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Pathophysiologyofshortbowelsyndrome
OfficialreprintfromUpToDate
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Pathophysiologyofshortbowelsyndrome
Author
JohnKDiBaise,MD

SectionEditors
JThomasLamont,MD
KathleenJMotil,MD,PhD

DeputyEditor
AlisonGHoppin,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Jun2016.|Thistopiclastupdated:Jun14,2016.
INTRODUCTIONShortbowelsyndrome(SBS)isamalabsorptiveconditionmostoftencausedbymassive
resectionofthesmallintestine[1].Clinicaldiseaseisonlyweaklycorrelatedwiththeamountofintestinethatis
resectedbecauseofthehighlyvariablelengthofthehumansmallbowelandtheremarkableabilityofthebowelto
compensateforbowelresection.Therefore,thebestdefinitionofSBSisbaseduponintestinaldysfunction,ie,the
presenceofsignificantmalabsorptionofbothmacronutrientsandmicronutrients.SBSisthemostcommoncauseof
intestinalfailure,atermthatdescribesthestatewhenanindividual'sgastrointestinalfunctionisinadequatetomaintain
hisorhernutrientandhydrationstatuswithoutintravenousorenteralsupplementation.Othercausesofintestinal
failureincludediseasesorcongenitaldefectsthatcauseseveremalabsorption,bowelobstruction,anddysmotility(eg,
pseudoobstruction).
SBSinadultsusuallyresultsfromsurgicalresectionofthesmallintestineforCrohndisease,trauma,malignancy,
radiation,ormesentericischemia.Inaddition,SBScausedbypostoperativevascularandobstructivecatastrophes
requiringmassiveintestinalresectionseemstobeincreasinginincidence.AdvancesinthetreatmentofCrohndisease
mayleadtoareductioninSBShowever,theseimprovementsdonotyetappeartohaveledtoareductioninthe
numberofpatientsrequiringhomeparenteralnutrition(PN)[2].Ininfantsandsmallchildren,necrotizingenterocolitis
andcongenitalintestinalanomalies,suchasmidgutvolvulus,atresias,orgastroschisis,arethemostcommoncauses
ofSBS.
ChallengestoestimatingtheprevalenceofSBSincludeitsmultifactorialetiology,varyingdefinitions,anddifficultyin
estimatingintestinallength.Therefore,estimatesoftheincidenceandprevalenceofSBSarebasedondatafrom
registriesofpatientsonhomePN,forwhichSBSisthemostcommonindication.Onesuchstudyreportedthatthe
annualprevalenceofhomePNintheUnitedStatesisapproximately120permillionpopulation,ofwhomabout25
percenthaveSBSthisamountedtoabout10,000individualsin1992[3].
ThepathogenesisofSBSwillbereviewedhere.ThecomplicationsofSBSandthemanagementofthisdisorderare
discussedseparately:

(See"Managementoftheshortbowelsyndromeinchildren".)
(See"Chroniccomplicationsofshortbowelsyndromeinchildren".)
(See"Managementoftheshortbowelsyndromeinadults".)
(See"Chroniccomplicationsoftheshortbowelsyndromeinadults".)

INITIALDETERMINANTSOFINTESTINALFUNCTIONThemaindeterminantsofintestinaldysfunctioninthe
initialphasesafterbowelresectionare:

Lengthoftheintestinalresection(relativetoageorbodysize)
Lossoftheileumandileocecalvalve
Lossofallorpartofthecolon
Continuityversusincontinuityoftheintestines

Intestinalfunctionisoftenfurtherdisruptedbygastrichypersecretion,whichinterfereswithfunctionofpancreatic
enzymes,byalteredgastrointestinalmotility,andbyanymucosaldiseaseintheremainingintestine.Eachofthese
factorswillbediscussedindetailinthefollowingsections.
SmallintestinelengthThelengthofthesmallintestineremainingaftersurgicalresectionisonedeterminantof
intestinalfunctionandprognosisforeventualfreedomfromparenteralnutrition(PN)orparenteralfluid(PF)support.
However,itmaybedifficulttoestablishanaccurateestimateofbowellength.Thebestinformationcomesfromthe
operativereport,anditisimportantforsurgeonstorecordthelengthandsegmentofbowelremaining,notjustthe
lengthremoved.Theappearanceoftheremainingbowel(pink,necrotic,ormatted)shouldalsobenotedgivenits
implicationsfortheshorttermprognosis.Alternatively,bariumcontrastradiographyorcomputedtomography(CT)can
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beusedtoestimatesmallbowellengthsuchstudiesmayalsodelineateotherstructuralfeaturesthatmayberelevant
tointestinalfunctionandprognosis,suchasthepresenceofastrictureorboweldilatation.
