Cannabis Microbiome and the Role of Endophytes in Modulating the Production of Secondary Metabolites: An Overview

Abstract

Plants, including cannabis (Cannabis sativa subsp. sativa), host distinct beneficial microbial communities on and inside their tissues and organs, including seeds. They contribute to plant growth, facilitating mineral nutrient uptake, inducing defence resistance against pathogens, and modulating the production of plant secondary metabolites. Understanding the microbial partnerships with cannabis has the potential to affect the agricultural practices by improving plant fitness and the yield of cannabinoids. Little is known about this beneficial cannabis-microbe partnership, and the complex relationship between the endogenous microbes associated with various tissues of the plant, and the role that cannabis may play in supporting or enhancing them. This review will consider cannabis microbiota studies and the effects of endophytes on the elicitation of secondary metabolite production in cannabis plants. The review aims to shed light on the importance of the cannabis microbiome and how cannabinoid compound concentrations can be stimulated through symbiotic and/or mutualistic relationships with endophytes.

Full text

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Microorganisms2020,8,355;doi:10.3390/microorganisms8030355www.mdpi.com/journal/microorganisms
Review
CannabisMicrobiomeandtheRoleofEndophytesin
ModulatingtheProductionofSecondary
Metabolites:AnOverview
MeysamTaghinasabandSuhaJabaji*
PlantScienceDepartment,FacultyofAgriculturalandEnvironmentalSciences,MacDonaldCampusof
McGillUniversity,QCH9X3V9,Canada;meysam.taghinasab@mcgill.ca
*Correspondence:suha.jabaji@mcgill.ca
Received:13January2020;Accepted:28February2020;Published:2March2020
Abstract:Plants,includingcannabis(Cannabissativasubsp.sativa),hostdistinctbeneficialmicrobial
communitiesonandinsidetheirtissuesandorgans,includingseeds.Theycontributetoplant
growth,facilitatingmineralnutrientuptake,inducingdefenceresistanceagainstpathogens,and
modulatingtheproductionofplantsecondarymetabolites.Understandingthemicrobial
partnershipswithcannabishasthepotentialtoaffecttheagriculturalpracticesbyimprovingplant
fitnessandtheyieldofcannabinoids.Littleisknownaboutthisbeneficialcannabis‐microbe
partnership,andthecomplexrelationshipbetweentheendogenousmicrobesassociatedwith
varioustissuesoftheplant,andtherolethatcannabismayplayinsupportingorenhancingthem.
Thisreviewwillconsidercannabismicrobiotastudiesandtheeffectsofendophytesonthe
elicitationofsecondarymetaboliteproductionincannabisplants.Thereviewaimstoshedlighton
theimportanceofthecannabismicrobiomeandhowcannabinoidcompoundconcentrationscanbe
stimulatedthroughsymbioticand/ormutualisticrelationshipswithendophytes.
Keywords:Cannabissativa;marijuana;hemp;microbiome;endophytes;secondarymetabolites;
Cannabinoids;gutmicrobiota;rootmicrobiota
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1.Introduction
Cannabis(CannabissativaL.)referstogeneticallydifferentbiotypesofboth(nonintoxicant)
industrialhempandmarijuana[1].Differentiatingstrainsofhempfrommarijuanaisbasedonan
arbitrarythresholdpointofthepsychoactivecompound,Δ9‐tetrahydrocannabinol(THC)at0.3%,a
criterionestablishedbySmallandCronquist[2].
OriginatingfromtheHimalayas,industrialhemp(C.sativaL.)isthemostancientdomesticated
crop.Itistypicallybredforseedandfiber,andalsoformultipurposeindustrialusessuchasoilsand
topicalointments,aswellasfiberforclothing,andconstructionmaterialforhomesandforbuilding
electriccarcomponents[3,4].BothhempandherbalmarijuanavarietiesaremembersoftheC.sativa
species;however,industrialhempcultivarsarecultivatedforfiberproducts,edibleseeds,andoilseed
andnonpsychoactivemedicinaldrugs[1].
Herbalmarijuana,atermdesignatedfortheformofcannabisthatisusedformedicaland
recreationalpurposes,producessomeprincipalcomponentsofphytocannabinoidssuchasthe
intoxicatingcompoundΔ9‐tetrahydrocannabinol(THC),andwithatherapeuticeffectsuchas
cannabinol(CBN),cannabidiol(CBD),cannabidiol‐carboxylicacid,cannabigerol(CBG),
cannabichromene(CBC),allofwhicharecurrentlyundergoingpromisingresearch[1].Incannabis
plants,cannabinoidsaccumulateascannabinoidacidsandnonenzymaticallydecarboxylizedinto
theirneutralformsduringstorage.Thebiosyntheticpathwaysofthemajorphytocannabinoids(CBC,

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CBD,CBGTHC)withpentylsidechains‐C5H11beginswiththeproductionofCBGwhichisproduced
bycondensationofaphenol‐derivedolivetolicacid,aprecursorofthepolyketidebiosynthetic
pathway,andaterpene‐basedgeranylpyrophosphate,aprecursoroftheplastidalbiosynthetic
pathway.FromCBG,Δ‐THC,CBD,andCBCaresynthesizedeachbyaspecificenzyme[1].Formore
completeanalysesofphytocannabinoidbiosynthesis,seeAndreetal.[5]andHanusetal.[6].
