Edible Plants and Their Influence on the Gut Microbiome and Acne

16 Pages·2017·1.38 MB·English

International Journal o f
Molecular Sciences
Review
Edible Plants and Their Influence on the Gut
Microbiome and Acne
AshleyK.Clark1,KellyN.Haas2andRajaK.Sivamani2,3,*
1 SchoolofMedicine,UniversityofCalifornia–Davis,Sacramento,CA95816,USA;[email protected]
2 DepartmentofDermatology,UniversityofCalifornia–Davis,Sacramento,CA95816,USA;
[email protected]
3 DepartmentofBiologicalSciences,CaliforniaStateUniversity,Sacramento,CA95819,USA
* Correspondence:[email protected]@ucdavis.edu;
Tel.:[phone];Fax:[phone]
AcademicEditor:Woo-SikJeong
Received:31March2017;Accepted:8May2017;Published:17May2017
Abstract: Acne vulgaris affects mostpeople at some point in their lives. Due to unclearetiology,
likelywithmultiplefactors,targetedandlow-risktreatmentshaveyettobedeveloped. Inthisreview,
weexplorethemultiplecausesofacneandhowplant-basedfoodsandsupplementscancontrolthese.
Theproposedcausativefactorsincludeinsulinresistance,sexhormoneimbalances,inflammationand
microbialdysbiosis. Thereisanemergingbodyofworkonthehumangutmicrobiomeandhowit
mediatesfeedbackbetweenthefoodsweeatandourbodies.Thegutmicrobiomeisalsoanimportant
mediatorofinflammationinthegutandsystemically. Alow-glycemicloaddiet,onerichinplant
fibersandlowinprocessedfoods,hasbeenlinkedtoanimprovementinacne,possiblythroughgut
changesorattenuationofinsulinlevels. Thoughthereismuchinterestinthehumanmicrobiome,
thereismuchmoreunknown,especiallyalongthegut-skinaxis. Collectively,theevidencesuggests
thatapproachessuchasplant-basedfoodsandsupplementsmaybeaviablealternativetothecurrent
firstlinestandardofcareformoderateacne,whichtypicallyincludesantibiotics. Thoughpatient
compliancewithmajordietarychangesislikelymuchlowerthanwithmedications,itisatreatment
avenuethatwarrantsfurtherstudyanddevelopment.
Keywords: acne;gastrointestinaltract;skin;microbiota;botanicals;polyphenols;probiotics;insulin
resistance
1. Introduction
Acneaffectsbetween40and50millionindividualsintheUnitedStates[1], includingmainly
adolescentsandadults. Factorsinfluencingacnedevelopmentincludeexcessivesebumproduction,
follicular hyperkeratinization of pilosebaceous ducts, and an increased release of inflammatory
mediators. Additionally,somehavehypothesizedthatandrogensandmicrobialcolonizationwith
Propionibacteriumacnescontributetothepathogenesisofacne[2,3]. TheroleofP.acnesisnotclear,
asthisbacteriumisubiquitous. However,certainstrainsofacnemaybemoreassociatedwithacne
andbepro-inflammatory[4–6]. RegardlessoftheongoingdebateregardingP.acnes,antibioticsused
inthetreatmentofacneappeartohaveanti-inflammatoryeffectsindependentoftheirantimicrobial
effects [7–9]. As a result, the first-line treatment of acne involves broad-spectrum oral and topical
antibiotics,whichrequireprotractedtreatmentsofaminimumof3–6months. Chronicantibioticsmay
havelong-termsideeffectsanddetrimentaleffectsonthehostmicrobiome,includingselectionfor
multidrugresistantbacteriaontheskinandinthegut[10]. Forexample,theuseofclindamycinhas
beenassociatedwithpseudomembranouscolitis[11],tetracyclinehasbeenshowntochangeskincolor,
anderythromycincanprecipitatehepaticdysfunction[12]. Othermedicationsusedforacnesuchas
Int.J.Mol.Sci.2017,18,1070;doi:10.3390/ijms18051070 www.mdpi.com/journal/ijms
Int.J.Mol.Sci.2017,18,1070 2of16
isotretinoin,whileeffective,requireclosemonitoringandhavemanysideeffects,includingariskof
teratogenicity[13].Therefore,thereisaneedforsafeandeffectivealternativestotreatacne.Plant-based
approacheshavebeenpracticedinmultiplemedicalperspectives,includingChinesemedicineand
Ayurveda. Ourunderstandingofmedicinalplantefficacyandtheirmechanismsisgrowingasdemand
for natural, holistic approaches and fears over the ramifications of chronic antibiotic use increase.
