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European Journal of Endocrinology 10.1530/EJE-17-0403 evidence thatshowthelong-term benefitofbariatric mechanistic basisofthese benefits,thereisclinical additional studiesareneeded tofurtherdemonstrate and becomingaworldwide healthproblem.Although psychological disorders,isattracting increasingattention as type 2 diabetes (T2D), cardiovascular disease and Obesity, combinedwithitsrelatedcomorbidities, such Introduction alterations inhumanmetabolism. surgery. Deeperinvestigationsarerequiredtoconfirmthemechanismsthatlinkgutmicrobiomeandmetabolic Conclusions including bodycompositionandglucosehomeostasis. debate. Faecalibacteriumprausnitzii,LactobacillusandCoprococcuscomesareimplicatedinmanyoftheoutcomes, , Clostridiales,,BlautiaandDorea.However, thechangeinmicrobialdiversityisstillunder Enterobacteriales Enterobacteriaceaeandseveralgeneraspeciesincreased.Decreasedmicrobialgroupswere Firmicutes, LactobacillalesandEnterococcusincreased;withinthephylumProteobacteria,, (, , andProteobacteria)increasedaftersurgery;withinthephylum Results microbiota. Modulationofshort-chainfattyacidandgutgeneticcontentwasalsoinvestigated. between gutmicrobiotaandhostmetabolism.We appliedthesystem ofevidenceleveltoevaluatethealteration were screened.Themainoutcomemeasuresalterationsofgutmicrobiotaafterbariatricsurgeryandcorrelations Methods Design a strongconnectionbetweengutmicrobiotaandbariatricsurgery. Objective Abstract *(Y Guo,Z-PHunagandC-QLiucontributedequallytothiswork) South University, Changsha,Hunan,China Changhai Hospital,Shanghai,China,and Shanghai EasternHepatobiliarySurgeryHospital,Shanghai,China, 1 Da-Jin Zou Yan Guo surgery systematic review oftheeffect ofbariatric Modulation ofthegutmicrobiome: a Department ofEndocrinology, ChanghaiHospital,Shanghai,China, https://doi.org/ www.eje-online.org Clinical Study : Systematicreview. : Totally 12animalexperimentsand 9clinicalstudieswereincluded.Basedonstrongevidence,4phyla : ThePubMedandOVIDEMBASEwereused,articlesconcerningbariatricsurgerygutmicrobiota 1 : Bariatricsurgeryisrecommendedforpatientswithobesityandtype2diabetes.Recentevidencesuggested , *, Zhi-PingHuang 10.1530/EJE-17-0403 1 : Thereisstrongevidencetosupportaconsiderablealterationofthegutmicrobiomeafterbariatric

© 2017EuropeanSociety2018 ofEndocrinology 2, 3 , *, Chao-QianLiu 4 and others Y Guo,Z-PHunag,C-QLiu Department ofOrthopaedics,theSecondXiangyaHospital,Central Printed inGreatBritain 3 , *, LinQi 3 Department ofGeneralSurgery, Shangai 2 Third DepartmentofHepaticSurgery, 4 , Yuan Sheng between thegeneticcontent ofthehumanandratgut ( host metabolisminpatients undergoingbariatricsurgery been recognizedasapotential contributorforregulating type 2diabetesandobesity ( forpeoplewith among theanti-diabetesinterventions ( surgery Microbiota andbariatricsurgery 3 Published byBioscientifica Ltd. , 4 ). Furthermore,recentresearch foundagreatsimilarity 1 ), supporting the inclusion of bariatric surgery ), supportingtheinclusionofbariatricsurgery 3 and Downloaded fromBioscientifica.com at09/24/202108:48:44PM 2 ). Thegutmicrobiomehas (2018) Endocrinology European Journal of com com shengyuan.smmu@aliyun. Email to YShengor D-J Zou should beaddressed Correspondence 178 or 178 : 1 178 zoudajin@hotmail. :1 , 43–56