Additionally,thenoncannabinoidcompounds,includingterpenoidsandflavonoids,deserve
attentionastheymayprovideanti‐inflammatoryactivity[7].
Phytocannabinoidsaccumulateinallpartsoftheplant;however,theyaremoreconcentratedin
specializedsecretorystructures,thetrichomesofthefemaleflowerbuds[5,8].Inadditionto
phytocannabinoids,cannabisproducesaplethoraofsecondarymetabolitesthatareproducedasan
adaptationforspecificfunctionsinplantsmostlytoimproveplantgrowthordefenceagainstbiotic
andabioticstress[9].Thesemetabolitesprovidediversebiologicalactivitiesforuseinhuman
medicineandthepharmaceuticalindustry[10,11].Theuseofmetabolicengineeringapproachesis
promisingasitopensupthepossibilityofincreasingtheproductionlevelsofdesiredtargeted
phytocannabinoid‐derivedcompounds[10,11].Interestingly,CBDexhibitsstrongantimicrobial
propertiesagainstclinicallyrelevantmultidrug‐resistantbacteria(MDR)suchasthemethicillin‐
resistantStaphylococcusaureus(MRSA)strains,andthedrug‐resistantMycobacteriumtuberculosis
XDR‐TBwithminimuminhibitoryconcentration(MIC)rangingfrom0.5–2μg/mL.Theseactivities
comparefavourablywithstandardantibioticsforthesestrains[12].Essentialoilsofcannabisshowed
moderatepotencywithanIC50of33μg/mLagainstseveralyeasts,includingCryptococcusneoformans,
Candidaglabrata,andC.krusei[13].
BeforethelegalizeduseofC.sativaindifferentcountries,cultivationwasrestrictedtohemp
varietiesofhigh‐yieldingfiberwithsignificantlylowlevelsofthepsychoactiveΔ9‐THC.Therecent
legalizationofcannabisinvariouscountries,includingCanada,Uruguay,andelevenstatesinthe
UnitedStatesfortheproductionofmedicaland/orrecreationalpurposes,havegenerateddemand
notonlyforhighyieldingvarietiesofΔ9‐THCand/orcannabinoidsbutfirmandreliablecannabinoid
profiles.However,thelegalityofcannabisformedicalandrecreationalusesvariesbycountry,in
termsofitspossession,distributionandcultivation,consumptionandusesformedicalconditionsit
canbeusedfor[14,15].
Althoughbeyondthescopeofthisreview,itisworthmentioningtheimportanceofthe
productionmethodsandenvironmentalconditions,allofwhichinfluencetheproductionof
commercialandhigh‐grademedicaland/orrecreationalmarijuanaunderindoorcultivation[16].The
criticalconditionsforoptimalcannabisgrowth,includelightintensity,qualityandphotoperiod[17],
storagetemperaturesandhumidity[18],fertilization[19,20],abioticelicitorsincluding
phytohormones[21,22],andthemicrobiome[23].Forcannabis,smallerquantitiesoftheinvisible
ultraviolet(UV‐B)lightreportedlyelicitsΔ9‐THCaccumulationinleavesandbuds[24,25],however,
theeffectofspectralcompositiononcannabinoidconcentrationremainstenuous.Thestressresponse
isoneofthemajorfactorsthatalterplantchemicalcomposition[26].Droughtstressisknownto
reduceplantgrowthsignificantlybutcanalsoincreasesecondarymetabolitecontent[27].For
cannabisandhempplants,thereisinconclusiveevidencelinkingdroughtordecreasedhumidityto
increasedcannabinoidandΔ9‐THCproduction[28,29].Moreworkisneededtounderstandbetter
theroleofwaterstressincannabinoidandTHCproduction.
Thisreviewaimstocharacterizethemicrobialdiversityassociatedwithhempandmarijuana,
showwithrecentexamplesthediversityofmicrobialcommunities(endophytes)thatinternalizetheir
tissues,andlistthebenefitsthattheyconfertotheirhosts.Wealsohighlightthevaluesofthe
biologicallyactivecompoundsproducedbyendophytesthatcontributetoincreasedplantfitnessand
toleranceagainstbioticandbioticstress.Moreover,weprovidesomeevidencethatthemicrobial
bioactivecompoundsproducedbysomeendophytesarederivativesand/oranalogsoftheir
associatedhostplants.
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2.TheMicrobiome
Themicrobiomeisatermthatdescribesthecollectivegenomeofmicrobialcommunities,theso‐
calledmicrobiota,whichisassociatedwithhumans,animals,andplants.Duringrecentyears,the
impactofmicrobialcommunitiesonshapingthehostimmunesystemandfitnessoftheirhosthas
gainedattention[30].Thecompositionofmicrobiotaresidinginahostisaffectedbyenvironmental
conditionssuchastemperature,pH,andnutrientavailability[31].Theoveruseofxenobioticsin
agriculture,alongwiththeemergenceofantibioticandpesticide‐resistancestrainsinagricultureand
humanmedicine,canaffectthehostcapacitytointeractproperlywiththemicrobiota[30].Compared
tothenumberofstudiesonthemicrobiotaofhumansubjects,thereisaminimalnumberofstudies
focusingoneconomicallyagriculturalcrops.Itisbecausethemicrobiotaofagriculturalorganismsis
affectedbyplantspeciesandgenotypes,developmentalstages,rootexudation,soiltype,and
environmentalconditions.