Here,wediscusstheimportanceofthegutmicrobiomeinacnepathogenesisandthepotentialfor
phytotherapeutictreatments(Table1).
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Table1.Summaryoforalplantextractsforacnetreatment.
Phytotherapeutic Mechanisms StudyType Comparison NumberofSubjects Outcomes Reference
Antibacterialand
Ayurvedicplantextracts: anti-inflammatoryactivity
Thestudyfoundthatthecombined
Aloebarbadensis, Azadirachtaindica=antipyretic
Invitro treatmentoftabletsandtopical
Azadirachtaindica,Curcuma andanthelmintic 53mildtomoderately
Double-blind, formulationoftheplantextracts
longa,Hemidesmusindicus, Curcumalonga(turmeric)and Placebo severeacnepatients Lallaetal.(2001)[14]
placebo-controlled showedbetterresultsthanthetablets
Terminaliachebula, Azadirachtaindica=anti-inflammatory 14–28yearsoldtested
clinicaltrialinIndia alone,buttheoralpreparationwas
Terminaliaarjunaand effectsbysuppressingPropionibacterium
moreefficaciousthanthetopicalalone
Withaniasomnifera acnes-inducedreactiveoxygenspecies
andpro-inflammatorycytokines
Relieveinsulinresistance
Antimicrobialagainstcommonskin Nodifferencebetweentheberberine Heetal.(2015)[15];
Randomized
microbes,likePropionibacteriumacnes, Herbalsupplement andminocyclinegroup;thissuggests Slobodníkováetal.(2004)[16];
controlledtrial 92patientswith
Berberine Staphylococcusspp.andMalasseziaspp. vs.controlgroup thatherbalsupplementationmaybe Huetal.(2016)[17];
Hepaticcellsinvitro acnevulgaris
Antiproliferativeeffectonkeratinocytes takingminocycline justaseffectiveasthestandard Mulleretal.(1995)[18];
Inhamsters
Decreaselipogenesisof antibioticswithoutthedrawbacks[15] Sekietal.(1993)[19]
sebaceousglands
Berryextract(mostdataon Polyphenolwithunknown Berryextractreducedglucoseuptake Kimetal.(2016)[20]
Invitro None None
strawberries) molecularmechanism byhumanintestinalepithelialcells Luetal.(2016)[21]
Improvedinsulinsensitivityand
Antibacterial,attenuationofdenovo Invitro attenuatedLPS-inducedinflammation Hayamizuetal.(2003)[22];
Garcinia(αmangostin) None None
lipidsynthesis Human Topicalapplicationimproved Pan-Inetal.(2015)[23]
acneseverity
Epigallocatechin-3-gallate(EGCG),
themajorpolyphenolingreentea,
haspotentanticarcinogenic,
Randomized, 1500mgof
anti-inflammatoryand 8025–45year-old Decreasedacnelesionsin
double-blind,placebo decaffeinatedgreen
Greenteaextract antimicrobialactivities; womenwith postpubescentfemaleswithatrending Luetal.(2016)[21]
controlled teaextractvs.placebo
EGCGcanmodulateseveralkey post-adolescentacne decreaseinfastingbloodsugar
clinicaltrial (cellulose)
pathologicalfactorsofacne,including
hyperseborrhea,lipogenesis,
inflammationandP.acnesovergrowth
Bothproducedaprogressivereduction
Potenthypolipidemicagent; inthelesions;withtetracycline,the
Antimicrobial,anthelmintic, Randomized Tetracycline500mg Twentypatientswith percentagereductioninthe Thappaetal.(1994)[24];
Gugulipid
anti-inflammatory,anti-arthriticand controlledtrial vs.gugulipid25mg nodulocysticacne inflammatorylesionswas65.2%as Goyaletal.(2011)[25]
antioxidantproperties comparedto68%withgugulipid
(p>0.05)
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Table1.Cont.
