GI Microbiota and Regulation ofthe Immune System ADVANCES INEXPERIMENTALMEDICINEAND BIOLOGY EditorialBoard: NATHANBACK,State UniversityofNewYorkatBuffalo IRUN R.COHEN,TheWeizmannInstitute ofScience ABELLAJTHA,NS.KlineInstituteforPsychiatricResearch JOHN D.LAMBRlS, UniversityofPennsylvania RODOLFOPAOLETII,UniversityofMilan RecentVolumesinthisSeries Volume627 TRANSGENESISANDTHEMANAGEMENTOFVECTOR-BORNEDISEASE EditedbySerapAksoy Volume628 BRAINDEVELOPMENTINDROSOPHILAMELANOGASTER EditedbyGerhardM.Technau Volume629 PROGRESSINMOTORCONTROL EditedbyDagmarSternad Volume630 INNOVATIVEENDOCRINOLOGYOFCANCER EditedbyLevM.BersteinandRichardJ.Santen Volume631 BACTERIALSIGNALTRANSDUCTION EditedbyRyutaroUtsumi Volume632 CURRENTTOPICS INCOMPLEMENTII EditedbyJohn.D.Lambris Volume633 CROSSROADSBETWEENINNATEANDADAPTIVEIMMUNITYII EditedbyStephenP.Schoenberger,PeterD.Katsikis,andBali Pulendran Volume634 HOTTOPICSININFECTIONANDIMMUNITYINCHILDRENV EditedbyAdamFinn,NigelCurtis,andAndrewJ.Pol1ard Volume635 GIMICROBIOTAANDREGULATIONOFTHE IMMUNESYSTEM EditedbyGaryB.HutTnagleandMairi C.Noverr AContinuationOrderPlanisavailableforthisseries.Acontinuationorderwillbringdeliveryofeachnew volumeimmediatelyuponpublication.Volumesarebilledonlyuponactualshipment.Forfurtherinformation pleasecontactthepublisher. GI Microbiota and Regulation of the Immune System Edited by Gary B.Huffnagle,PhD DepartmentofInternalMedicine, DivisionofPulmonaryandCriticalCare Medicine, UniversityofMichigan MedicalSchool,AnnArbor, Michigan, USA Mairi C.Noverr, PhD DepartmentofImmunologyandMicrobiology, WayneState University,Detroit, Michigan, USA Springer Science+Business Media, LLC Landes Bioscience Springer Science+BusinessMedia,LLC Landes Bioscience Copyright©2008Landes BioscienceandSpringerScience+BusinessMedia, LLC Allrightsreserved. Nopartofthisbookmaybereproducedortransmittedinanyformorbyanymeans,electronicormechani cal,includingphotocopy,recording,oranyinformationstorageandretrievalsystem,withoutpermission inwriting fromthepublisher,withtheexceptionofanymaterial suppliedspecificallyforthepurposeof beingenteredandexecutedonacomputersystem; forexclusiveusebythePurchaserofthework. PrintedintheUSA. SpringerScience+BusinessMedia,LLC,233SpringStreet,NewYork,NewYork10013,USA http://www.springer.com Pleaseaddress allinquiriestothepublishers: LandesBioscience,1002WestAvenue,Austin,Texas78701,USA Phone:512/6375060;FAX:512/6376079 http://www.landesbioscience.com GIMicrobiotaandRegulationoftheImmuneSystem, editedbyGaryB.HuffnagleandMairiC.Noverr, LandesBioscience1SpringerScience+BusinessMedia, LLC dual imprint1Springerseries:Advances inExperimentalMedicineandBiology ISBN:978-0-387-09549-3 Whiletheauthors,editorsandpublisherbelievethatdrugselectionanddosageandthespecificationsand usage ofequipmentanddevices, assetforthinthisbook, areinaccordwithcurrentrecommendations andpracticeatthe time ofpublication,they make nowarranty, expressedor implied, with respect to material describedinthisbook. Inview oftheongoing research, equipmentdevelopment, changes in governmentalregulationsandtherapidaccumulationofinformationrelatingtothebiomedicalsciences, thereader isurgedtocarefullyreviewandevaluatetheinformationprovidedherein. Library ofCongress Cataloging-in-PublicationData AC.I.P.catalogrecordforthisbookisavailablefromtheLibraryofCongress. PREFACE The idea that the microbial communities within the GI tract have aprofound influence on general human health actually originatedwith