Nevertheless,gutandrootmicrobiotasharecommonalitiesconcerningtheregulationofhost
geneexpression[32,33],enhancementofmetaboliccapacitiesoftheirhoststhroughcatabolicgenes
[34,35],andsuppressionofharmfulpathogens[36].Thesearefewillustrationsofthecommonalities
betweenrootandgutmicrobiota.Theliteratureonthistopicisfoundinrecentreviews[37,38].
Strategicandappliedresearchontheimpactofmicrobialcompositionconcerninghumanhealth
recognizestheroleofprebioticsthatincludeschangesinthestructureanddiversityofthemicrobiota
andstimulationoftheactivityofhealth‐promotingbacteriasuchasLactobacillusandBifidobacteria
[39,40].Oneofthehottopicsingutmicrobiotaisthenutritionalstrategyofaddingdietary
phytochemicalcompoundssuchasthesecondarymetabolites,flavonols,andquercetin,whichcan
influencetheimmunefunctionofthehostphysiology[41,42].Itisworthwhilementioningthat
flavonoidsandquercetinareimportantphytochemicalsincannabis,andtheircombinationmakes
thempotentantioxidants[7].Dataontheantioxidantpotentialofnoncannabinoidsarebasedonin
vitrostudies.Undoubtedly,theireffectsinvolvingclinicaltrialsdeserveattention.
ThePlantMicrobiome
Plants,includingcannabishostdistinctbeneficialmicrobialcommunitiesonandinsidetheir
tissues,designatedtheplantmicrobiotafromthemomentthattheyareplantedintothesoilasseed.
Theplantmicrobiomeiscomposedofspecificmicrobialcommunitiesassociatedwiththerootsand
thesoilsurroundingtheroots(i.e.,therhizosphere),theair‐plantinterface(i.e.,thephyllosphere),
andtheinternaltissuesoftheplant,theso‐calledtheendosphere[43,44].Seedsharbourdiverse
groupsofmicrobiotathatareasourceofbio‐inoculumforjuvenileplantspromotingprotection
againstbioticandabioticstressatseedgerminationandlaterstages[45,46].Verticaltransmissionof
endophytesfromseedstoseedlingsoccursinrice,wheat,andbioenergycrops[47,48].Eachofthese
microhabitatsprovidessuitableconditionsformicrobiallife,whichalsohasarespectivefunctionfor
thehost.Plantmicrobiomeisacontributingfactortoplanthealthandproductivity[49].Anincreasing
bodyofevidencehighlightstheimportanceofplantmicrobiomeasasystemicboosteroftheplant
immunesystembyprimingacceleratedactivationofthedefencesystem[50].Manystudiesfocused
ontherhizospheremicrobiomeduetothesoil‐derivedmicrobialdiversitysurroundingtheroot,and
apotentialsourceforselectingbeneficialmicrobesthatpositivelyaffectplanthealth[49,51,52].
Severalreviewsaddressedtheroleoftherhizospheremicrobiomeinconferringdisease
suppressivenessandimprovingdroughtresistance[49,53,54];othersstudiedcontributingchemical
componentstoselectiveenrichmentofmicroorganismsintherhizosphere[55,56].Generally,above‐
groundplantmicrobiotamostlyoriginatedfromthesoil,seed,andairadaptanendophyticlifestyle
inhabitingtissuesoftheplantinternallyandplayvitalrolesinplantdevelopmentandfitness.These
microbialcommunitiesthatinternallyinhabitplanttissues,arereferredtoasendophytes,andplaya
crucialroleinplantdevelopmentandgrowth[57].Inthisreview,weusethetermendophytebased
onthedefinitionofPetrinitosignify‘allorganismsinhabitingplantorgansthatatsometimeintheir
lifecancolonizeinternaltissueswithoutcausingharmtotheirhosts[58].


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3.TheFunctionsofPlantMicrobiomeareEssentialfortheHost
Thereisaconsiderableamountofinformationonthefunctionalroleofmicrobialcommunities
associatedwithplantsandtheirinternaltissues.Plant‐growthpromotingrhizobacteria(PGPR)and
endophytesstimulateplantgrowthbyproducingphytohormonessuchasauxins[50]gibberellins
(GAs)abscisicacid(ABA),andethylene(ET),orbymodulatingtheplant’sendogenous
phytohormonelevels[59,60].Undergreenhouseconditions,PGPRfavouredplantgrowthand
development,aswellasplantsecondarymetabolitesaccumulationand,consequently,antioxidant
capacity.Seedandroot‐exudatedflavonoidsareinducersforthenodulationgenesinrhizobia‐
legumeinteractions,andinmycorrhizationofhostplants[61,62]whichremarkablyiscomparableto
themodulationofgutmicrobiotabydietaryflavonoids.
Ingeneral,Proteobacteria,andespeciallyγ‐Proteobacteria,suchasPseudomonasandPantoeaare
thedominantendophyticbacteriaisolatedfromavarietyofplantspecies[63].Moreover,Gram–
positiveandGram‐negativebacteria,includingPseudomonas,Azospirillum,Azotobacter,Streptomyces,
Enterobacter,Alcaligenes,Arthrobacter,Burkholderia,andBacilluscouldenhancetheplantgrowthand
suppressphytopathogens[64].DiversestrainsofPseudomonas,Bacillus,Arthrobacter,andPantoea
speciesassociatedwithsoybeanandwheatrootsexhibitedgrowth‐promotionpropertiessuchas
phytohormoneproduction,mineralsolubilization,andtheproductionoftheenzyme1‐amino
cyclopropnae‐1‐carbixylate(ACC)deaminase[65,66].ACCdeaminasereducestheendogenouslevel
ofthestresshormoneETbylimitingtheamountofplantACCdeaminase,andpreventsET‐induced
rootgrowthinhibition.Inreturn,itpromotesplantgrowthandloweringstresssusceptibility,in
return,resultinginmorenitrogensupplyforbacteria[67].