Estimatedbowellengthismoderatelycorrelatedwithoutcomes:
Ininfants,thenormallengthofthesmallintestineisapproximately125cmatthestartofthethirdtrimesterof
gestationand250cmatterm(range,200cmto300cm)[4].Infantswithresidualsmallintestinelengthofless
than75cmareatriskfordevelopingSBS[5].InoneseriesofinfantswithSBSduetosurgicalresectionduring
theneonatalperiod,thelikelihoodofachievingindependencefromPNwasmorethan60percentforinfantswith
residualsmallintestinelength>38cm,ascomparedwith7percentinthosewithresidualsmallintestinelength
<15cm[6].Inaseparateseriesfromacenterwithexpertiseinintestinalrehabilitation,theprobabilityofweaning
fromPNforinfantswithatleast50cmofsmallintestinewas88percentafter12monthsand96percentafter24
months[7].Forinfantswithlessthan50cmofsmallintestine,theprobabilityofweaningwas23percentafter12
months,38percentafter24months,and71percentafter57months.
Inadults,thenormallengthofthesmallintestineisapproximately480cm,butrangeswidelyfrom300cmto800
cm.Adultswithresidualsmallintestineoflessthan180cmareatriskfordevelopingSBS[5].Thepresenceof
thecolonhelpstomitigatefunctionalimpairmentinSBS,suchthatpresenceofatleastonehalfofthecolonis
approximatelyequivalenttohavinganadditional50cmofsmallbowel.Similarly,lossoftheileumandileocecal
valvecausesmoreintestinaldysfunctionthanlossofasimilaramountofjejunum[8,9].(See'Siteofintestinal
resection'belowand'Lossofthecolon'below.)
SiteofintestinalresectionThejejunumoccupiestheproximaltwofifthsofthesmallintestine,andtheileum
consistsofthedistalthreefifths.ThesymptomsassociatedwithbowelresectionandeventualindependencefromPN
orPFarehighlydependentuponthephysiologyoftheremainingsmallbowelbecauseeachbowelsegmenthasunique
characteristicsforabsorption(figure1).Inaddition,theileumisbetterabletoadaptafterintestinalresectioncompared
withthejejunum[1012](see'Ilealversusjejunaladaptation'below).Theduodenumandproximaljejunumare
uncommonsitesofresectioninSBS,atleastinadults,duetothedifferentcausesoftheSBSandthebloodsupplyto
thissectionofthegut.Nevertheless,whenthesesectionsoftheintestineareinvolved,theirresectiontypicallyresults
inmorepronouncedhypergastrinemiaandgastrichypersecretion,anddeficienciesincertainmicronutrientsincluding
ironandfolate(figure1).(See'InfluenceofSBSongastricandpancreaticfunction'below.)
Threecategoriesofbowelanatomyafterresectionaretypicallydescribedintermsofthelocationoftheanastomosis,
andthishasimplicationsforprognosis:
JejunocolicanastomosisThisistheresultafterresectionoftheentireileum,ileocecalvalve,partofthecolon,
andvariableamountsofthejejunum.ThisisthemostcommonanatomyinSBSwithaprognosisthatdepends
uponthelengthofremainingjejunum.
JejunoileocolonicanastomosisThisistheresultafterresectionofaportionoftheileumwithretentionofthe
ileocecalvalveandtheentirecolonthisanatomygenerallyhasthebestprognosis.
EndjejunostomyThisistheresultafterresectionoftheentireileumandcolonorcolonpresentbut
disconnectedthisanatomygenerallyhastheworstprognosis.
Thereasonsforthesedifferencesinprognosisaredetailedinthefollowingsections.
JejunalresectionThejejunum,withitslongvilli,largeabsorptivesurface,highlyconcentrateddigestive
enzymes,andmanytransportcarrierproteins,istheprimarydigestiveandabsorptivesiteformostmacroand
micronutrients.Indeed,mostmacronutrientabsorptionoccurswithintheproximal150cmofsmallintestine.Thus,
whenthejejunumisresected,atemporaryreductioninabsorptionofmostnutrientsoccurs.Thejejunumexhibits
modestadaptivechangesinresponsetointestinalresection,andmostofthesechangesarefunctional(changesin
transportandenzymeactivity)ratherthanstructural(changesinabsorptivearea)[13].(See'Intestinaladaptation'
below.)
Fluidabsorptionisanotherimportantroleofthesmallintestine.ThegastrointestinaltractinhealthyadultswithoutSBS
secretesabout4Loffluid(0.5Lsaliva,2Lgastricacid,and1.5Lpancreaticobiliarysecretions)inresponsetothe2
to3Loffoodanddrinkconsumedeachday.Waterabsorptionisapassiveprocessresultingfromthetransportof
nutrientsandelectrolytessodiumtransportcreatesanelectrochemicalgradientthatdrivestheuptakeofnutrients
acrosstheintestinalepithelium.Inthejejunum,thejunctionsbetweentheepithelialcellsarerelativelylargecompared
withotherareasofthebowel,resultinginarapidfluxoffluidsandnutrientsandinefficientfluidabsorption.Becauseof
these"leaky"intercellularjunctions,thejejunalmucosaisunabletoconcentratetheluminalcontentsandsodium
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diffusesfreelyintothelumen.Notably,sodiumabsorptioninthejejunumoccursagainstaconcentrationgradient,is
dependentuponwaterfluxes,andiscoupledtotheabsorptionofglucose[14].Thecompositionoforalrehydration
solutions,andparticularlythesodiumandglucoseconcentrations,isdesignedtotakeadvantageofcotransportof
glucoseandsodiumtooptimizejejunalabsorption.(See"Oralrehydrationtherapy".)
