rev bras hematol hemoter. 2014;36(6):390–391
Revista
Brasileira
de
Hematologia
e
Hemoterapia
Brazilian
Journal
of
Hematology
and
Hemotherapy
w w w . r b h h . o r g
Scientific
comment
‘Leaky
gut’
in
hematological
malignancies
夽
Carolina
Costa-Lima,
Erich
Vinicius
De
Paula
∗UniversidadeEstadualdeCampinas(UNICAMP),Campinas,SP,Brazil
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Articlehistory:
Availableonline1October2014
Inhumans,theintestinalepitheliumisasinglelayerofcells thatconstitutesoneofthemostimportantbarriersbetween internaland external environments. Theso-called ‘intesti-nalbarrier’(IB)isadynamicstructurecomposedofdifferent typesofcellularjunctionsthatcanberegulatedby physio-logicalandpathologicalstimuli,andactasaselectivebarrier toantigensand pathogens. Physiological mechanismsthat regulate IBfunction are important for nutrient absorption andantigenpermeation,withpotentialrolesinthe regula-tionoftolerancetonon-selfantigens.1However,pathological
stimulisuchaspathogens,cytokinesandimmunecellsare alsocapableofaffectingIBfunctionasdemonstratedin stud-ies about tumornecrosis factor alpha (TNF-␣)-mediated IB
disruption.2 Accordingly,amodelknownas‘leaky gut
syn-drome’hasemergedbasedontheconceptthatTNF-mediated cyclesofincreasedIBpermeabilitymayleadtotranslocation ofmacromoleculesfromthelumenintothelaminapropria, and toamplificationofmucosal immuneactivation.Inthe absenceofappropriateregulatorysignals, thisviciouscycle mayresultinlocalorsystemicimmune-mediateddiseases, suchasCeliac disease,Crohn’s disease,foodallergies, and eventype-1diabetesmellitus.3
DOIoforiginalarticle:http://dx.doi.org/10.1016/j.bjhh.2014.07.007. 夽
SeepaperbyLeiteetal.onpages409–13.
∗ Correspondingauthorat:HematologyandHemotherapyCenter,UniversidadeEstadualdeCampinas(UNICAMP),RuaCarlosChagas,
480,13081-878Campinas,SP,Brazil.
E-mailaddress:erich@unicamp.br(E.V.DePaula).
DisruptedIBfunctionhasbeendescribedinpatientswith hematological malignancies, in whom it can occur as a consequenceofcytotoxictherapy-inducedepithelialdamage or leukemicinfiltration.4,5 Themoststraightforward
conse-quences of IB disruption for these patients are increased antigenpermeation,whichcouldfacilitatepathogen translo-cation, bacteremia, and nutrient malabsorption.6
Interest-ingly,anadditionalconsequenceofIBdisruptioninpatients with hematological malignancies is a higher risk of acute graft-versus-host disease (aGVHD)inpatients submittedto allogeneic hematopoietic stem cell transplantation (HSCT). In thiscontext,translocationofluminalcontentsand acti-vation of the underlying antigen presenting cells would enhance activation and proliferation of alloreactive donor cells. This could result in greater inflammatory cytokine production, sustained damage to endothelial and epithe-lial barriers, and donor T-cell infiltration. Together, these events have the potential of facilitating the development of aGVHD, as suggested by the observation of a higher risk ofaGVHDin patients withincreasedIB permeability.7
Of note, it has been proposed that barrier-protecting agents could be beneficial for conditions associated with
http://dx.doi.org/10.1016/j.bjhh.2014.09.007
revbrashematolhemoter.2014;36(6):390–391
391
this pathogenic model, although no clinical data are yet available.3
Inthecurrent editionoftheRevistaBrasileirade Hema-tologiaeHemoterapia,Leiteet al.reportthemeasurement ofIBpermeability inpatientswithleukemia.8Althoughno
statisticallysignificant resultscould bedemonstrated, and thecategorizationof‘leukemias’usedbytheauthors,which includes acute myeloid leukemia (AML), chronic myeloid leukemia(CML) andchroniclymphocytic leukemia(CLL) as asinglegroup,isoflittle biologicalsignificance,the report hasthe meritofreintroducing the subjectofIBdisruption to the agenda of malignant hematology. Using a classical measurement tool, based on the differential absorption of lactulose and mannitol, the authors demonstrate a clear trendtowardincreasedIBpermeabilityinpatientswithacute leukemia,beforechemotherapy.Previousstudiesfound sim-ilarresults,5,9 indicatingthatIBdisruptionisindeedpresent
insomeofthesepatients,evenbeforechemotherapy. Contro-versialresultswereobtainedinpatientsbeforeconditioning priortoHSCT,butIBdisruptioncouldalwaysbedetectedafter chemotherapy.7,9
Considering the critical role of IB function in immune regulation, aswell asrecent insights into the cellular and molecularmechanismsthatregulatebarrierfunctionin phys-iologicalandpathologicalconditions,thereismuchmorethan ‘gutfeeling’tosupporttherelevanceofthequestionaddressed byLeiteetal.tothefieldofmalignanthematology.8
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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