Phytotherapeutic Mechanisms StudyType Comparison NumberofSubjects Outcomes Reference
Treatmentwasassociatedwith
significantreduction(p<0.01)in
SunderVati lesioncountofapproximately60%;
(Holarrhenaantidysenterica, AnIndiandouble-blind therewasasignificantreductionin
Unknown Placebo 20 Paranjpeetal.(1995)[26]
Emblicaofficinalisand placebo-controlledtrial thetotalnumberofinflammatory
Zingiberofficinale) lesionswithin2weekswithfurther
reductionateachobservationperiod
duringthe6-weektreatment
Severalstudieshaveshowngrowth
inhibitionofthecommonskin
Liuetal(2013)[27];
Antimicrobial,anti-inflammatory bacteriaPropionibacteriumacnes,
Turmeric Invitro None None Munetal.(2013)[28];
andantidiabetic Staphylococcusepidermidisand
Heggeetal.(2012)[29]
Staphylococcusaureuswhencurcumin
isusedtopically
Bindstoestrogenreceptors
Commonlyusedintraditional
Actsonfollicle-stimulatinghormone
Chinesemedicineformenopausal Allahtavakolietal.(2015);
andluteinizinghormonelevelsinthe
Vitex Invitro None None symptoms,buttheirroleasestrogen Bedietal.(2002);
pituitarytoincrease
analoguesalsomakesthem Ahangarpouretal.(2016)
progesteronelevels
promisingforattenuationofacne
Increaseinestrogenlevel
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2. Methods
InJanuary2016,wesearchedOvidMEDLINEdatabasesforpublishedclinicalstudiesexamining
the use of oral plant-derived products for the treatment of acne vulgaris. Search terms such as
“phytotherapy,”“plantmedicinalproduct,”“herbalmedicine,”“herbaceousagent,”“polyphenols,”
“microbiota,”“gastrointestinaltract,”“insulin,”“diabetic”and“acnevulgaris”wereusedinthesearch
strategy. Studiesinvolvingplant-derivedcompoundsandacnevulgarisasanoutcomemeasurewere
included. Bibliographiesweresearchedforadditionalstudiesthatmettheinclusioncriteria.
3. GutMicrobiomeandtheSkin
3.1. AlteredGutFunctionImpactstheSkin
The bacteria in our intestines function akin to an organ. Our gut bacteria perform multiple
functions, including maintaining structural and functional integrity of the gut, immune system
regulation, food breakdown, providing nutritional benefits to the host (biotin and vitamin K),
andpreventingthegrowthofharmfulbacteria. Inthe1930s,StokesandPillsburyusedexperimental
evidenceandanecdotestoidentifyanassociationbetweenmicrobialfloraandinflammationofthe
skin[30]. Theyfoundasmanyas40%ofthosewithacnehadhypochlorhydriaandhypothesizedalack
ofacidwouldinduceamigrationofbacteriafromthecolontothesmallintestineanddisruptnormal
intestinalflora. Inrecentyears,hypochlorhydriahasbeenconfirmedtobeasignificantriskfactor
forsmallintestinalbacterialovergrowth(SIBO),whichcancauseincreasedintestinalpermeability
(or “leaky gut”), leading to systemic inflammation [31,32]. The excess bacteria can compete with
thehostfornutrients,producetoxicmetabolites,andcausedirectinjurytoenterocytesinthesmall
intestine[33]. Studiesasearlyas1916suggestedintestinalpermeabilitymightbeaugmentedinacne
vulgaris[34].Inonesuchstudyof57acnepatients,researchersusedabloodserumcomplementfixation
testtodemonstrateenhancedreactivitytostool-isolatedcoliformsin66%oftheacnepatientscompared
to none of the control patients [34]. Later in 1983, a study involving 80 acne patients showed the
presenceoflipopolysaccharide(LPS)endotoxinsfromEscherichiacoliintheserumofacnepatients[35].