43 –56 via freeaccess European Journal of Endocrinology www.eje-online.org (c) (b) (a) The inclusioncriteriawereasfollows: Study selection and ‘microbial’. ‘DJB’, ‘RYGB’, ‘GastrointestinalMicrobiome’,‘flora’ ‘Gastrojejunostomies’, ‘duodenal–jejunalbypass’, ‘Sleeve gastrectomy’, ‘Gastrojejunostomy’, Surgery’, studies weretrieved.Themainsearch termswere‘Bariatric 2016. Inaddition,wesearched thereferencelistof OVID Embase.Thedateofthelastsearch wasDecember the search ( meta-analysis (PRISMA)guidelineswereusedtoguide The preferredreportingitemsforsystematicreviewsand Data sources Subjects andmethods ( of theinteractionbetweenhostmetabolismand andgainabetterunderstanding after bariatricsurgery identify thealterationofgutmicrobialcomposition So wecomposedthissystematicreviewtofurther investigation duetothelackofaquantitativesummary. stillwarrants on patientsundergoingbariatricsurgery of gutmicrobiotaandthehost–microbiotacrosstalk microbiota profilesrecently( onmetabolicandgut the impactofbariatricsurgery post-surgery. and themaintenanceofbenefitforhostmetabolism weightloss community contributestosurgery-mediated ( has onhostmetabolismthroughseveralmechanisms .Giventheimpactthatmicrobiota rearrangement, whichmayaffectthemodificationof including decreasedacidproductionandanatomicalgut (RYGB), inducesimportantchangesinthedigestivetract, from bothhumanandrodentsareneeded. ( 6 5 ), itisprobablythatthiscomplexentericmicrobial ), suggestingthatmoreinvestigationsongutmicrobiota Clinical Study composed inEnglish. was used asanoutcomemeasure; surgery alteration ofthegutmicrobiota profileafterbariatric dataofbariatricsurgery; primary experiments reporting clinical trials orobservational Magouliotis Bariatric surgery, particularlyRoux-en-Ygastricbypass 9 ). We retrievedstudiesfromPubMedand 2 , 8 et al. ). composedameta-analysistoreport 7 ); however, thealteration and others Y Guo,Z-PHunag,C-QLiu manuscript: title, abstract, introduction, method, results (ARRIVE) guideline,whichreferstoseveralpartsofthe Animal Research: Reporting of the We alsoevaluatedthe included animal reports with The article regardingselection,comparabilityandoutcome. ( ‘The Newcastle–OttawaScale(NOS)forcohortstudies’ quality ofthehumantrials,weusedguidelinecalled studies and extracted data from them. To assess the Two investigators independently reviewed the selected Data extractionandqualityassessment (e) (d) We appliedtheexclusioncriteriaasfollows: human studiesand12animal experiments,wereincluded and a total of 22 papers reporting 21 studies, including 9 Initially, 477reports wererecoveredduringtheretrieval Studies includedandmethodologicalquality Results of alteration( reported the specific microbiota showed the same trend consistent whenmorethan75%ofthestudiesthat manifesting thisalteration.Findingswereconsidered methodological quality andthe consistency ofstudies of microbiotabystrictlyconsideringthenumber, the the evidenceofalterationeachspecifictaxon was performed( a quantitativeanalysisofthesystemevidencelevel Considering theheterogeneityofstudymethodology, Data synthesisandlevelofevidence between thetwoinvestigators. The thirdassessorwasneedediftheredisagreement thestudywaslabeled‘poorquality’. than 7.Otherwise, clinical studytobeofgoodqualityifthescorewasmore be ofgoodqualityifthescorewasmorethan14anda and discussion( Microbiota andbariatricsurgery 10 , gastric tumorsorlowergastrointestinaltumors. diseases, suchasCrohn’s disease,ulcerativecolitis, the studyincludedpatientscombinedwithcertain or review; letters to the editor, conference proceedings, abstracts Importantly, weconsideredananimalresearch to 11 ), whichcontains8itemsbasedon3sectionsofthe Table 1 12 al 1 Table ). ). ) ( Downloaded fromBioscientifica.com at09/24/202108:48:44PM 13 , 14 , 15 In Vivo 178 , 16 :1 ). We evaluated Experiments 44 via freeaccess European Journal of Endocrinology richness, asestimatedbyChao1( wasstillcontroversial.Thegutmicrobiota after surgery The changeintherichnessanddiversityofmicrobiota Microbial richnessanddiversity analyzed inonlyonestudywereomitted. data 1 Table Supplementary new findingsbasedon thelevel ofevidence ( The results of the population of the microbiota represent Altered microbial composition 5 clinicalstudieswereofgoodquality( the 21overallstudies,wefoundthat6animalstudiesand Using the above-described criteria to define the quality, of bilio-intestinal bypass (BIB) and ileal interposition (IT). sleeve gastroplasty(SG),duodenal–jejunalbypass(DJB), were applied:RYGB, verticalbandedgastroplasty(VBG), in thisreview( Inconclusive Weak Moderate Strong Table 1 Flow chartofstudyselection. Figure 1 Clinical Study givenattheendofthisarticle),andmicrobialspecies Levels ofevidence. Fig. 1 ). Intotal,6typesofbariatricsurgeries Inconsistent findings,orlessthan3low-qualitystudiesavailable Findings ofonehigh-qualitystudyorconsistentfindings( Consistent findings( Consistent findings( , seesection on and others Y Guo,Z-PHunag,C-QLiu 17 ) andabundance- Tables 2 ≥ ≥ 75%) inonehigh-qualitystudyandatleastlow-quality 75%) inatleast2high-qualitystudies supplementary supplementary Table 5 , 3 and and 4 ). RYGB ( Verrucomicrobia wasfoundtobeincreasedin patientsafter Fusobacteria in2016( DJB ( ( onanimalexperiencesafterRYGBobserved ( ( inpatientsundergoingeitherRYGBalso observed orVBG that this higher richness was maintained at 1 year ( that thishigherrichnesswasmaintainedat1 year that richness was higher 3 months after RYGB and ( aftersurgery increased 1 year al. et subjects( estimated byChao1inpost-surgery significant decreaseinthemeanmicrobialrichness model ( human study( based coverageestimators,increasedafterRYGB ina the effectofRYGB ( ( of ,specifically shifts of the main gut phyla toward higher concentrations RYGB ( showed anincreaseofProteobacteriaafterDJB( obesity afterRYGB ( indiet-inducedmicewith Proteobacteria wasobserved ( undergoing BIBsurgery inastudyfocusingonpatients the resultsobserved increased populationofProteobacteria( before andafterRYGB indiabeticpatients exhibitedan Metagenomic sequencingofthehumangutmicrobiome undergoing RYGB ( both in animal studies ( Shannon index,wasreportedtobehigheraftersurgery However, thegutmicrobiotadiversity, asestimatedbythe level ofevidence ( The populationof21microbialtaxawasalteredonastrong Microbiota alteredonstrongevidence postoperatively ( weeks RYGB groupremainedsignificantly depressed 3 the Shannondiversityindexofgutmicrobiota index beforeandafterRYGB. In2016, it wasshownthat study in2014( Microbiota andbariatricsurgery 31 30 E. hormaechei ). However, results were provided on rats after contrary ). An upregulation of the abundance of Bacteroidetes was ). AnupregulationoftheabundanceBacteroideteswas 28 demonstratedthatthemeannumberofspecies 24 ). Two studiesreported theincreaseofphylum 19 19 ) andmiceafterRYGB ( , ). ForpatientsundergoingBIB,there was a 25 ≥ ), from a non-obese rat model characterizing ), fromanon-obeseratmodelcharacterizing 75%) inatleast3ormorelow-qualitystudies ). Inaddition,Li 18 24 25 ) butshowednodifferenceinananimal ) showedasimilarShannondiversity ). al 5 Table 22 29 ) and BIB ( 19 27 ). Anincreasein 19 Downloaded fromBioscientifica.com at09/24/202108:48:44PM , ). Experimental results on rats ). Experimentalresultsonrats 20 , 22 and 23 ). An increased population of ). Anincreasedpopulationof ). The abundance of phylum ). Theabundanceofphylum ) and in people with obesity 21 27 upeetr al 1 Table Supplementary ). Anotherstudyshowed t al. et 20 hormaechei ) andDJB( ). However, ahuman 178 found substantial foundsubstantial 22 www.eje-online.org E. hormaechei :1 , 26 19 ), resembling ), resembling 32 20 , 27 ). ). Murphy ) and SG ) andSG 28 ) and ) and was was 45 22 via freeaccess ). ). ).