IlealresectionHavingresidualileumisadvantageousbecauseofitsspecializedfunctions:
VitaminB12absorptionThedistal50to60cmofileumistheprimarysiteforabsorptionofvitaminB12,bound
tointrinsicfactor(figure1).Resectionoftheterminalileum,whichiscommoninSBS,isassociatedwith
malabsorptionofvitaminB12andcanleadtoclinicaldeficiencyunlesssupplemented.Thelengthofileal
resectionthatcausessuchconsequencesininfantsisnotwelldefined.Lifelongmonitoringandsupplementation
ofvitaminB12isimportantinallSBSpatients,particularlyinthosewholackaterminalileum.(See
"Managementoftheshortbowelsyndromeinchildren"and"Managementoftheshortbowelsyndromeinadults",
sectionon'Taperingofparenteralnutrition'and"EtiologyandclinicalmanifestationsofvitaminB12andfolate
deficiency".)
BileacidabsorptionThedistalileumalsoistheselectivesiteforabsorptionbileacids.Inadults,resectionof
>100cmofterminalileumleadstodisruptionoftheenterohepaticcirculation,eventuallyresultinginbileacid
deficiencybecausebileacidlossesexceedthecompensatoryincreaseinhepaticbileacidproduction[15].The
diminishedbileacidpoolexacerbatesmalabsorptionoffatandfatsolublevitamins.Inaddition,theincreased
passageofbileacidsintothecolonmayinduceacolonicsecretomotordiarrhea(cholereticenteropathy).(See
"Chroniccomplicationsofshortbowelsyndromeinchildren",sectionon'Waterydiarrhea'.)
Malabsorptionofbileacidsalsoleadstoincreasedabsorptionofoxalate,resultinginhyperoxaluriaandincreasing
theriskofoxalatenephrolithiasisandchronickidneydisease.(See"Chroniccomplicationsoftheshortbowel
syndromeinadults"and"Chroniccomplicationsofshortbowelsyndromeinchildren",sectionon'Hyperoxaluria
andkidneystones'.)
"Ilealbrake"Unabsorbedlipidsreachingtheileumcauseadelayingastricemptying(the"ilealbrake"),whichis
beneficialinthesettingofSBSbecauseitfacilitatesabsorptionofnutrientswithinthesmallintestine.Thiseffect
ismediatedbyseveralhormonessecretedbytheileumincludingglucagonlikepeptide1andpeptideYY[16,17].
PatientswithSBSlackingileumlosethebeneficialeffectsoftheilealbrake,resultinginrapidtransitand
decreasedabsorptionofnutrientsinsmallintestine.(See'Guthormones'below.)
FluidabsorptionComparedwiththejejunum,theileumhastighterintercellularjunctions,resultinginlesswater
andsodiumflux[14].Theileumalsohasactivetransportofsodiumchloride,sothatitisabletoreabsorb
substantialamountsoffluidandconcentratetheilealcontents.Asaresult,theileumnormallyreabsorbsalarge
portionofthefluidsecretedbythejejunumduringthedigestiveprocess,whichisparticularlyimportantwiththe
largeamountsoffluidsthatenterthelumeninresponsetohypertonicfeedings[14,18].Thus,patientswholosea
substantialportionoftheileumhavealimitedabilitytoabsorbfluidsandelectrolytes.Suchpatientsoftencannot
toleratelargebolusfeedingsorthosewithhighosmolarity,suchashighconcentrationsofsimplecarbohydrates.
IntestinaladaptationTheileumhasagreatercapacityforintestinaladaptationcomparedwiththejejunum[19].
(See'Ilealversusjejunaladaptation'below.)
LossoftheileocecalvalveTheileocecalvalveactsasabarriertorefluxofcolonicmaterialfromthecoloninto
thesmallintestineandhelpstoregulatethepassageoffluidandnutrientsfromtheileumintothecolon(figure1).
InchildrenwithSBS,lossoftheileocecalvalvetendstobeanegativepredictoroftheabilitytoweanapatientfrom
PN.Asexamples,absenceoftheileocecalvalvetypicallyisassociatedwithalongerdurationofPNwhenresection
occursinchildhood[20],andinfantswithlessthan30cmofsmallbowelandlackingtheileocecalvalvearelesslikely
tobeweanedfromPN[21].Theseeffectsarethoughttobeduetoreductionofsmallintestinaltransittime,which
impairsnutrientabsorption.Inaddition,lossoftheileocecalvalvepromotessmallintestinebacterialovergrowth
(SIBO),whichmayresultinreductioninvitaminB12anddeconjugationofbileacids,furthercontributingtofat
malabsorptionanddiarrhea[22].MoreseverecomplicationsofSIBO,includingbacterialtranslocation,liverinjury,D
lacticacidosis,arthritis,andcolitis,canalsooccur[22,23].(See'ThemicrobiomeofSBSandpathophysiologyof
bacterialovergrowth'below.)