Russian scientist Elie Metchnikovat the turnofthelast century.Alsoknown asthe "fatherofimmunol ogy", Metchnikovbelievedthatputrefactivebacteriainthegutwereresponsiblefor enhancingthe aging process. Hetheorized thatingestionofhealthy bacteriafound infermented foods couldcounteract toxicbacteria and was thekeytogoodhealth. His theoriesconcerninggood bacteriaandhealth can be found inhis treatise "The ProlongationofLife:OptimisticStudies".ThesewritingspromptedJapanesescientist MinoruShirotatobegininvestigationofhowfermentativebacteriaimprovehealth. Hesucceededinisolating astrainofLactobacillusthatcouldsurvivepassagethrough the intestine,whilepromotingahealthy balance ofmicrobes. The "Shirotastrain" is still usedtoday in the fermented beverage Yakult.Itisclear from a commercial standpointthat these ideas have inspired the development ofaprobiotic industry, which has expandedgreatlyintheU.S. overthepast 5-10years. Likewise, scientificstudiesinvestigatingthemicrobiotaandtheimmunesystem have increasedsignificantlyinrecentyears.Thisincreaseinresearch isalsodue to advancesintechnologiesthatenabletheinvestigationoflargemicrobialcommunities, aresurgence in gnotobioticanimal research, ang)rnprovedmethods formolecular analysis ofprobioticbacterialspecies. Ourinterestinthisareastemsfromourlabo ratory observationsindicatingthat antibiotics andfungi can skew microbiotacom positionandsystemicimmuneresponses. Ourinitialbaseofreferences uponwhich to develop further hypotheses concerning the mechanisms involvedin microbiota regulationofimmuneresponses waslimited.However, inpresentingtheresearch at nationalscientificmeetingsandatuniversities acrossthecountry,thefeedback and interestwere overwhelming.Itbecame clearthatabookdedicatedtocurrenttrends in investigating the GI microbiota was warranted. Dissection ofthe relationship betweenthemicrobiotaandtheimmune systemiscurrentlybeing approachedfrom avarietyofangles that we have soughttoincorporateinto thisbook. This bookopens with two general reference chapters,which provide an over view ofcurrent knowledge ofgastrointestinal immunology and the commensal microbiologyofthe gut.Next aretwochapters dedicatedtocurrent methodologies v vi Preface used toinvestigatethe microbiotaandhost: molecularanalysis ofmicrobialdiver sity and gnotobiotic research. Both positiveand negative interactionsbetweenthe microbiotaandtheimmune systemcantakeplaceinthegut,withchaptersdedicated toprobioticsandintestinaldiseasesassociatedwithunhealthyrnicrobiota.Environ mental factors play anenormous roleinshaping the microbiotacomposition.Host, microbial, anddietary factorstakepartinacomplexinterplay,whichprovidesmany distinct and diverse researchsubjects. Wehave includedachapterdiscussingdiet, functional foods, andprebiotics,whicharedietary supplementsusedto specifically enhance the growth ofbeneficial members ofthe microbiota. Several laboratories are investigating how the different members ofthe microbiota communicate with each other and with the immune system. Achapterreviewing how bacteria sense and respondto signaling compounds in the gut environmentprovides insightinto thesignaltransductionpathways thatmediate interactionsbetweenthehostandmi crobiota.Ahighly detailedandwell-investigatedmodelofbacterial-hostsymbiosis providesanimmenseamountofbackgroundandinsightfor the developingfield of host-microbiotastudies. Wehave includedachapterreviewingthe unique interac tions that take