European Journal of Endocrinology Table 2 *ARRIVE, reportingofthe ( ( ( ( ( ( ( ( ( ( ( ( Study www.eje-online.org ( ( ( ( ( ( ( ( ( Study Table 3 humans andrats( ( revealed thesametrendofalteration and furtherclinicalinvestigationsfocusingonRYGB diabetic IT-operated ratsandmiceafterRYGB ( increases in the population of were found in of Alistipes after gastric bypass ( studies indicatedanupregulationoftheconcentration obesity undergoingBIB( obesity aftergastricbypass( sample fromanon-obeseratmodel( quantity accordingtothepyrosequencinganalysisoffecal The family of showed an increase in increase inthepopulationofEnterobacteriales( and acliniccohortinvestigating BIB demonstratedan from an experiment using rat models undergoing RYGB to increaseafterbariatricsurgeries( Gammaproteobacteria ( RYGB orBIBalsoimpliesasignificant increaseof ( surgery in ratsafterRYGB ( 34 33 37 31 28 23 32 29 27 19 25 63 35 24 36 26 18 21 22 20 30 18 Clinical Study ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ), ( ) ) ) ) , The population of Gammaproteobacteria increased 30

38 ). The increase of was observed on ). TheincreaseofEnterococcuswasobserved ) 1 1 1 1 1 1 1 1 1 1 1 1 1 34 Methodological assessmentforanimalexperiments. Methodological assessmentforhumanstudies. ★★★★★ ). Thefecalsamplesfrompatientsundergoing Selection ★★★★ ★★★★ ★★★★ ★★★★ ★★☆☆ ★★★☆ ★★★☆ ★★★★ 1 1 1 1 1 1 1 1 1 1 1 1 2 Newcastle–Ottawa scaleforcohortstudies 19 1 1 0 1 0 0 1 1 1 1 1 1 3 19 , in vivo 30 , 20 25 1 0 1 1 1 1 1 1 1 1 1 1 4 ). Additionally, thepopulationof experiments. Comparability , 20 , 35 29 ). Bothanimalandhuman 29 0 0 1 0 0 1 1 1 0 0 1 0 5 ★☆ ★☆ ★☆ ★☆ ★☆ ★☆ ★☆ ★☆ ★★ ). Lactobacillaleswasfound ), DJB( ) andelevenpeoplewith 18 and others Y Guo,Z-PHunag,C-QLiu , 0 1 1 1 0 1 1 1 0 1 1 1 6 19 35 20 33 , ), threepeoplewith 27 , 0 0 1 0 1 1 1 1 1 1 1 1 7 ), SG( 25 ). Postoperative ). Theresults 0 0 0 0 1 0 0 0 1 0 1 1 8 Outcome Number ofitemsARRIVE*checklist 23 Escherichia ★★★ ★★★ ★★★ ★★☆ ★★★ ★★★ ★★★ ★★★ ★★★ ) andIT 27 20 0 0 0 0 1 1 1 1 0 1 1 1 9 , , 34 27 10 0 1 1 1 0 0 0 0 0 0 1 1 ), ).

11 0 1 0 1 0 1 1 0 1 1 1 0 gordonii pneumoniae rats ( abundance ofParabacteroides wasverifiedby2studieson ( Enterobacter afterbariatricsurgery in 2013( in agreementwithastudy conductedin9individuals and theyfoundanincreaseaftersurgery, whichwas enterica Enterobacter cancerogenus of thegenus 35 found an increase in abundance of in2animalstudies( was observed Table 1Supplementary ( specific microbialtaxachangedaftersurgery There ismoderateevidencethatthepopulationof20 Microbiota alteredonmoderateevidence reduction inDorea. RYGB ( decreased in 4 studies ( ( after RYGB ( the same result was stated in 2016 by Patrone 2013 demonstratedamarkeddecreaseinBlautia( impact ofRYGB onthemodificationsof gutmicrobiotain a reductionofClostridiaceae( severely obesepeoplewhoexperiencedBIBalsorevealed Wistar ratsafterRYGB operation( concentration ofClostridiaceaewasfoundinnon-obese Microbiota andbariatricsurgery 19 ). In2015,Tremaroli , The decrease of the phylum Firmicutes was observed The decreaseofthephylumFirmicuteswasobserved 12 1 1 1 1 1 1 1 1 1 1 1 1 19 31 18 ( ( , ). TheabundanceofClostridialeswerefound S. gordonii 31 S. enterica ), SG( 13 0 1 1 1 1 1 1 0 1 1 1 1 26 ). TheabundanceofVeillonella wasfound to 21 ). Two studiesshowed the increaseof , 14 0 0 0 1 1 0 1 0 0 0 0 1 36 24 ) andBIB( ) ascendedin2clinicalstudies( , ) and ( 15 29 1 1 1 1 1 1 1 1 1 1 1 1 E. faecalis ( ). The increase of Erysipelotrichales ). TheincreaseofErysipelotrichales ), asverifiedin2studiesafterSG K. pneumoniae Downloaded fromBioscientifica.com at09/24/202108:48:44PM and ( t al. et 16 20 1 1 0 1 1 0 1 1 1 1 0 1 boydii E. cancerogenus , 20 20 25 analyzedthepopulation 17 ), 0 1 1 0 1 0 0 1 1 1 0 0 ) couldcauseasignificant ). Anexaminationofthe , 29 32 23 26 18 Akkermansia ). Fecalsampleof11 1 1 1 1 1 1 0 1 1 1 1 1 178 , , , ) and 36 30 25 :1 ( andthespecies 19 ). The reduced ). Theincreased ). Threestudies 1 1 0 1 0 1 1 1 1 1 1 1 S. boydii ), Streptococcus Table 5 20 Salmonella et al. 1 0 1 0 1 1 0 1 1 1 0 0 ( ( 18 22 E. coli 24 ) ( ), and ( Score , , and 46 10 13 13 14 14 14 15 15 15 16 16 16 30 20 30 27 via freeaccess ), ). ). ), , European Journal of Endocrinology

Table 4 Study characteristics of included studies. Clinical Study

Sample Microbiota analysis Microbiome Fecal samples Reference Country Objects BMI (kg/m2) Comorbidities Surgery size technique samples extraction (35) China Human 27.7 ± 4.1 Not stated RYGB 9 Sanger sequencing Distal colon 8 and 15 months and high- after operation throughput pyrosequencing (38) France Human ≥40 Hypertension, T2D, RYGB 43 Real-time Distal colon Before, 3 months dyslipidemia, polymerase chain after and obstructive sleep reaction 6 months after apnea syndrome operation (18) France Human ≥40 Not stated RYGB 30 High-throughput Distal colon Before, 3 months pyrosequencing after and