However,atleastinadults,ithasbeensuggestedthattheileocecalvalvedoesnotindependentlyaffectsmallbowel
transit,theriskofSIBO,orthelikelihoodofweaningfromPN[24].Instead,theincreasedriskforSIBOwasthoughtto
berelatedtoreducedileallengthandperistalsis,andthesefactorsweretheprimarypredictorsofthelikelihoodof
weaningfromPN,ratherthanthepresenceoftheileocecalvalveitself.Therefore,theileocecalvalvemaybeless
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relevanttooutcomesofSBSinadults.
LossofthecolonThecolonhasanimportantroleinabsorptionofwater,electrolytes,andshortchainfatty
acids(figure1).Comparedwiththejejunumandileum,thecolonhastheslowesttransit,tightestintercellularjunctions,
andgreatestefficiencyofwaterandsodiumabsorption.Inhealthyadults,about1to1.5Loffluidentersthecolon
eachday,andallbut150mLisreabsorbed.Inpatientswithextensivesmallbowelresection,substantiallymorefluid
exitsfromthedistalsmallintestine.Ifthecolonispresent,itcanabsorbupto6Lofthisexcessfluideachday,which
mitigatesthefluidloss[25].Conversely,patientswithextensivesmallbowelresectionandwithoutacolon(ie,those
withanendjejunostomy)areathighriskfordehydrationandelectrolytedepletion.Suchpatientsusuallyrequirelong
termPN.
Inadditiontoabsorbingfluid,thecoloniscapableofabsorbingsomenutrients,primarilyintheformoffermented
malabsorbedcarbohydrates.Inhealthyadults,thecolonabsorbsupto15percentofdailyenergyrequirements.In
patientswithSBSonahighcarbohydratediet,thecoloncanabsorbasmuchas50percentofenergyrequirements
[2628].Thus,inanadultpatientwithSBSandacolon,adietthatishighincomplexcarbohydratesisadvantageous.
However,suchadietmaybedisadvantageousforpatientswithoutacolonandforinfantsandyoungchildrenbecause
concentratedcarbohydrateshavehighosmolarity,whichcanleadtodiarrhea.(See"Managementoftheshortbowel
syndromeinchildren",sectionon'Enteralfeeding'.)
Thecolonalsohelpstoslowintestinaltransitandstimulateintestinaladaptation.Theretainedcolonundergoes
adaptationaftersmallbowelresection,withgradualincreasesinenterocytesandothercellsandinguthormones
includingglucagonlikepeptide1(GLP1)andpeptideYY[29].(See'Guthormones'below.)
Foralloftheabovereasons,patientswhoretaintheircolonaremorelikelytotolerateamajorsmallintestinal
resection.Indeed,intestinalfunctioninadultpatientswithlittleornocolonissimilartothatinpatientswithatleast
onehalfthecolonbutwhosesmallintestineis50cmlonger[30].Adultswithlittleornocolonandlessthan50to100
cmofjejunumarelikelytorequirepermanentPN[11,31].Studiesininfantsandchildrenhavereachedinconsistent
conclusionsaboutwhetherornotthepresenceofthecolonisanimportantpredictorofweaningfromPN[24,32,33].
Thus,thepresenceofacolonmaybealessimportantpredictorofsurvivaloffofPNininfantscomparedwithadults.
InfluenceofSBSongastricandpancreaticfunctionLargeresectionsofthesmallintestinetendtotriggergastric
hypergastrinemiaandhypersecretion(unlessthestomachhasalsobeenresected,whichisunusual),probably
becausethenegativefeedbackmechanismforinhibitinggastrinsecretionandreducinggastricacidproductionhas
beenremoved[34].AlthoughresectionsinvolvingtheduodenumandproximaljejunumareuncommoninSBS,
particularlyinadults,thosewhohaveundergoneresectionsofthesebowelsegmentsseemtobeatevenhigherriskof
severehypergastrinemiawithvoluminousgastricsecretions.Thisincreasesthevolumeofsecretionsenteringthe
smallbowelandlowersthepHofthesecretionsintheproximalgut,potentiallyaggravatingfluidlossesandleadingto
pepticcomplicationsandimpairmentinthefunctionofdigestiveenzymes.Thegastrichypersecretionmayleadtovery
highstoolorostomyoutputandmaylastforupto12monthspostoperativelymanagementincludesvigorousfluid
replacementandacidblockade.(See"Managementoftheshortbowelsyndromeinchildren",sectionon'Early
management'and"Managementoftheshortbowelsyndromeinadults",sectionon'Earlymanagement'.)
MostSBSpatientswhoarenotatcompletebowelrestdemonstratenormalpancreaticenzymeandbilirubinsecretion.
Anexceptionistherarepatientwithextensiveproximalsmallbowelresection,whichmayresultinlossofsitesof
secretinandcholecystokininpancreozymin(CCKPZ)synthesisanddecreasedpancreaticandbiliarysecretions[35].
INTESTINALADAPTATIONIntestinaladaptationistheprocessfollowingintestinalresectionwherebythe
remainingbowelundergoesmacroscopicandmicroscopicchangesthatservetoincreaseitsabsorptiveability.