Aswithbacterialendophytes,fungalendophytescanfacilitatemineralnutrientuptake,promote
plantgrowthanddevelopment,andinducedefenceresistanceagainstpathogens[68,69].
Furthermore,theyenhanceabioticstresstolerance,notably,thedarkseptateendophyticfungus,
Curvulariasp.providedthermalprotectionforhostplantathightemperature[69].Indeed,bacteria
andnonmycorrhizalfungihavetheadvantageofaxenicpropagationthatplacesthemasanideal
modeloftheagri‐horticultureapplication.
Oneofthetoolstocontrolplantpathogenswiththeleastimpactontheenvironmentis
biocontrol.Therearenumerousexamplesofbiocontrolactivitiesofbacterialandfungalendophytes
againstpathogeninvasionanddiseases[43,70,71].Variousmechanismsunderliethebeneficialeffects
ofbacterialendophytesontheirhosts.Theseincludeantibioticproduction,inductionofhost
defences,andimmunityviainducedsystemicresistance(ISR),parasitism,competition,andquorum
sensing[72].Equally,endophyticfungicanprotectplantsagainstpathogensbytriggeringhost
resistanceviasystemicacquiredresistanceandISR[73,74],orbyantibiosisandmycoparasitism[71].
4.TheMicrobiomeofHempandMarijuana
Understandingmicrobialpartnershipswithindustrialhempandmedicalandrecreational
marijuanacaninfluenceagriculturalpracticesbyimprovingplantfitnessandproductionyield.
Furthermore,marijuanaandhempareattractivemodelstoexploreplant–microbiomeinteractionsas
theyproducenumeroussecondarymetaboliccompounds[75].Together,theplantgenomeandthe
microbialgenomeinsideplanttissues(i.e.,theendorhiza)thatformstheholobiontisnowconsidered
asoneunitofselectioninplantbreeding,andalsoacontributortoecologicalservicesofnutrient
mineralizationanddelivery,protectionfrompestsanddiseases,andtolerancetoabioticstress[76].
Increasingevidencesuggeststhatthehostgenotypeinfluencesthecompositionandfunctionof
certaincriticalmicrobialgroupsintheendorhiza,which,inturn,affectshowtheplantreactsto
environmentalstresses[45]withplanttraitsessentialforhostingandsupportingbeneficialmicrobes.
Particularly,populationsofrhizosphericbacteriaindiseasesuppressivesoilsareenrichedandactas
thefirstlineofdefenceinthehostplantagainstrootpathogens,therebyactivatingsecondary
metabolitebiosyntheticgeneclustersthatencodeNRPSsandPKSstoenhancethelevelofdefence
metabolites[77].Agrowingbodyofevidencesignalsthatatwo‐stepselectionmodelwhereplant
typeandsoiltypearethemaindriversofdefiningsoilmicrobialcommunitystructure[78,79].The
soiltypedefinesthecompositionoftherhizosphereandrootinhabitingbacterialcommunities,

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whereasmigrationfromtherhizosphereintotheendorhizatissueisdependentonplantgenotype
[80].Accordingly,theinfluenceofsoiltypeandplantgenotypeonthemicrobialcommunitystructure
ofmarijuanaofferssupportofthetwo‐tiersystemmodelwherebysoiltypeisadeterminantof
microbialcommunitiesintherhizosphere,andcannabiscultivarsareafactorofcommunitystructure
intheendorhiza[23].Thisviewthattherhizosphericmicrobiomeinfluencestheselectionofthenext
generationcannabiscultivarsthatareresilienttobioticandabiotictypesofstressopensupanew
approachofbreeding.Ofparticularinterest,thecommunitystructureofendorhizacorrelates
significantlywithcannabinoidconcentrationandcomposition[23].Futurestudiesonusingmicrobial
communitiesofcannabisnotonlyincreasefitnessbutaugmentderivedmetaboliteproductionthat
areworthpursuing.