6 months after and others Y Guo,Z-PHunag,C-QLiu operation (26) Germany Human ≥40 T2D RYGB 6 Metagenomic Distal colon Before and sequencing 3 months after operation (24) USA Human ≥40 Not stated RYGB 14 High-throughput Distal colon Before and DNA sequencing 6 months after operation (36) Germany Human 45.8 ± 0.9 Not stated SG 10 Shotgun Distal colon One day before, sequencing 3 month after and 6 months after surgery (30) Sweden Human y RYGB: 42.2*VBG: 43.0* Not stated RYGB and VBG 14 Shotgun Distal colon 9.4 years after sequencing operation Microbiota andbariatricsurgery (20) Italy Human >35 Hypertension, T2D Bilio-intestinal 11 Illumina high- Distal colon 6 months after bypass throughput operation sequencing (22) Denmark Human >35 T2D RYGB 13 Shotgun Distal colon Before and metagenomic 3 months and sequencing 12 months after RYGB (21) New Zealand Human RYGB: 38.4* SG: 36.9* T2D RYGB and SG 14 Illumina high- Distal colon 1 year post throughput operation sequencing Downloaded fromBioscientifica.com at09/24/202108:48:44PM (29) UK Male Wistar rats None RYGB 12 High-throughput Distal colon 2 and 8 weeks (non-obese) pyrosequencing after operation (34) USA UCD-type 2 T2D Ileal 48 High-throughput Cecum 4.5 months after diabetes interposition pyrosequencing operation, cecum mellitus rats

(27) USA Diet-induced None RYGB 23 High-throughput Distal colon Before and weekly 178 obese C57BL/6J pyrosequencing for 3 months www.eje-online.org mice after operation :1 (63) Switzerland Male Wistar rats None RYGB 16 Metagenomic Cecum and Unknown sequencing distal colon (31) China Male diabetic T2D SG 30 Sanger sequencing Distal colon 1 month after Goto-Kakizaki operation

rats 47

via freeaccess (28) China Male Wistar rats None DJB 20 16S ribosomal RNA Distal colon 2 weeks and gene sequencing 12 weeks after operation

(Continued) European Journal of Endocrinology www.eje-online.org Table 4 Continued. Clinical Study

Sample Microbiota analysis Microbiome Fecal samples Reference Country Objects BMI (kg/m2) Comorbidities Surgery size technique samples extraction (37) Japan Male Otsuka None DJB 18 Illumina high- Distal colon 12 weeks after Long-Evans throughput operation Tokushima sequencing fatty rats (23) Italy Male Wistar rats None SG 60 High-throughput Distal colon 10 weeks after pyrosequencing operation (33) Japan Male Otsuka None DJB 6 The PCR-clone Distal colon 8 weeks after Long-Evans library method operation Tokushima targeting the 16S

fatty rats ribosomal RNA and others Y Guo,Z-PHunag,C-QLiu (25) China Male Sprague– None RYGB and SG 18 Illumina high- Distal colon Before and 1, 3, 6, Dawley rats throughput and 9 weeks sequencing after operation. (19) China Male Zucker None RYGB and SG 40 Pyrosequencing Distal colon 10 weeks post diabetic fatty operation rats (32) China Timo mice None DJB 15 16S ribosomal RNA Distal colon 9 weeks post gene amplicon operation sequencing

* values are the mean BMI. BMI, body mass index; DJB, duodenal–jejunal bypass; RYGB, Roux-en-Y gastric bypass; SG, sleeve gastrectomy; T2D, type 2 diabetes; VBG, vertical banded gastroplasty. was foundinpeoplewithobesityundergoingBIB( after SGinacohortstudy( 3 months whichwasobserved weight lossintervention, of Ruminococcaceaewasshowntoreduceaftersurgical ( after bariatric surgery surgery ( dispar studies onRYGB demonstratedtheincreaseof increase afterRYGB forbothhumansandrats( reduction ofFaecalibacteriumwasconfirmedinpatients undergoing 3differentbariatricsurgeries( in thepopulationofCoprococcuswasfoundpatients after BIBconfirmedthisphenomenon( ( exhibitedadecreaseinthepopulationof bariatric surgery in patients( in metagenomicsequencingofthehumangutmicrobiome A reduction inthepopulationofAnaerostipeswasshown of which6weregoodquality ( The followinganalysiswas mainlybasedon9reports, metabolic parameters Associations betweenbacterial populationandhost Table 1Supplementary Shigella, Treponema, and ( , ,Rahnella,,, Peptostreptococcus, Phenylobacterium,, Oscillibacter, , Parasutterella,, Klebsiella, Lactococcus,Megasphaera,Neisseria, Filifactor, Fusobacterium, Gemmiger, Granulicatella, Eubacterium, , Elusimicrobium,, , Dermacoccus, Desulfurispirillum,, , Anaerofilum,Campylobacter, Acidaminococcus,, , Peptostreptococcaceae and Veillonellaceae and Eubacteriaceae, ,Lactobacillaceae, Bacteroidaceae, Carnobacteriaceae,Coriobacteriaceae, Selenomonadales andVerrucomicrobiales, family and ,classBetaproteobacteria,order on aweaklevelofevidence:thephylumArchaea The populationof51microbialtaxachangedbased Microbiota alteredonweakandinconclusiveevidence studies ( decreased abundanceofTuricibacter intwo wasobserved were foundtodecreasein4studies( ( undergoing bariatricsurgery Microbiota andbariatricsurgery Four studiesdemonstratedthedecreaseofclostridia ( V. dispar 18 22 , , 37 26 20 31 ). ). , ) and , 26 37 ). Ratmodelsofdiabetesundergoing ) andfurtherexplorationofpatients Veillonella parvula ). 23 Downloaded fromBioscientifica.com at09/24/202108:48:44PM , 29 36 , ), andadditionalevidence 35 20 18 , , 36 178 , 26 20 19 ). The population ( ). , :1 , 23 V. parvula 20 20 20 , ). Adecrease , al 5 Table , 31 19 26 21 Veillonella , , , , 26 36 36 25 ) after ). Two ). The ). The and , 48 20 38 via freeaccess ). ) European Journal of Endocrinology genera ( using a pyrosequencing method and found 5 bacterial In 2013,thesameresearchers extendedtheresults by for negative correlationwasfoundwiththesameparameters calorie intake and leptin concentration; however, a correlated tobodymassindex(BMI),weight, The abundanceofBifidobacteriumwaspositively Corpulence parameters significant results( were frequentlyusedinrelevantstudies.Onlystatistically component analysisandunivariatelinearmixedmodels methods, suchasSpearman’s correlationtests,principal and 3wereofpoorquality( Species Genus Family Order Class Phylum Increase aftersurgery Species Genus Family Order Class Phylum Decrease aftersurgery Table 5