Adaptationishighlyvariableandusuallyoccursduringthefirsttwoyearsfollowingintestinalresectioninadultsandfor
longerandperhapsmorevigorouslyinchildren.Adaptivechangesareusuallymostprominentintheileumandtoa
lesserextent,inthejejunumandcolon.Thesechangesaremediatedbyavarietyofinternalandexternalstimuli
includingnutrients,gastrointestinalsecretions,hormones,andgrowthfactorsandothergeneticandbiochemical
factors.Inparticular,adaptationdependsuponthenutrientcomponentsofthedietandoninfluencesfromthe
remainingsegmentsoftheintestine.
Bothstructuralandfunctionalchangescanoccur:
Structuraladaptivechangesincludedilationandelongationoftheremnantbowel,anincreaseinintestinalwet
weight,proteinandDNAcontent,villuslengthening,expansioninmicrovilli,andanincreaseincryptcelldepth
andenterocytenumber.Thesemorphologicchangesinthemucosaaredrivenbyaproliferativestimulusthat
affectscellularprogressionalongthecryptvillusaxis,resultinginanincreaseinmucosalweightandenlargement
inmucosalfolds.Adaptationofthegutmusclelayersalsotakesplace,leadingtoanincreaseinmuscle
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thickness,circumference,andlength.
Functionaladaptivechangesoccurringincludemodificationsofthebrushbordermembraneenzymeactivity,
fluidityandpermeability,upordownregulationofcarriermediatedtransport(eg,upregulationofNa+/glucose
cotransporters,Na+/H+exchangers,andotherenzymesinvolvedindigestionandabsorption)andaslowingin
therateoftransit,allowingmoretimeforabsorptiontooccur[12,36].Adaptivechangesingutmicrobiota[37],
motoractivity[38],andbarrierandimmunefunctionsaftermassiveintestinalresectionarepoorlyunderstood.
AnimalmodelsofSBSprovideinsightintotheadaptiveprocess.Afterbowelresection,epithelialhyperplasiaisseen
within24to48hours[3944].Thelengthofvilliandintestinalabsorptiveareaincreasesanddigestiveandabsorptive
functiongraduallyimprove.Thesemorphologicchangesareassociatedwithchangesinexpressionofavarietyof
genes[4547],someofwhichareknownmediatorsofintestinalgrowth.Someoftheseeffectsmaybemediatedby
microRNAs,whichareshortnoncodingRNAsthatareabletosilencenumerousgenes[48].Otherobservedchanges,
suchasupregulationofgenesassociatedwithintestinalangiogenesisandnewbloodvesselgrowth,appeartobea
resultratherthanacauseoftheadaptiveprocess[49].Theseadaptivechangesaremoreapparentintheanimal
modelscomparedwithhumanswithSBS[42,43,49].Furthermore,moststudiesinvestigatingtheprocessofadaptation
haveutilizedanimalmodelswithajejunoileocolonicanastomosis,arelativelyuncommonbowelanatomyinhumans
withSBS.Thus,thephysiologicandstructuralchangesthatoccurintheanimalmodelsareofunclearclinical
relevance.
IlealversusjejunaladaptationTheileumiscapableofundergoingmarkedadaptationaftersmallbowelresection,
withsignificantgrowthinvillussurfacearea,aswellasincreasesinintestinallength,diameter,andmotorfunction
[50,51].Thesestructuralchangesareprimarilyresponsibleforenhancementofnutrientuptakeinagivensegmentof
bowel[52].However,thereisalsosomeevidenceforfunctionalimprovementofabsorptionthroughupregulationof
transportersandofbrushborderenzymes[10].Theseadaptivechangesleadtoagradualimprovementin
macronutrientabsorptionduringthefirstonetothreeyearsafterjejunalresection[6,53].
Thejejunumexhibitsmoremodestadaptivechangesinresponsetointestinalresection,andmostofthesechanges
arefunctional(changesintransportandenzymeactivity)ratherthanstructural(changesinabsorptivearea)[10].
Jejunaladaptationappearstodependoninfluencesfromotherremainingsegmentsofthebowelpatientswithajejuno
colicanastomosisdemonstratefunctionalsmallboweladaptation,whereasthosewithanendjejunostomyshowlittle
tonoadaptation.Despitelimitedevidence,similareffectswouldbeexpectedinthosewithcolonincontinuityversus
thosewhosecolonremainsbutisnotincontinuity,giventhelackofnutrientexposuretotheexcludedcolon.This
reinforcestheimportanceofthecolonintheprognosisofthepatientwithSBS.(See'Siteofintestinalresection'
above.)
NutrienteffectsThebestestablishedstimulantofintestinaladaptationisthepresenceofnutrientsintheintestinal
lumen[54].Thiseffectismediatedprimarilybygrowthfactorsproducedbytheintestine.Studiesofparenterallyfed
animalmodelsofSBShavedemonstratedthatadaptationrequiresenteralfeedingandwillnotoccurwithexclusively
parenteralfeeding[55].Nutrientsrequiringdigestiveprocessingpriortoabsorptionserveasimportantstimulifor
intestinaladaptation.Assuch,disaccharidesandlongchainfatsstimulateadaptationmorethanmonosaccharidesand
mediumchainfat,respectively[56,57].