4.1.FungalEndophytesAssociatedwithDifferentOrgansofHempandMarijuana
Thediversityoffungalandbacterialendophytesassociatedwithdifferenttissuesofhempand
marijuanasampledfromvariousgeographicandecologicalregionsislistedinFigure1.Almostall
ofthenonsymbioticfungalendophytesreportedbyseveralstudiesbelongedtotheAscomycetes,
exceptfortwostudiesthatreportedthepresenceofstrainsbelongingtotheBasidiomycetes,suchas
Irpex,Cryptococcus[81]andSchizophyllumcommune[82].Dependingonthegeographicalregion,the
abundanceoffungalendophytesassociatedwithcannabistissuesvaried.Forexample,the
abundancenumberoffungalstrainsbelongingtoAspergillus,Penicillium,Phoma,Rhizopus,
Colletotrichum,Cladosporium,andCurvulariainleafsamplesfromHimachalPradesh,India[83]was
higherascomparedtothoseinstemsandpetioles[83].Similarly,thefungalstrainsCochliobolusand
AureobasidiumisolatedfromCanadianhempsampleswereabundantinleaftissue[81].Leaf,twig,
andbudtissuesofBedrocanBVMedicinalmarijuanafromtheNetherlandswereassociatedwith
endophyticcommunitiesbelongingtothePenicilliumspecies(predominantly,Penicilliumcopticola),
Eupenicilliumrubidurum,Chaetomiumglobosum,andPaecilomyceslilacinus[84].Differentspeciesof
Aspergillus(A.niger,A.flavus,andA.nidulans),Penicillium(P.chrysogenumandP.citrinum),andsome
pathogens,suchasRhizopusstolonifer,Alternariaalternata,andCladosporiumsp.werefoundin
marijuanastemtissues[83].Moreover,strainsbelongingtoAlternaria,Cryptococcus,Aspergillus,
Cladosporium,andPenicillium[81,83,85]wereisolatedfrommarijuanaandhemppetioles,whereas
AureobasidiumandCladosporiumwereisolatedfromhempseeds[81].Intensivemycorrhizationof
hemprootsbythearbuscularmycorrhizal(AM)fungi,Diversisporasp.,Funneliformismosseae,
Funneliformisgeosporum,Glomuscaledonium,andGlomusoccultumenabledtheplanttotoleratesoils
contaminatedwithphosphogypsumandsewagesludge,andrespondedpositivelyregarding
biomassproduction[86].Itishighlyprobablethathempselectivelyestablishedrelationshipswith
mycorrhizalfungitocounteractabioticstressthroughsymbiosis.

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
Figure1.ThemostcommonendophytesharbouredindifferenttissuesofCannabissativaplants
obtainedfromdifferentgeographicallocations.
4.2.BacterialEndophytesCompositioninDifferentOrgansofC.sativa
ThemicrobialcommunityofbacterialendophytesassociatedwithdifferentcultivarsofC.sativa
belongtoϒ‐proteobacteriaandα‐proteobacteria,includingPseudomonadaceae,Oxalobacteraceae,
Xanthomonadaceae,andSphingobacteriales,andallarewell‐knownendophyticbacteriawhich
substantiateobservationsfromotherplantsystems(Figure1)[87].Themostabundantstrainsisolated
fromleavesbelongtoPseudomonasandBacillus.Namely,Bacilluslicheniformis,Bacillussubtilis,Bacillus
pumilus,andBacillusmegateriumformedthemostabundantGram‐positivebacterialendophytes
populationintheleaf[81,88].StrainsofPantoeaandStaphylococcuswereassociatedexclusivelywith
cannabispetioles[81],whilestrainsofPantoea,Staphylococcus,Bacillus,andEnterobacterwereisolated
fromtheseed[81].ThemostprominentisolatedgenerafromrootsincludedAcinetobacter,
Chryseobacterium,Enterobacter,Microbacterium,andPseudomonas[87].
Thesefindingspromptedustofocusonwhethercannabis‐associatedbacterialandfungal
communitiescould(i)increasehempandmarijuanayield,(ii)controlplantpathogensinfectionof
cannabisplants,andpromotediseaseresistance,(iii)modulatetheproductionofcannabissecondary
metabolites.
5.Endophytes,AsCannabisMicrobialBiostimulants
Associated‐bacterialendophyteswithplantspeciescanpromoteplantgrowthinplantsvia
severalmechanisms:Nitrogenfixation,siderophoreproductiontochelateironandmakeitavailable
toplantroots,mineralsolubilizationmainlyphosphorusandcalcium,andproductionofseveral
phytohormonesincludingauxins,ABA,cytokinins,andGAs[75,79,89,90].Theproductionofsuch
bioactivemetabolitescanenhancehostplantgrowthandtolerateenvironmentalstresses.Thereare
limitedstudiesontheuseofgrowth‐promotingbacterialendophytesandtheireffectoncannabis
growthandyield.Pagnanietal.[91]evaluatedthesuitabilityofmultispeciesconsortiumconsisting
ofAzospirillumbrasilense,Gluconacetobacterdiazotrophicus,Herbaspirillumseropedicae,andBurkholderia
ambifariaisolatedfromrootsorstemsofcorn,sorghum,sugarcane,andbermudagrass[92]toenhance
hempbiomass.Thebacterialconsortiumfavouredplantgrowthdevelopmentandtheaccumulation
ofsecondarymetabolites(i.e.,CBDandTHC).Conantetal.[93]reportedonsignificantmarijuana
budyieldof16.5%andplantheightasaresultoftreatmentwiththemicrobialbiostimulant

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MammothPTM,amultispeciesconsortiumcomprisedoffourbacterialtaxaEnterobactercloacae,
Citrobacterfreundii,Pseudomonasputida,andComamonastestosteroni[94].Inthecaseoffungal
endophytes,rootinoculationofhempbyAMfungienhancedtoleranceofhemptoaccumulateCd,
Ni,andCr[95].