Clinical Study E. coli

Bifidobacterium, Blautia,, Lactobacillus Level ofevidenceforalterationsmicrobiome. , observed in patientsundergoingRYGB, observed ( Blautia, Dorea Clostridiaceae Clostridiales Firmicutes Enterobacter hormaechei,Enterococcus Alistipes, Enterococcus,Escherichia Enterobacteriaceae Enterobacteriales, Lactobacillales Gammaproteobacteria Bacteroidetes, Fusobacteria, Strong pneumoniae, Streptococcusgordonii faecalis, Escherichiacoli,Klebsiella Proteobacteria, Verrucomicrobia P

≤

0.05) wereextracted. and others Y Guo,Z-PHunag,C-QLiu 26 , 28 , 36 ). Statistical

Erysipelotrichales , Moderate Enterobacter Akkermansia, Ruminococcus Clostridium, Turicibacter, Faecalibacterium, , parvula dispar, Veillonella boydii, Veillonella enterica, Shigella Salmonella cancerogenus, Veillonella Salmonella, Parabacteroides, Enterobacter, Citrobacter, and 38 ). Levels ofevidence Faecalibacterium prausnitzii abundance ofBacteroidetes after SG( weight wasfoundtobenegatively correlatedwiththe inversely associatedwithBMI ( ( pallidum roseumThermomicrobium succinogenes, Lactobacillusacidophilus,reuteri, johnsonii correlated to10bacterialspecies,ofwhich Graessler with mostcorpulenceparameters( Peptostreptococcus Escherichia, Alistipes,Campylobacter, Neisseria,Filifactor, corpulence parameters, andanother 8 genera( Turicibacter Microbiota andbariatricsurgery 26 ). Furthermore, ( ( et al. T. pallidum Verrucomicrobiales Cyanobacteria, , Eubacterium, Gemmiger, Granulicatella, Peptostreptococcaceae, Carnobacteriaceae, Weak Acidaminococcus, Acinetobacter, Aeromonas, Bacteroidaceae, Lactobacillaceae,Veillonellaceae

A. johnsonii ) showedpositivecorrelationswithmost Selenomonadales, Archaea Lactococcus, Oscillibacter Lachnospiraceae Coriobacteriaceae, Eubacteriaceae, Shigella, Treponema, Vibrio,Yersinia Pseudomonas, Rahnella,Serratia,Shewanella, Phenylobacterium, Proteus,Providencia, Pectobacterium, Peptostreptococcus, Megasphaera, Neisseria,Pantoea,Parasutterella, Filifactor, Fusobacterium,Klebsiella, Dickeya, Edwardsiella,Elusimicrobium,Erwinia, Cronobacter, Dermacoccus,Desulfurispirillum, Aggregatibacter, Anaerofilum,Campylobacter, foundthatBMIofpatientsundergoingRYGB and E.cancerogenus ) weredirectlyassociatedwithBMI Gemella ), Downloaded fromBioscientifica.com at09/24/202108:48:44PM ( Coprococcus comes ( T. roseum ) werenegativelycorrelated F. prausnitzii 26 ). Moreover, thebody 18 and 36 178 ). Inthesameyear, ) and ), Treponema after www.eje-online.org :1 V. dispar ), ( Acinetobacter Bacteroides, C. comes Fibrobacter Treponema were 49 via freeaccess ), European Journal of Endocrinology www.eje-online.org Table 6 of microbiota altered on strong/moderate level of evidence. This table is to illustrate the commonalities of taxonomic distribution of microbiota Clinical Study altered on strong/moderate level of evidence, specifically, classes Bacteroidia, and Gammaproteobacteria cover most groups of microbiota in this table, and this table is organized according to the detailed taxonomy to make these commonalities more obvious.

Taxonomic Levels of Name level Trend evidence Phylum Class Order Family Genus Parabacteroides Genus Increase Moderate Bacteroidetes Bacteroidia Bacteroidales Porphyromonadaceae Alistipes Genus Increase Strong Bacteroidetes Bacteroidia Bacteroidales Rikenellaceae Bacteroidetes Phylum Increase Strong Enterococcus Genus Increase Strong Firmicutes Bacilli Lactobacillales Enterococcaceae Enterococcus faecalis Species Increase Strong Firmicutes Bacilli Lactobacillales Enterococcaceae Enterococcus Streptococcus gordonii Species Increase Strong Firmicutes Bacilli Lactobacillales Streptococcaceae Streptococcus Lactobacillales Order Increase Strong Firmicutes Bacilli and others Y Guo,Z-PHunag,C-QLiu Turicibacter Genus Decrease Moderate Firmicutes Bacilli Bacillales Turicibacteraceae Anaerostipes Genus Decrease Moderate Firmicutes Clostridia Clostridiales Clostridiaceae Clostridium Genus Decrease Moderate Firmicutes Clostridia Clostridiales Clostridiaceae Faecalibacterium Genus Decrease Moderate Firmicutes Clostridia Clostridiales Clostridiaceae Clostridiaceae Family Decrease Strong Firmicutes Clostridia Clostridiales Blautia Genus Decrease Strong Firmicutes Clostridia Clostridiales Lachnospiraceae Coprococcus Genus Decrease Moderate Firmicutes Clostridia Clostridiales Lachnospiraceae Dorea Genus Decrease Strong Firmicutes Clostridia Clostridiales Lachnospiraceae Ruminococcus Genus Decrease Moderate Firmicutes Clostridia Clostridiales Ruminococcaceae Ruminococcaceae Family Decrease Moderate Firmicutes Clostridia Clostridiales Clostridiales Order Decrease Strong Firmicutes Clostridia

