowel diverticula,and concurrent use of aPPI.In fact,a study from Lucknow