Theseresultssuggestthatgutmicrobesmayenhancethepresenceofcirculatingendotoxinsintheblood
ofacnevulgarispatientscomparedtohealthycontrols. Althoughthemechanismsforhowthegutand
skincommunicatearepoorlyunderstood,acneappearstohaveapotentialgut-skinconnectionthat
maybeamanifestationofasystemicprobleminvolvingintestinalbacteriaandincreasedpermeability.
3.2. GutMicrobiomeDysbiosisandAcne
Thehumanintestineiscolonizedbyacomplexmicrobialecosystemthatishypothesizedtobe
involvedinthebioavailabilityoforally-administereddrugs,aswellasanumberofdiseasestates[36].
Theintestinalmicrobiotaisacomplexanddynamicbacterialcommunitythatplaysanimportantrole
inhumanhealth. Alterationsinmicrobiotacompositionandfunctionhavebeenrelatedtodifferent
intestinalandextra-intestinaldiseases[37]. Thefirstattemptstoexaminetheintestinalbacterialflora
inacnepatientswasconductedin1955byLovemanetal.[38]. Theauthorsconcludedtherewere
no major differences in a small subset of pathogenic bacteria. However, Bacteroides species were
morecommonlyisolatedfromtheacnepatients[38]. Onlyafewresearchershaveyetinvestigated
the intestinal microbiome in acne patients. Russian investigators who studied 114 patients with
acnevulgarisnotedthat54%ofacnepatientshavedifferencesintheirintestinalflora. Additionally,
theyfoundwhenacnepatientswithdysbiosisintheirintestinalflorareceivedprobiotics,therewas
areductioninthedurationoftreatment[39]. Thepotentialdysbiosisintheentericmicrobialprofileof
acnepatientsneedsfurtherinvestigationandremainsapotentialsourceforalternativetreatments.
Differences in the gut microflora are not unique to patients with acne vulgaris. Investigators
haveidentifiedlowercountsofBifidobacteriuminfecalspecimensfrompatientswithatopicdermatitis
comparedtohealthycontrols[40]. Furthermore,thecompositionanddiversityofthegutmicrobiota
inyoungchildrenwhodevelopatopicdermatitiswerefoundtobedifferentfromchildrenwhonever
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developthedisease[41]. Themechanismsbywhichthegutmicrobiomeexertsitseffectsandlinks
betweenthegutfloraandthepathogenesisofskindiseasearenotclearyetandremainanactivearea
inresearch.
4. ProbioticsImproveAcne
Numerous studies have reported beneficial interactions between the human body and its
microbiota. These relationships have suggested that modulation of the microbiota through
prebiotics and probiotics may prevent or resolve various diseases such as pediatric infectious
diseases[42],skindisease,gastrointestinaldisorders[43],andallergicdiseases[44]. Probioticsarelive
microorganismsthatcanalterguthomeostasisandimmunity[45]. Here,wediscusscurrentevidence
supportingprobioticsforthetreatmentofacnevulgaris.
BifidobacteriaandLactobacilliarelacticacid-producingbacterianormallyfoundinthegutthat
mayassistinthetreatmentofinflammatoryskindiseases,suchasacne[46]. Physicians,asearlyas
the1930s,usedorally-administeredLactobacillusacidophilusculturesasaprobiotictotreatacne[47].