Clostridia Class Decrease Moderate Firmicutes Microbiota andbariatricsurgery Firmicutes Phylum Decrease Strong Erysipelotrichales Order Increase Moderate Firmicutes Erysipelotrichia Veillonella dispar Species Increase Moderate Firmicutes Negativicutes Selenomonadales Veillonellaceae Veillonella Veillonella parvula Species Increase Moderate Firmicutes Negativicutes Selenomonadales Veillonellaceae Veillonella Veillonella Genus Increase Moderate Firmicutes Negativicutes Veillonellales Veillonellaceae Fusobacteria Phylum Increase Strong Citrobacter Genus Increase Moderate Proteobacteria Gammaproteobacteria Enterobacteriales Enterobacteriaceae Enterobacter Genus Increase Moderate Proteobacteria Gammaproteobacteria Enterobacteriales Enterobacteriaceae Enterobacter cancerogenus Species Increase Moderate Proteobacteria Gammaproteobacteria Enterobacteriales Enterobacteriaceae Enterobacter

Downloaded fromBioscientifica.com at09/24/202108:48:44PM Enterobacter hormaechei Species Increase Strong Proteobacteria Gammaproteobacteria Enterobacteriales Enterobacteriaceae Enterobacter Escherichia Genus Increase Strong Proteobacteria Gammaproteobacteria Enterobacteriales Enterobacteriaceae Escherichia coli Species Increase Strong Proteobacteria Gammaproteobacteria Enterobacteriales Enterobacteriaceae Escherichia Species Increase Strong Proteobacteria Gammaproteobacteria Enterobacteriales Enterobacteriaceae Klebsiella Salmonella Genus Increase Moderate Proteobacteria Gammaproteobacteria Enterobacteriales Enterobacteriaceae Species Increase Moderate Proteobacteria Gammaproteobacteria Enterobacteriales Enterobacteriaceae Salmonella 178 Species Increase Moderate Proteobacteria Gammaproteobacteria Enterobacteriales Enterobacteriaceae Shigella Enterobacteriaceae Family Increase Strong Proteobacteria Gammaproteobacteria Enterobacteriales :1 Enterobacteriales Order Increase Strong Proteobacteria Gammaproteobacteria Gammaproteobacteria Class Increase Strong Proteobacteria Proteobacteria Phylum Increase Strong Akkermansia Genus Increase Moderate Verrucomicrobia Verrucomicrobiae Verrucomicrobiales Verrucomicrobiaceae