Theeffectsofspecificnutrientsonintestinaladaptationhavebeenstudiedinanimalsand,toalesserextent,in
humans.Theseincludetheaminoacids,arginineandglutamine,andmediumandlongchaintriglycerides.
ArginineorcitrullineAnimalstudieshavedemonstratedthatparenteralargininesupplementationreduces
intestinalpermeability[58].Similareffectsareseenwithenteralorparenteralsupplementationofcitrulline,which
ismetabolizedtoarginine[59,60].Studiesinanimalmodelssuggestthatsupplementingcitrullineintotal
parenteralnutrition(PN)canenhanceintestinaladaptation.
Consistentwithapossibleroleasagrowthfactor,plasmacitrullinelevelscorrelatewithenterocytemassin
childrenwithSBS[61],andlowlevelsofplasmacitrullinecorrelatewithcatheterrelatedbloodstreaminfectionsin
childrenwithintestinalfailure[62].Measurementofserumcitrullineconcentrations(anonproteinaminoacid
producedbyintestinalmucosa)hasbeenproposedtopredictpermanentversustransientintestinalfailure[63].
ThelevelofserumcitrullineassociatedwithpermanentdependenceonPNvariesamongseveralstudies,but
typicallyislessthan15micromol/L[64].
GlutamineParenteralsupplementationofglutaminereversedintestinalhypoplasiainananimalmodel[65,66].
Enteralglutaminesupplementationinanimalsyieldslittleornoimprovementinintestinaladaptation[67].Studies
inhumanshaveshownthatenteralglutaminesupplementationprovidesmodestbenefitinbodyweightandfluid
andelectrolytebalance[68].However,mostpatientsinthesestudieswerealsosupplementedwithgrowth
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hormone.(See"Managementoftheshortbowelsyndromeinchildren".)
TriglyceridesInanimalmodels,enteralsupplementationwithlongchaintriglyceridesappearstobemore
beneficialthanmediumchaintriglyceridesinpromotingintestinaladaptation,althoughmediumchaintriglycerides
maybemoreeasilyabsorbed[69,70].Humandataarelimited.Oneseriesdemonstratedthatfeedingswith
relativelyhighconcentrationsoflongchaintriglycerides(asinbreastmilkorsomeaminoacidformulas)are
associatedwithimprovedintestinaladaptationinneonateswithSBS,comparedwithfeedingswithlower
concentrationsoflongchaintriglycerides[71].(See"Managementoftheshortbowelsyndromeinchildren",
sectionon'Composition'.)
Omega3fattyacidsDietaryfishoil,whichisrichinomega3fattyacids,appearstobebeneficialininducing
adaptationinthesmallintestineandcolon.ThiswasshowninananimalmodelofSBSinwhichfishoilreduced
diarrheaandfecalfatexcretionascomparedwithcornoil[72].Inaseparatestudy,parenteraladministrationof
omega3fattyacidsalsoinducedintestinaladaptationinrats[73].Inthismodel,parenteraladministrationwas
moreeffectivethanenteraladministrationofthenutrient.
Mostofthestudiesofomega3fattyacidsupplementationinhumansareobservationalandlimitedtothe
pediatricpopulation.However,increasingevidencesuggeststhatparenteraladministrationoflipidsderivedfrom
fishoil(richinomega3fattyacids)mayreduceserumbilirubinlevelsandreverseintestinalfailureassociated
liverdisease,comparedwithconventionalsoybasedlipids.(See"Intestinalfailureassociatedliverdiseasein
infants",sectionon'Fishoilbasedlipidemulsions'.)
GuthormonesNutrientsprobablypromoteintestinaladaptationbyinducingreleaseofoneormoretrophic
gastrointestinalhormones,astimulusthatismediatedprimarilybyfat.Severalenterocytederivedmediatorsofthe
adaptationprocesshavebeendescribed.
Glucagonlikepeptide2(GLP2)isanintestinalgrowthfactorproducedbytheenteroendocrineLcellsoftheileumand
colon[74].Inanimalmodelsundergoingmidsmallbowelresection,plasmaconcentrationsofGLP2increaserapidly,
andthisinducesadaptationintheremainingintestine[75].FurthersupportingtheroleofGLP2asanintestinotrophic
agent,thisresponsedoesnotoccuriftheGLP2producingcellsintheileumandproximalcolonareresected.
ExogenousadministrationofGLP2inducesmarkedvillushyperplasiaoftheileumandjejunumwithinfourdaysof
administrationtomicewithSBS[76],accompaniedbyanincreaseinglucoseabsorptionandadecreaseinintestinal
permeability[77].Evidencesuggeststhatteduglutide,alongeractingGLP2analogue,promotesintestinaladaptation
andabsorptionandhasmodestbenefitswithrespecttoweaningofPNinadultswithSBS[78,79].(See"Management
oftheshortbowelsyndromeinchildren".)