Mostoftheabovefindingsillustratetheuseofendophyticbacteriaisolatedfromplantspecies
otherthanhempormarijuanawiththeabilitytotriggersomephysiologicalplantresponses.Our
laboratory,alongwithotherresearchers,hasreportedonthediversityofendogenousfungaland
bacterialendophytesandtheabundanceoftaxonomicgroupsindifferenttissuesofhempand
marijuanawithgrowthpromotioncapabilities(Table1)andbiologicalcontrolpotential(Table2)[81–
84,87,96].SomeoftheseisolateswereabletotriggertheproductionofIAA‐likemoleculesintheplant,
reinforcingthenotionthatbeneficialendophytesmodulateplantdevelopmentandgrowththrough
theproductionofphytohormones.However,themechanismbehindthisisnotfullyclarified.
Performingexperimentswithendophytesasgrowthelicitorswouldfacilitatetheevaluationof
secondarymetabolitesprofiles,particularlyforTHC,cannabinoidscompounds,andterpenesof
cannabisplantsinoculatedwithendophytes.
Table1.Plantgrowthpromotingbacteriaandfungiassociatedwithcannabisandtheirmodeof
action.
OrganismActivityReferences
Bacillussp.Psolubilizing
J
oeetal.2016[97]
B.amyloliquefaciensGAsproductionShahzadetal.2016[98]
PantoeavagansMOSEL‐t13IAAproductionAfzaletal.2015[87]
PseudomonasfulvaBTC6‐3PsolubilizingandIAA Scottetal.2018[81]
P.geniculataMOSEL‐tnc1IAAproductionAfzaletal.2015[87]
SerratiamarcescensMOSEL‐w2IAAproductionAfzaletal.2015[87]
Bipolarissp.CS‐1IAAandGAsproductionLubnaetal.2019[96]
IAA:Indoleaceticacid;Gas:Gibberellins;P:Phosphate.
Duetopastlegalrestrictionsontheproductionofmarijuanaandhemp,growthpromotiontrials
applyingendogenousmicrobiomeisolatedfromhempandmarijuanaarefew.Itseemsreasonableto
hypothesizethatendogenousendophyticbacteriaandfungipossessthegeneticinformationto
triggerphenotypicdrasticgrowthpromotion,andpositivelyincreasecannabissecondary
metabolitesintheirrespectivehostsascomparedtoendophytesisolatedfromdifferentplantspecies.
WiththelegalizationofmarijuanainCanadaandothercountries,intensiveinvestigationsonhow
hormone‐likemoleculesproducedbyendophytesinfluenceplantadaptationandgrowthbecome
possible.
Table2.Cannabisendophyteswithantagonisticeffectsagainstpathogens.
OrganismTargetpathogenActivityReferences
Fungi 
PenicilliumcopticolaL3TrichotheciumroseumGrowthinhibitionKusarietal.2013[84]
PaecilomyceslilacinusA3
AlternariaalternataCN1
Aspergillusniger2
Botrytiscinerea
Fusariumsolani
Curvularialunata
Growthinhibition
Growthinhibition
Growthinhibition
Kusarietal.2013[84]
Qadrietal.2013[82]
Gautametal.2013[83]

Bacteria
PseudomonasfulvaBTC8‐1BotrytiscinereaCellulase,HCNSiderophoreScottetal.2018[81]
P.orientalisBTG8‐5BotrytiscinereaCellulase,IAA,
SiderophoreScottetal.2018[81]
Paenibacillussp.MOSEL‐w13
A
spergillusniger
FusariumoxysporumGrowthinhibitionAfzaletal.2015[87]


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6.CannabisEndophyteswithAntagonisticEffectAgainstPathogens
Therearelimitedbioprospectingstudiesonantagonisticactivityofmicrobialendophytes
associatedwithhempandmarijuanaagainstinvadingpathogensandcontaminatingmycotoxigenic
fungi[81,84,87].Thesestudiesusedthebioprospectingrationalethathempandmarijuanacontain
medicinalcompoundsthatmightalsoharbourcompetentmicrobialendophytescapableofproviding
healthbenefitstothehostplant.Thehemp‐associatedstrainsofPseudomonasfulva(BTC6‐3andBTC8‐
1)andPseudomonasorientalis(BTG8‐5andBT14‐4),exhibitedantifungalactivitiesagainstBotrytis
cinereaindualconfrontationassays[81].Thesestrainsaretopproducersofhydrogencyanide(HCN),
cellulose,siderophore,IAA,andcouldsolubilizeP[81].Additionally,Pseudomonasstrainsproduce
well‐characterizedsecondarymetabolitesasdiffusibleantibiotics,includingphenazinessuchas
phenazine‐1‐ carboxylicacid(PCA),2,4‐diacetylphloroglucinol(DAPG),pyocyanine,pyoluteorin,
pyrrolnitrin,phloroglucinols,lipopeptides,andthevolatilemetaboliteasHCN[99].Allthese
attributesmakePseudomonasstrainseffectivebiocontrolagents.Theendophyticbacterialstrains,
BacillusmegateriumB4,BrevibacillusborstelensisB8,Bacillussp.B11,andBacillussp.B3,employ
quorumquenchingasastrategytodisruptcell‐to‐cellquorumsensingsignalsinthetargetorganism
[88].Thisstrategyprovidesdefenceagainstplantpathogensandpreventsthepathogenfrom
developingresistanceagainstthebioactivesecondarycompoundsproducedbytheplantandorthe
endophytes.