Verrucomicrobia Phylum Increase Strong 50 via freeaccess European Journal of Endocrinology with lithocholicacid(LCA) wasfoundforF. prausnitzii, As forpatientsreceivingSG, a significantdirectcorrelation Bile acid Veillonella ( total cholesterol and Parasutterella, Treponema and and SGin2016showedanegativecorrelationbetween found ( E. cancerogenus, T. pallidum triglyceride and5bacterialspecies( patients undergoingRYGB ( cholesterol andlow-densitylipoprotein in enterica moreover, lipid parametersinanotherstudyapplyingRYGB ( were significantlypositivelycorrelatedwithseveral T. roseum, C.spiroforme Furthermore, inpatientsundergoingRYGBmetabolism, observed ( Phenylobacterium, were associatedwithcholesterol Alistipes, Bacteroides,Blautia,Dorea,Escherichiaand Overall, 6discriminatinggutmicrobiotagenera, Lipid profile Veillonella ( Dorea, Enterococcus,Fusobacterium,Parabacteroidesand the abundanceofAlistipes,Anaerofilum,Clostridium, undergoing SGandRYGB negatively correlatedwith ( correlation forDialisterandMegamonaswithHOMA-IR on patients receiving RYGB or SG showed a negative also exhibitedinpatientsundergoingBIB( the variationofClostridiumandbloodinsulinwas patients afterRYGB ( T. roseum Graessler (HOMA-IR) andinsulinemia)( homeostasis model assessment of insulin resistance parameters (fastingglycemia,glycatedhemoglobin, with oneormoreofthe4glucosemetabolism-related 14 discriminatinggutmicrobiotagenerawerecorrelated Ling-Chun Kong homeostasis of thephylumFirmicutesafterSG( and SG ( RYGB andSG( 21 Clinical Study ). Guo werenegativelycorrelatedwithplasmatotal 26 25 and ). Inaddition,ananimalstudyapplyingRYGB t al. et et al. ) and positively correlated with the abundance E. cancerogenus, V. V. parvula, dispar 19 19 F. succinogenes,A.johnsonii,T. pallidum, ). ). V. parvula 19 foundthattheseruminsulininpatients indicatedcorrelationsfor ) andGammaproteobacteriaafterRYGB et al. 26 foundthatafterRYGB, 10ofthe and ). Apositiveconnectionbetween withglucosehomeostasisin and 26 18 ). Aconnectionbetween and others Y Guo,Z-PHunag,C-QLiu ). However, astudyby 36 A. johnsonii,caccae, V. parvula ). F. prausnitzii, ) was also ( 20 A. caccae , and ). Study 26 18 S. ); ). ) reuteri Second, theLactobacillusanditsspecies after bariatric surgery ( after bariatric surgery and thetwo-componentsystem werealsoupregulated RYGB ( were enrichedafterVBG( proved by2humanstudies ( system (PTS) was upregulated after RYGB ( pathways ( microbiota throughrelatedKEGGmodulesand the genesandanalyzedmetaboliccapacityofgut KEGG Othologues(KOs)andannotatedthefunction of studies assignedtheextractedgutgenestodifferent Genomes (KEGG)biologicalcategories,atotalof6clinical By applyingtheKyotoEncyclopediaofGenesand Change ofgeneticcontent decrease intheSCFAs/BCFAs ratio( BIB ( RYGB ( levels wereconsistentbetweenanimalswithandwithout chain fattyacids(BCFAs), itwasfoundthattheSCFAs By measuringthelevelsoffecalSCFAs andbranched Change ofshort-chainfattyacids(SCFAs) Further investigationofthefunctionsmicrobiota patients undergoingSG( and CRPinpatientsundergoingRYGB ( C. comes patients undergoingRYGB ( and orosomucoidlevelsinpatientsreceivingRYGB ( factors suchasC-reactiveprotein(CRP),interleukin-6 ( with BMIandglucoselevelinpatientsundergoingRYGB First, thespecies different parametersaccordingtomorethanonestudy. Some specificmicrobiotashowedconnectionswithseveral Highlighted microbiota with theabundanceofBacteroidetes( the abundanceofProteobacteriaandnegativelycorrelated that colonictotalbileacidwaspositivelycorrelatedwith undergoing DJB, significant connections have been found C. comes correlated withtheabundanceofClostridiumsp.L2-50, whereas plasmadeoxycholicacid(DCA)waspositively Microbiota andbariatricsurgery 26 ), LCAinpatientsundergoingSG( 20 werefoundtobepositivelycorrelatedwithBMIin 27 18 ). However, patientsundergoingRYGB showeda wasfoundtobepositivelycorrelatedwithBMI and ); thiswasalsodemonstratedforpatientsafter ). Nitrogenmetabolism,fatty acidmetabolism 18 , 21 Lachnospiraceae bacterium , F. prausnitzii 22 , 26 30 , Downloaded fromBioscientifica.com at09/24/202108:48:44PM 36 30 ). Moreover, three KOs related ). 18 30 , 36 , ) anddownregulatedafter hadapositivecorrelation 22 26 ). Thephosphotransferase , ). Third,thevariationof 30 30 36 178 ). ABCtransporters ). 28 ) and inflammatory ) andinflammatory www.eje-online.org ( :1 ). 26 36 ) andDCAin ). Asforrats Lactobacillus 26 ), further 51 38 via freeaccess ). European Journal of Endocrinology www.eje-online.org for thischangeinmicrobiota diversity, suchasreducing suggested that the change in eating habits might account the modulationofgut microbiota. Kong allowed or the metabolic benefit conferred by surgery ( diversity, as estimated by the Shannon index after surgery reached anagreementonthehighergutmicrobiota procedures, four studies had to the bariatric surgery change ofrichnessanddiversitymicrobiotarelated Although controversialresultswerefoundregardingthe of Bacteriodetesinindividualswithobesity( bacterial diversityandalowerrelativeabundance conditions afterbariatricsurgery. contribute a greatdealtoregulatingobesity-related our understandingofthegutmicrobiome,whichmay summarized. Theresultofthissystematicreviewfurthers and the gut microbiome be unbiasedly bariatric surgery statistical methodologycantheparticularcorrelationof and themicrobiome.Onlywithastandardizedstrict compiles theinteractionbetweenhostmetabolism surgery. Ourstudyisuniqueinthatitsystematically the gut microbiome of patients or rodents after bariatric review toquantitativelycomparethecurrentliteratureon To thebestofourknowledge,thisisfirstsystematic Discussion people withobesity’microbiota( RYGB andVGBmicrobiotathaninmice colonizedwith gain of less fat mass was found in mice colonized with colonized with a sham group microbiota ( mice colonizedwithRYGB microbiotathan thoseinmice adiposity index,alowerleptinlevelandmoreSCFAs in ( and thedonorsweremicepatients,respectively donorstogerm-freemicewasappliedin2studies, surgery Transplantation of the gut microbiota from bariatric Transplantation ofgutmicrobiota afterRYGBsystems wereobserved ( metabolism andanincreaseinseveralnutrienttransport use of sulfur relay and phosphotransferase systems, purine of macronutrients and micronutrients ( implied anincreasedoxygentoleranceandtheutilization microbial KEGGmodulesincreasedafterRYGB, which were significantly higher after SG ( to butanoate metabolism, K00074, K00929 and K00626, 27 19 Clinical Study , , Many previous studies observed an overall lower Many previousstudiesobserved 30 20 ).The resultsshowedsignificantweightloss,alower , 22 , 23 ). This fact revealed that the surgery itself ). Thisfactrevealedthatthe surgery and others Y Guo,Z-PHunag,C-QLiu 30 21 ). ). 