Linkbetweenintestinalinflammationandmicrobiome
StudybytheClusterofExcellence"PrecisionMedicineinChronicInflammation"clarifiestheanti-inflammatoryeffectofthefattyacidbutyratethatisformedbyintestinalbacteria.
Around500to1,000differenttypesofbacteria,fungiandothermicroorganismscolonizeourintestines.Allofthemtogetherformtheintestinalmicrobiome.Aswenowknow,thesemicrobesplayanimportantroleinmaintaininghealth.Thisisespeciallyevidentwhenthecompositionofthemicrobiomebecomesunbalanced,asisthecaseinpeoplewithchronicinflammatoryboweldiseases.Theirintestinalmicrobiomecontainsfewertypesofbacteriathanthatofhealthypeople.Butsofar,preciselyhowamodifiedmicrobiomecontributestothedevelopmentofdiseasesislargelyunknown.PDDr.FelixSommerandhisteamfromtheClusterofExcellence"PrecisionMedicineinChronicInflammation"(PMI)aretryingtobetterunderstandthecomplexinteractionsbetweenthehostandtheirmicrobiome.Whiledoingso,theyencounteredanenzymecalledhexokinase2(HK2).TheHK2enzymeisproducedingreaterquantitiesintheeventofinflammationandisregulatedbythemicrobiome."Wewereabletoshowintheanimalmodelthatbyadministeringtheshort-chainfattyacidbutyrate,theHK2levelsinintestinalepithelialcellswereloweredandinflammationwasameliorated.TheprotectiveeffectofthefattyacidbutyrateproducedbybacteriawasabsentinanimalswheretheHK2enzymewasremoved,"explainedSommer,headoftheFunctionalHost-MicrobiomeResearchworkinggroupattheInstituteofClinicalMolecularBiology(IKMB)atKielUniversity(CAU)andtheUniversityMedicalCenterSchleswig-Holstein(UKSH),CampusKiel.Theresultsofthestudy*havebeenpublishedintherenownedscientificjournalCellMetabolism.
Enzymehexokinase2:highlevelsinintestinalcellsindicateunhealthystate
IncooperationwithscientistsfromKiel,Lbeck,MunichandHanover,aswellasfromtheUSAandSweden,SommerandhisteaminvestigatedhowintestinalbacteriaregulatetheHK2enzymeandinfluenceinflammations,includingthroughstudiesusingmicewithoutthisenzymeintheirintestinalmucosacells."Thesemicewerelesssusceptibletoanexperimentally-inducedintestinalinflammation,"reportedthefirstauthorsFinnHinrichsenandJacobHamm,bothdoctoralresearchersattheIKMB.TheexperimentsalsoidentifiedmicrobialfactorsthatregulatetheproductionofHK2:short-chainfattyacidssuchasacetateandbutyrate.Thesefattyacidsaremainlynotabsorbedthroughfood,theyareproducedbybacteriaintheintestine-butonlybyveryspecificintestinalbacteria.AcetateincreasedtheconcentrationofHK2intheintestinalcells,whilebutyratedecreasedtheHK2levels,"saidSommer.Regardingtheinflammation,henoted:"Administeringacetateaggravatedanexperimentalintestinalinflammationinwild-typemice,whereasbutyratehadaprotectiveeffect.TheseeffectswerenotpresentinHK2-deficientmice,i.e.animalsthatlackedtheHK2enzyme."
Potentialtargetmoleculefornewanti-inflammatorytreatments
Thefactthattheshort-chainfattyacidbutyrate,alsocalledbutyricacid,stabilizestheintestinalbarrierandhasananti-inflammatoryeffect,wasalreadyknownfrommanypreviousstudies.However,theveryunpleasantsmellofbutyrateanditsstronglaxativeeffectareobstaclestotherapeuticuse,forexampleincasesofchronicinflammatoryboweldiseases."ByidentifyingHK2asatargetofbutyrate,wehavefoundapotentialentrypointfornewanti-inflammatorymedications.InhibitingHK2wouldbemorespecificthantreatmentwithbutyrate,"emphasizedSommer.