Thecannabisendophytes,PaecilomyceslilacinusA3,Penicilliumsp.T6,andP.copticolaL3
successfullyinhibitedthegrowthofcannabispathogens,B.cinerea,andTrichotheciumroseum[84].The
endophyticstrainsofPaenibacillussp.andPantoeavaganssuccessfullyantagonizedthepathogen
Fusariumoxysporumindualconfrontationassays[87].Takentogether,thesestudies,althoughlimited
inscope,revealthepotencyofendophytesincannabisplants,andtheirapplicationsholdgreat
promisenotonlyasbiocontrolagentsagainsttheknownandemergingphytopathogensofcannabis
plantsbutalso,asasustainableresourceofbiologicallyactiveandnovelsecondarymetabolites.
Thesebioactivemetabolitesareanidealsubstituteforchemo‐pesticide notonlytosupportlow
pesticideresiduelevelsincannabisflowersbutalsoforadoptingthezero‐tolerancepolicyofpesticide
residuesincompliancewithgovernmentregulatorybodies[100].
7.EndophytesofMedicinalPlantsasSourcesofPlantsSecondaryMetabolites
Anexhaustivelistofsomeofthesameantimicrobialnaturalproductsbiosynthesizedby
endophytesastheirhostplantisdescribedintherecentreviewbyMartinez‐Klimovaetal.[101].The
pharmaceuticalmoleculessuchastheantitumordrugs,vinblastineandvincristine[102],the
anticancerdrugcamptothecin[103],theaneoplasticpaclitaxel[104],andtheinsecticideazadirachtin
[105]areamazingexamplesofthesignificanceandimportanceofpotentiallyvaluablesecondary
metabolitesproducedbyendophytes.
Thereiscompellingevidencethatboththeplantandtheirendophytescanproduceacollection
ofsecondarymetabolitesfromsimilarprecursors,possiblyasanadaptationofthehostenvironment
[106].Someexamplesincludepodophyllotoxin[107,108],camptothecin,andstructuralanalogs
[103,109].Someoftheseendophytescanbiochemicallyproducecompoundssimilaroridenticalto
thoseproducedbytheirhostplants.Itisproposedthatsuchamolecularbasismayattributeto
horizontalgenerecombinationortransferduringtheevolutionaryprocess.Forexample,theability
ofthetaxol‐producingfungusClasdosporiumcladosporioidesMD2associatedwiththehostplantTaxus
mediaisattributedtothegene10‐deacetylbaccatin‐III‐10‐O‐acetyltransferase.Thisgeneplaysarole
inthebiosyntheticpathwayoftaxolandbearsa99%resemblancetothehostplantgene[106].The
latterendophyticfungusbeingthesourceofthisimportantanticancerdrug.Thebiosynthesisofthe
insecticideazadirachtinAandBbythefungalendophyteEupenicilliumpurviumisolatedfromthe
Indianneemplantlendsanotherevidenceontheabilityofendophytestoproducesimilarhostplant
metabolites[105].Therecentprogressinthemolecularbiologyofsecondarycompoundsandthe
cloningofgenesofendophyticmetabolitesofferinsightintohowtheplantandendophytegenesof
encodingthesecondarymetabolitesareorganized.

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7.1.EndophytesModulateSecondaryMetabolitesofMedicinalPlants
Accumulatedevidenceestablishedthatendophytesarecapableofelicitingphysiologicalplant
responses,whichinturninfluencetheproductionofsecondarymetabolitesinthehostplant[110].
TheproductionofbioactivesecondarymetabolitesofRumexgmeliniseedlingsisenhancedthrough
coculturewithendophyticfungi[111].AnendophyticbacteriumPseudonocardiasp.induced
artemisinin(antimalarialdrugs)productioninArtemisiaplant[112].Inoculationofthemedicinal
plantPapaversomniferumL.withamultispeciesconsortiumincreasedthemorphineyieldby
enhancingtheexpressionofCOR,anessentialgeneformorphinebiosynthesis[113].Thealkaloid
drugHuperzineA(HupA)usedtotreatAlzheimer’sdiseaseisnotonlyderivedfromtheHuperzia
serrataplantbutalsoisproducedandbiosynthesizedbythefungalendophytePenicilliumsp.LDL4.4
isolatedfromH.serrata[114].InthelegumeCrotalaria(subfamilyFabaceae),thebiosynthesisof
pyrrolizidinealkaloids(antiherbivore,nematicide)dependsonthenodulationbyBradyrhizobiumsp.
[115].Inanotherexample,thebacterialandfungalendophytesassociatedwiththeAgarwoodtree
(Aquilariamalaccensis)enhancedtheproductionofagarospirol,ahighlysoughtafterproductinthe
pharmaceuticalandperfumeryindustry,withinthreemonthsofartificialinfection[116].Despite
currentresearchontheabilityofendophyticmicroorganismstoproduceplant‐associated
metabolites,theirpotentialisnotfullyexploredandisfarfromexhausted.Exploitingthiscomplex
plant‐microberelationshipcanonlyenhancethesustainedproductionofphytochemicalsbythe
associatedmicroorganisms.
7.2.PossibleModulationofCannabisSecondaryMetabolitebyEndophytes
Endophytesarewellknowntoproducebiologicallyactivesecondarymetabolitesthatmimicthe
effectofthehostplantmetabolitesorproduceprecursorsofhostplantcompoundstoactivatethe
signalingpathwayaimingtomodulatesecondaryplantmetabolites[117].Theyinducethe
productionofphytohormonessuchasABA,GA,andETthatmayprovideasignificantpotentialfor
improvingcannabissecondarymetabolites.Secondarymetabolites,includingTHC,CBN,andCBD,
arethemostprevalentofcannabinoidcompoundsandinherentlyareemployedincannabisstress
responses[118].Thepreciseroleofcannabinoidinplantdefenceisnotyetknown.Theplantgrowth
regulators,includingABA,cycocel,ethephon,GAs,salicylicacid,γ‐Aminobutyricacid(GABA),and
mevinolincanmanipulatecannabinoidbiosynthesisandmodulatingsecondarycannabismetabolites
[22,118–121].