Growthhormonehasalsobeenexploredasapossiblepromoterofintestinaladaptation.StudiesinhumanswithSBS
haveevaluatedtheuseofgrowthhormone,withorwithoutglutamineorothergrowthfactors,butresultshavebeen
conflictingandinconclusive.(See"Managementoftheshortbowelsyndromeinadults"and"Managementoftheshort
bowelsyndromeinchildren".)
Othertrophicgastrointestinalhormones,suchasenteroglucagon(orfragmentsorprecursorsofthismolecule),
epidermalgrowthfactor,hepatocytegrowthfactor,trefoilpeptides,andinsulinlikegrowthfactor1(IGF1),are
producedbytheilealmucosa[80,81].Asaresult,ilealresectionmaydecreasethepotentialforadaptationinducedby
thesehormones.InanimalmodelsofSBS,epidermalgrowthfactorinduceschangesintheintestinalsmoothmuscle
andalsoenhancesmucosalintegrity[82].Similarly,IGF1deliveredviacolostrumsupplementationpositivelyaffects
themuscularismucosaintheintestinaltract[83].Thus,thesesubstancesappeartoplayaprimaryroleintissue
proliferation,butclinicaltrialsofthesehormonesinhumanswithSBSarelacking.
Somehormoneshaveantitrophiceffects.Transforminggrowthfactorbeta1inhibitsstemcells,enterocyte
proliferation,andadaptationinratintestinalmucosa[84,85].Octreotide,thesyntheticsomatostatinanalogue,impairs
gutstructuraladaptationbydecreasingcellproliferationfollowingmassiveresection[86].Thisinhibitoryeffectlimits
theutilityofoctreotideasatreatmentfordiarrheainSBS.Ingeneral,octreotideshouldbeavoidedduringthemost
criticalperiodofintestinaladaptation.(See"Managementoftheshortbowelsyndromeinadults"and"Managementof
theshortbowelsyndromeinchildren",sectionon'Antisecretoryagents'.)
GuthormonesalsocanaffectthepathophysiologyofSBSinwaysotherthanilealadaptation:
MotilityGastrointestinalmotilityisregulatedbyguthormones,andmassiveresectionofthesmallbowelmay
altervariousaspectsofgutmotility,suchasgastroduodenalemptyingandintestinaltransit.Resectionofthe
ileumhasparticularlyimportanteffectsonmotility.

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InindividualswithoutSBS,unabsorbedlipidsreachingthedistalileumreducesgastrointestinalmotility,knownas
the"ilealbrake."PatientswithSBSlackingileumlosethebeneficialeffectsoftheilealbrake.Theresultingrapid
transitwillfurtherreducethetimeofcontactofnutrientswiththemucosalsurface,impairingboththeirabsorption
andtheirtrophiceffectonthesmallintestine.However,ifsomeileumispresent,thefeedingoflipidsengages
theilealbrake,whichmightenhanceintestinaladaptationbydelayingtransitthroughthesmallbowel,resultingin
increasednutrientcontactwiththeepithelium.Thismechanismhasbeensupportedbyanimalexperimentsin
whichadministrationofmenhadenoilenhancedintestinaladaptation,withanassociatedincreaseinpeptideYY
anddelayingastrointestinalmotility[87].
GastrinHypergastrinemiaispresentinmanypatientswithSBS[34](see'InfluenceofSBSongastricand
pancreaticfunction'above).Asaresult,manypatientsbenefitfromacidsuppressionusingahistamine2
receptorantagonist(H2blocker)oraprotonpumpinhibitor,particularlyduringtheearlyphaseofSBS.(See
"Managementoftheshortbowelsyndromeinchildren",sectionon'Earlymanagement'and"Managementofthe
shortbowelsyndromeinadults".)
ProstaglandinsProstaglandinsstimulateintestinalproliferation[8890].Inhibitionofprostaglandinsynthesiswith
aspirin,nonsteroidalantiinflammatorydrugs,orcorticosteroidsmayinhibittheadaptationprocess.
THEMICROBIOMEOFSBSANDPATHOPHYSIOLOGYOFBACTERIALOVERGROWTHThemicrobial
populationoftheintestineisalteredinpatientswithSBS.InastudyofadultswithSBSandpartialcolonresection,
bacterialdiversityinthecolonwasreducedandLactobacilluswasoverrepresentedcomparedwithnormalcolonic
bacteria[37].
GutmicrobescanhavebeneficialeffectsinpatientswithSBS.Inpatientswithresidualcolon,colonicbacteria
participateinmetabolismandsalvageofmalabsorbedmacronutrients,therebyimprovingenergyextractionfromthe
diet.TheoverrepresentationofLactobacillusinSBSprobablyenhancesabsorptionofsugarsinthecolon,since
Lactobacillusisafacultativeanaerobe,capableoffermentingcarbohydrates[91].(See'Lossofthecolon'above.)