36 22 ). A total of 53 ). Theincreased 27 ). Further, a t al. et 39 , ( 40 18 ). ) colitis ( for symptomsrangingfrommilddiarrheatofulminant Clostridium difficile Additionally, theanaerobicgram-positivebacterium by mouth,whichshowedthattheabundanceof the antibioticsampicillin,neomycin,andmetronidazole representation ofthephylumProteobacteriawhengiven insulin sensitivityconcomitantwithasignificantover- resistance inducedbyahigh-fatdiethadimproved evidence ( Enterobacteriaceae alsoincreaseonstrongormoderate K.pneumoniae E. coli, Salmonella) and species ( genera (Citrobacter, Enterobacter, Escherichiaand Escherichia increasesafterbariatricsurgery. Several Enterobacteriales, familyEnterobacteriaceaeandgenus Proteobacteria and its class Gammaproteobacteria, order induced byRYGB maybefoodindependent. control group. Thus, theincreased microbiota diversity ( polysaccharides ( the amount of fat and increasing the consumption of a role by producing lactic acid and extracting energy of Lactobacillusand BMI ( and twostudiesindicatedcorrelations fortheabundance disease ( also foundatlowerabundanceinthosewithCrohn’s identified bygutmicrobiotaanalysis( commensalbacterium thatwas an anti-inflammatory demonstrated by3studies( process and glucose homeostasis, as the inflammatory Faecalibacterium, seemed to be of great importance in between them and host metabolism ( of suchbacteriafurthersthehighinterestoncrosstalk order Clostridiales,asignificantchangeofthepopulation be aunderlyingfeatureoffewbacterialtaxawithinthe ( in thefecalsamplesfromgutofpeoplewithobesity because several reports found the decline of Clostridium strong ormoderateevidence( on and Ruminococcaceae) that decreased after surgery Dorea andRuminococcus)2families(Clostridiaceae Clostridium, Faecalibacterium, Blautia, Coprococcus, the phylumFirmicutes),thereare7genera(Anaerostipes, linked ( phylum Proteobacteriaandinsulinsensitivitymaybe Microbiota andbariatricsurgery 19 20 ), the pair-fed group served astheRYGB), thepair-fedgroupserved diet-matched , Lactobacillus contributedmore tobodycomposition, F. prausnitzii Within theorderClostridiales(anabundant orderof Based onstrongevidence,thepopulationof 31 , 47 42 37 49 ). ). ). Becausetheproductionofbutyrateappearsto ). al 6 Table , thesoleknown species ofthegenus 41 causes intestinal responsible ). Micewithobesityandinsulin ). However, inourpreviousstudy and Downloaded fromBioscientifica.com at09/24/202108:48:44PM S. enterica E. cancerogenus, E. hormaechei, E. cancerogenus, E. hormaechei, 18 Table 6 , 26 26 , ). Lactobacillus can play 36 ). Thisistobeexpected ) belongtothefamily , 178 38 ). :1 43 F. prausnitzii 48 , 44 ), whichis , 45 , 52 46 is via freeaccess ). European Journal of Endocrinology bioinformatic methodsare neededtoinvestigatethe advanced sequencingtechnology andmetagenomic findings. More study designtogenerate complementary for thefieldtoharmonize techniquesandimprovethe asan incentive of research Thisreviewcouldserve forward. to elucidateusefulinformationthatcouldmovethisline existing literature, there is still a justified need in the field the evidencelevelsystemtoanalyzeandsummarize findings wereinevitable. Although inthisreview, weused on microbiotafollowingbariatricsurgery, inconsistent different methodologiesandtechniqueappliedinstudies of SCFAs afterbariatricsurgery. converge toacommonconclusionregardingthechange ( Thus, moreenergycanbeextractedfromacertaindiet expenditure throughthesympatheticneuronalnetwork. incorporation inadipocytesandmodulatesenergy may producemoreSCFAs, whichimpedeglucose obese microbiota and lean microbiota. Obese microbiota relationship betweenbileacidandgutmicrobiota( co-metabolism. Morestudiesareneededtodiscoverthe its metabolic complications in part through bile acid likely the gut microbiota mediates the phenotype and microbiome inabidirectionalway( from studiesinterferingwithBAhomeostasisandthegut microbiome arealsoseenfollowingSG,thisissupported composition of the gut microbiota. Changes to the gut flow after RYGB mayhaveconsiderable effectsonthe enterohepatic circulation ( and degradedbyintestinalbacteriaduringthe patients withCrohn’s disease( and healthysubjects,whichsuggestsitsimportantrolein Crohn’s patientsthanthatinulcerativecolitis to Previous studiesshowedthatagglutinatingantibodies unclear, whichsuggestsmoreinvestigations( the mechanismthataffectshostmetabolismremains the inflammationprocedureandbileacidhomeostasis, nutrients ( the colonicbacteriatoderiveenergyfrommalabsorbed sugars andaminoacidsinthelargeintestinemayactivate amino absorptioninthehosttract,increasesimple obesity ( regulate thecorpulencemetabolisminpeoplewith from thefermentationofdifferentsugars,whichhelps 61 Clinical Study , C. comes Due tothelimitednumberofincludedstudiesand Previous studieshaveshownthedifferencebetween Approximately 5–10%ofbileacidsarebiotransformed Although 62 ). However, theresultsofourstudyfailedto 50 51 ). Because bariatric surgery delaysglucoseand ). Becausebariatricsurgery aremorefrequentlyfoundintheseraof , C. comes 52 , 53 ). hasbeenfoundtobecorrelatedwith 58 54 ). Thealterationinbile and others Y Guo,Z-PHunag,C-QLiu , 56 , 59 57 ). Therefore,itis ). 54 , 55 60 , 56 ). ). our results. remainsunclearaccordingto typesofsurgery on varying gut microbiomemaybeaffected.Fourth,thedifference maychangealotwithtimegoing,sothe bariatric surgery inconsistent amongstudies,however, thedietafter Third, the time point to extract the fecal sample are diet andcomorbiditiesmayinfluencethegutmicrobiome. numbers mayinfluencetheresults.Second,different Our study has some limitations. First, the low cohort Limitation studies arecurrentlyextremelyscarce inthisfield. further research. However, randomizedanddouble-blind limited controlgroupintheanimalstudyareneededfor for controlinthehumanstudyandapair-fedweight- type ofdesign,anon-surgicalweightlosstreatmentgroup inhabitingthehumangut.Asfor EJE-17-0403. This is linked to the online version of the paper at Supplementary data on modulatinghostmetabolismafterbariatricsurgery. warranted toinvestigatethemechanismofgutmicrobiota regulation. Morelong-termprospectivestudiesare the potentialofmicrobiotainmodulatinghostmetabolic microbiome transplantationandSCFAs productionimply bariatric surgery. Theresults ofgutgeneticcontent, more relatedtothemetabolicalterationofpatientsafter Dorea. Lactobacillus, Firmicutes, Clostridiales,Clostridiaceae,Blautiaand increased. Thedecreasedmicrobialgroupswere Alistipes, Enterobacteriales, Enterobacteriaceae,Escherichia, within thephylumProteobacteria,Gammaproteobacteria, Enterococcus, withinthephylumFirmicutes,Lactobacillales, surgery; Verrucomicrobia andProteobacteria)increasedafter strong evidence,4phyla(Bacteroidetes,Fusobacteria, is greatlyalteredafterbariatricsurgery. Basedon In thisreview, wefoundthatmicrobialcomposition crosstalk ofhostmetabolicchangeandbariatricsurgery. and obesity, andgutmicrobiotawereimplicatedinthe is included in the treatment of T2D Bariatric surgery Conclusion Microbiota andbariatricsurgery .cl,E hormaechei E. coli,E. . faecalis E. . prausnitzii F. Downloaded fromBioscientifica.com at09/24/202108:48:44PM and S. gordonii and and 178 https://doi.org/10.1530/ www.eje-online.org :1 K.pneumoniae increased;and C. comes are 53 via freeaccess

European Journal of Endocrinology www.eje-online.org References Huang wrotethepaper;Yuan Sheng,Da-JinZouandLinQirevisedthepaper. Zhi-Ping HuangandChao-QianLiuanalyzedthedata;Yan Guo,Zhi-Ping Zhi-Ping HuangandChao-QianLiuperformedtheresearch;Yan Guo, Yuan ShengandDa-JinZoudesignedtheresearchstudy;Yan Guo, Author contributionstatement China awardNo.81300684and81700745. This studywassupportedbytheNationalNaturalScienceFoundationof Funding perceived asprejudicingtheimpartialityofcasestudyreported. The authorsdeclarethatthereisnoconflictofinterestcouldbe Declaration ofinterest

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Accepted 15September2017 Revised versionreceived14August2017 Received 17May2017

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