Thepotentialforsecondarymetaboliterecoverycanbeimprovedbytheexogenousapplication
ofinducers.Forexample,theapplicationofplanthormoneGA3at100μMlevelincreasedtheamount
ofTHCandCBD[120].Theexactmechanismofhowtheadditionofexogenoushormonescanaffect
thecontentofTHCandCBDisnotyetunderstood.Oneplausiblehypothesisisthattheexogenous
applicationofGA3contributestotheregulationof1‐aminocyclopropane‐1‐carboxylicacid[92]
content,whichinturnelevatesETlevelsthatleadtohigherTHCandCBDcontents[120].Ethephon,
anotherplantgrowthregulator,increasedTHCcontentofmaleflowers,andCBDcontentoffemale
flowers[118].SuchanincreaseisattributedtoETlevelsthatmayfunctionasaswitchbetweengrowth
andsecondarymetabolitessynthesis.Accordingly,theexogenousapplicationoftwostresssignaling
molecules,salicylicacid(1mM)andGABA(0.1mM)improvedTHCcontentbutdeterioratedCBD
contentsimultaneously.Thiseffectsuggeststhatthesesignalingmoleculescouldaffectthe
cannabinoidbiosynthesispathwaythroughelicitationofexpressionofcriticalgenesleadingto
eventualchangesintheamountofthefinalproducts[22].
Theconcentrationofcannabinoidcompoundscanbeconceivablystimulatedthroughbiotic
elicitationbysymbioticandormutualisticrelationshipswithendophytes.Thisraisesthequestionof
whethertheproductionofidenticalmoleculestoplanthormonesbyendophytesintheplantwould
beusefulaswiththeexogenousapplicationofelicitors.Amixtureoffourbacterialendophytes
significantlyimprovedCBDandTHCcontents[91].EndophytecouldmanipulatethatACC
deaminaselevel,theprecursorofTHCbiosynthesisintheplant[59,67,122].Despitetheseadvances,
themechanismsunderlyingtheregulationofTHCsynthesishavenotbeencompletelyelucidated.

Microorganisms2020,8,35510of15
Itmightbeusefultodrawananalogybetweenthemedicinalplant‐endophyteassociationand
theengagementoftheendophytestoproducestructurallysimilarsecondarymetabolitesofmedicinal
cannabis.However,theexactroleofthenaturalproductsproducedbyendophytesinsidecannabis
fromtheperspectiveofhelpinginplantfitnessisnotpreciselyknown.Unfortunately,thispotential
hasnotyetachieved.
8.ChallengesandFutureDirections
Todate,basicinformationoncannabisendophytesdiversityandcompositionispublished.Most
publicationsarerestrictedtoisolationandidentificationofcannabisendophytes,buttheirbiological
effectsoncannabisgrowthpromotionandmodulatingofsecondarycompoundsareunrevealed.
Thus,itisimperativetounderstandthemicrobialpartnershipswithcannabisasithasthepotential
toaffectagriculturalpracticesbyimprovingplantfitnessandtheproductionyieldofcannabinoids.
Interestingly,theactivemetabolitesofmicrobialendophytespossessexcellentbiologicalactivities
thatnotonlyhavethepotentialtowagewaronplantbioticandabioticstress,butarealsousefulfor
humanhealthtopreventorcurefatalillness.Theaboveobservationshighlightthewealthof
untapped,andasofyetunknownfunctionaltraitsofendophytesharbouringcannabisthatneedto
bediscoveredandcharacterizetheirroleintheenrichmentofcannabissecondarymetabolites.The
importanceofendophyticmicroorganismsproducingcompoundssimilartotheirplantshasgained
momentum.Synthesizedplantcompoundsbymicrobialendophytesarestudiedtoproduce
secondarymetabolitesthatareoriginallyidentifiedintheirhostplants.Theycouldturnoutsome
importantmedicinalcompoundsindependently,whichenablethepharmacologicalindustryto
large‐scalefermentationofcannabinoids,independentofcannabiscultivation.Thisreview
emphasizesthegreatimportanceofmorestudiesoncannabisendophytesandtheirbiological
properties.Theexamplespresentedinthisreviewindicatethatthereisanurgentneedtounderstand
themolecularandbiochemicalmechanismsthatmightelicitsimilarresponsesinbothplantsand
theirassociatedendophytesthatleadtotheproductionofsimilarsecondarymetabolites.
AuthorContributions:Writethefirstdraft,M.T.;writemanysectionsandcorrectedseveraldrafts,S.J.All
authorshavereadandagreedtothepublishedversionofthemanuscript.
Funding:ThisresearchwasfundedbytheNaturalSciencesandEngineeringresearchCouncilofCanada,
throughaDiscoverygrant(RGPIN‐2016‐04805)toS.Jabaji,andalsobytheMITACSIT15824ELVProgram‐.
ConflictsofInterest:Theauthorsdeclarenoconflictofinterest.
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