placeinanon-mammaliansystem, the Squid-Vibriomodel. Finally, we close the bookwith two chapters outlining currenthypotheses concernedwith redefiningourunderstandingoftherelationshipbetweenmicrobes,disease, andthe basic mechanismsofimmune system function. GaryHuffnagle, PhDandMairi C.Noverr,PhD ABOUT THE EDITORS... GARYB.HUFFNAGLE,PhD,isaProfessorofInternalMedicine(Pulmonary Diseases)andMicrobiologyandImmunologyattheUniversityofMichiganMedical School. He holds a BS in microbiology fromPennsylvaniaState University and a PhD in immunology from the University ofTexasSouthwesternMedical School. In addition to conductingresearch, he teachesundergraduate and graduate classes in eukaryotic microbiology, microbial symbiosis, and experimental immunology at the University ofMichigan. Dr.Huffnagle's research focuses on the regulation ofpulmonaryimmunityto infectious agents andallergens. Inthe past 5years, his attention has turned to the role ofthe indigenous microbiota in immune system functioning, as well as the role ofprobiotics inanimal and human health. He has been awarded research grants from the National Heart, Lung and Blood Institute (NHLBI),NationalInstituteofAllergyandInfectiousDiseases(NIAID),theFrancis Families Foundation, and the Burroughs-Wellcome Fund. Dr.Huffnagle serves or has servedon editorialboards for theAmerican Society for Microbiology (ASM) andtheAmericanAssociationofImmunologists (AAI), aswell asonadvisoryand review panels for theNational Institutes ofHealth(NIH). vii ABOUT THE EDITORS... MAIRI C. NOVERR, PhD, is an Assistant Professor of Immunology and MicrobiologyatWayneStateUniversity Medical School. Sheearned aBAinbiol ogyfromKalamazoo Collegein 1996andaPhDinmicrobiologyandimmunology fromtheUniversityofMichiganin2002.Dr.Noverr'scurrent researchfocuses on investigatingmechanismsofimmunomodulationbytheopportunisticyeastCandida albicansduring host-pathogen interactions and how interactions with other mem bers ofthe microbiotainfluence these interactions. Her laboratory is investigating signaling compounds calledoxylipins that are producedby both Candida and the host, which can influence the microbiology ofthe fungus and the activity ofhost immune system cells.Projectsinthelaboratory include molecularcharacterization ofthe fungal oxylipin biosynthetic pathways and determining the effects ofoxy lipinsduring Candidapathogenesis, inmodulatinghost immune cell function, and during fungal-bacterial interactions. Shehas been awardedresearch funding from theFrancis Families Foundation. viii PARTICIPANTS ChristopherA.Allen Lesley Hoyles DepartmentofMicrobiology FoodMicrobialSciences Unit and Immunology School ofFood Biosciences UniversityofTexasMedicalBranch TheUniversityofReading Galveston,Texas Whiteknights,Reading USA UK Charles L. Bevins GaryB. Huffnagle DepartmentofMicrobiology DepartmentofInternal Medicine and Immunology Division ofPulmonaryandCritical UniversityofCaliforniaDavis School CareMedicine ofMedicine UniversityofMichiganMedical Davis, California School USA AnnArbor, Michigan USA ArturoCasadevall DepartmentofMedicine Erika Isolauri DepartmentofMicrobiology DepartmentofPaediatrics DivisionofInfectiousDiseases UniversityofTurku AlbertEinsteinCollegeofMedicine Turku Bronx,New York Finland USA Marko Kalliomaki Michael S.Gilmore DepartmentofPaediatrics DepartmentofOphthalmology UniversityofTurku HarvardMedical School Turku and Finland SchepensEye ResearchInstitute Boston, Massachusetts USA ix