GutbacteriaalsocanhavedetrimentaleffectsinpatientswithSBS.WhereashumanswithoutSBStendtohaveonly
asmallpopulationofbacteriaintheproximalsmallintestine(mostlyaerobic),thosewithSBStendtohavemore
bacteriainthesmallintestine,includingmoreanaerobes[22].Invasionofthesmallintestinewithexcessiveor
imbalancedpopulationofbacteriacanleadtosmallintestinebacterialovergrowth(SIBO),whichmayexacerbate
malabsorptionandcausegasandothergastrointestinalsymptomsthatmayreduceoralintake,therebyimpeding
weaningfromparenteralnutrition(PN).Theexcessbacteriamayalsoexacerbatemalabsorptionbyseveral
mechanisms.First,bacterialdeconjugationofbileacidsdiminishestheintestinalabsorptionofmonoglyceridesand
fattyacids[22].Second,theinflammatoryresponsecausedbybacterialovergrowthdamagestheabsorptivesurface,
resultinginfurthermalabsorption,includingofcarbohydratesandproteins.Third,bacteriawithinthelumenofthesmall
intestinecompeteforvitaminB12.(See"Smallintestinalbacterialovergrowth:Etiologyandpathogenesis",sectionon
'Pathophysiology'.)
DiagnosisandmanagementofbacterialovergrowthinpatientswithSBSisdiscussedinseparatetopicreviews.(See
"Chroniccomplicationsofshortbowelsyndromeinchildren",sectionon'Smallintestinebacterialovergrowth'and
"Chroniccomplicationsoftheshortbowelsyndromeinadults",sectionon'Smallintestinalbacterialovergrowth'.)
SUMMARYConsiderationofthepathophysiologyoftheshortbowelsyndrome(SBS)isimportantinmakingmany
decisionsregardingpatientmanagement.
ResectionoftheileumhasimportantimplicationsforpatientswithSBSbecauseoftheileum'sspecialrolesin
absorbingvitaminB12andbileacids(figure1)andreducingintestinalmotilitywhenstimulatedbyfat(the"ileal
brake"),anditsabilitytoundergoadaptivechanges.(See'Ilealresection'above.)
Lossoftheileocecalvalvereducesthelikelihoodthatapediatricpatientwillbeabletobeweanedfrom
parenteralnutrition(PN).Thisisbecauseofreducedintestinaltransittimeandpromotionofsmallbacterial
overgrowth.TheileocecalvalveappearstobelessrelevanttooutcomesofSBSinadults.(See'Lossofthe
ileocecalvalve'above.)
Thecolonhasanimportantroleinabsorptionofwaterandelectrolytesandthesalvageofenergyintheformof
shortchainfattyacids.ThelattercanprovideasignificantportionofenergyrequirementsinpatientswithSBS,at
leastinadults.Thecolonalsohelpstoslowintestinaltransitandstimulateintestinaladaptation.(See'Lossof
thecolon'above.)
Intestinaladaptationreferstochangesthatoccurafterintestinalresectionthatincreaseabsorptivecapacity.Both
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structuralandfunctionalchangesoccur.Mostintestinaladaptationoccursintheileum,butsomefunctional
adaptionmayalsooccurinthejejunumorcolon.Thisprocessleadstoagradualimprovementinmacronutrient
absorptionduringthefirstonetothreeyearsafterintestinalresection.(See'Ilealversusjejunaladaptation'
above.)
Thebestestablishedstimulantofintestinaladaptationisthepresenceofnutrientsintheintestinallumenasa
result,enteralfeedingisthecornerstoneoftreatmentforpatientswithSBS.Thiseffectismediatedbygrowth
factorsproducedbytheintestineandbyfunctionalandhormonaleffectsofbiliaryandpancreaticsecretions.
(See'Nutrienteffects'aboveand'Guthormones'above.)
Glucagonlikepeptide2(GLP2)isanimportantmediatorofintestinaladaptation.Exogenousadministrationof
GLP2promotesadaptationandnutrientabsorptioninanimalmodelsofSBS.Studiesinhumanssuggestthata
teduglutide,alongeractingGLP2analogue,promotesintestinaladaptationandabsorptionandhasmodest
benefitsintheweaningofPNinpatientswithSBS.(See'Guthormones'above.)
Implementationofthesepathophysiologicprinciplesintoclinicalcareisdiscussedinseparatetopicreviews.(See
"Managementoftheshortbowelsyndromeinadults"and"Managementoftheshortbowelsyndromein
children".)
ACKNOWLEDGMENTTheeditorialstaffatUpToDatewouldliketoacknowledgeJonAVanderhoof,MD,and
RosemaryJPauleyHunter,NPC,MS,RN,whocontributedtoanearlierversionofthistopicreview.
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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GRAPHICS
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ContributorDisclosures
JohnKDiBaise,MDConsultant/AdvisoryBoards:NaiaPharmaceuticals[ShortBowelSyndrome(Phase1drug
development)],PotomacCenterforMedicalEducation[ShortBowelSyndrome(CMELectureseries)].JThomas
Lamont,MDNothingtodisclose.KathleenJMotil,MD,PhDNothingtodisclose.AlisonGHoppin,MDNothingto
disclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressed
byvettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthe
content.AppropriatelyreferencedcontentisrequiredofallauthorsandmustconformtoUpToDatestandardsof
evidence.
Conflictofinterestpolicy

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