Theoretically,itwouldalsobepossibletobuilduptheintestinalmicrobiomebyadministeringfattyacid-producingbacteria,aspointedoutbythelastauthor,ProfessorPhilipRosenstiel."Todate,manyapproachesherehavebeenratherbroad-based.Thestudyprovidesanimportantindicationthatwemayactuallybeabletospecificallyselectindividualbacteriainordertocontrolcertainmetabolicprocessesintheintestinalmucosa,andthusalsoinflammation,"explainedIKMBDirectorRosenstiel.
*ThestudywasfundedbytheClusterofExcellencePMI,theResearchGroupFOR5042"miTarget:Themicrobiomeasatherapeutictargetininflammatoryboweldiseases",theResearchTrainingGroupRTG1743"Genes,Environment,Inflammation"andtheCollaborativeResearchCentre(CRC)1182"OriginandFunctionofMetaorganisms".
Microscopicimageofintestinaltissue.Green:epithelialcellswhichproduceHK2.Red:bacteriainsidetheintestine.
Abacteriumfightsfiretheinflammationintheintestinewithbutyrate.
Originalpublication:
HinrichsenF,HammJ,WestermannM,RosenstielP,SommerF.Microbialregulationofhexokinase2linksmitochondrialmetabolismandcelldeathincolitis.CellMetabolism(2021)https://doi.org/10.1016/j.cmet.2021.11.004
ScientificContact:
FinnHinrichsen
InstituteofClinicalMolecularBiology(IKMB),
CAU,UKSH
+49(0)431500-15146
f.hinrichsen@ikmb.uni-kiel.de
JacobHamm
InstituteofClinicalMolecularBiology(IKMB),
CAU,UKSH
+49(0)431500-15146
j.hamm@ikmb.uni-kiel.de
Prof.Dr.PhilipRosenstiel,
InstituteofClinicalMolecularBiology(IKMB),CAU,UKSH
+49(0)431500-15111
p.rosenstiel@mucosa.de
PDDr.FelixSommer,
InstituteofClinicalMolecularBiology(IKMB),CAU,UKSH
+49(0)431500-15146
f.sommer@ikmb.uni-kiel.de
AbouttheClusterofExcellencePMI
TheClusterofExcellence"PrecisionMedicineinChronicInflammation"(PMI)isbeingfundedfrom2019to2025throughtheGermanExcellenceStrategy(ExStra).Itsucceedsthe"InflammationatInterfacesCluster,whichwasalreadyfundedintwoperiodsoftheExcellenceInitiative(2007-2018).Around300membersfromeightinstitutionsatfourlocationsareinvolved:Kiel(KielUniversity,UniversityMedicalCenterSchleswig-Holstein(UKSH),MuthesiusUniversityofFineArtsandDesign,KielInstitutefortheWorldEconomy(IfW),LeibnizInstituteforScienceandMathematicsEducation(IPN)),Lbeck(UniversityofLbeck,UniversityMedicalCenterSchleswig-Holstein(UKSH)),Pln(MaxPlanckInstituteforEvolutionaryBiology)andBorstel(ResearchCenterBorstel-LeibnizLungCenter).
Thegoalistotranslateinterdisciplinaryresearchfindingsonchronicinflammatorydiseasesofbarrierorganstohealthcaremoreintensively,aswellastofulfilpreviouslyunsatisfiedneedsofthepatients.Threepointsareimportantinthecontextofsuccessfultreatment,andarethereforeattheheartofPMIresearch:theearlydetectionofchronicinflammatorydiseases,thepredictionofdiseaseprogressionandcomplications,andthepredictionofindividualresponsestotreatment.
Presscontact
kerstin.nees@hamburg.de+49431880-4682
ClusterofExcellence "PrecisionMedicineinChronicInflammation"
ScientificOffice
Head:Dr.habil.SusanneHolsteinPostal
Christian-Albrechts-Platz4,24118Kiel,Germany
Contact:SonjaPetermann
 +49(0)431880-4850,fax:+49(0)431880-4894
spetermann@uv.uni-kiel.de
Twitter:PMI@medinflame
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