Despitevariousanecdotalreports,therewaslittleresearchtodetermineefficacyatthetime. Thefirst
formalcasereportsdescribingtheuseandbenefitsofLactobacilliwerenotuntil1961[48]. Thestudy
gave probiotic tablets containing both L. acidophilus and Lactobacillus bulgaricus to 300 patients for
16 days with an interim two-week washout after the first eight days. The author reported 80% of
patientswithacnehadsomedegreeofclinicalimprovement,withthegreatestimprovementinthose
withsevereinflammatoryacne. Unfortunatelythestudydidnothavecontrols,andtheauthorssimply
concludedthatthereisaninteractionbetweentheskinmanifestationofacnevulgarisandmetabolic
processesintheintestinaltract[48].
In recent decades, only a few studies have investigated oral probiotics in the treatment of
acne vulgaris. One study tested an oral supplement composed of lyophilized L. acidophilus and
Bifidobacterium bifidum in 40 patients as an adjuvant to standard antibiotics in half of the group.
Theauthorsreportedpatientstreatedwithaprobiotichadimprovedclinicaloutcomesandreported
fewersideeffectsfromthestandardantibiotics[49]. Likewise,aRussianstudytestedtheeffectiveness
of probiotics as adjuvants to standard acne treatment and found that patients taking probiotics
experiencedimprovementssoonerintheiracnetreatmentcomparedtocontrols[39].
Whilethemechanismofprobioticsisnotwellunderstood,recentresearchhasshownthatthey
mayreduceoxidativestressandinflammation. Patientswithacnehaveahighlocalburdenoflipid
peroxidationplacingahighdemandonblood-derivedantioxidants[50]. Orally-consumedpre-and
pro-bioticshavebeenshowntoreducesystemicmarkersofinflammationandoxidativestress[51].
Additionally,oralprobioticshavebeenshowntoregulatethereleaseofinflammatorycytokinesin
theskinandreduceinterleukin-1α[46,52]. Lastly,probioticscanchangethemicrobialcommunity
at distant sites outside of the gastrointestinal tract [53]. Therefore, the ability of oral probiotics
toreducesystemicoxidativestress, regulatecytokines, andreduceinflammatorymarkersmayall
contributetoitseffectsonacne. Takentogether,thesestudiessuggestthatthegutmicrobiomemay
playanimportantroleinacnepathogenesisandthatwecanmodulateitforclinicalimprovements,
butfurtherinvestigationintothemechanismsandeffectsoforalprobioticsinacnevulgarisisneeded.
5. EdiblePlantsandAcne
The beneficial role of fruits and vegetables in health maintenance is well known, though the
mechanismshaveonlybeenelucidatedinrecentyears. Thegutmicrobiomeplaysanintegralrolein
almosteveryaspectofhumanhealththroughtransformationoffoodandthroughdirectsignaling.
Mostresearchondietaryeffectsdonotconsiderwhethertheeffectonthehostortheeffectonthe
host’smicrobiomeisprimarilyaffectingtheobservedresponse.
Oneofthefirstdietaryinterventionstudiesonacnevulgariswasperformedin2007bySmithetal.
andcomparedtheeffectofalow-glycemicloaddietonacneseverity[54]. Forty-threemalesaged
15–25 with moderate acne were fed a low-glycemic load diet for 12 weeks. The number of acne
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lesions,sexhormonelevels,andinsulinmarkerswerecomparedatbaselineandafterintervention.
ThepatientsbothlostweightandshowedimprovementofacnecomparedtoaconventionalWestern
(high-glycemicload) diet. Free androgen and fasting insulin levels were significantly lower in
patientsonthelow-glycemicloaddiet. Thepatientsdesignedtheirowndiets,basedonnutritional
counseling,whichinstructedtheexperimentalgrouptoconsumemoreproteinandlowerglycemic
indexcarbohydrates,suchaswholegrainsandfruits. Theevidencesuggeststhathigh-glycemicload
dietscancontributetoacnebyinducinghyperinsulinemia,whilelow-glycemicloaddietsmayprevent
hyperinsulinemiabyloweringpostprandialinsulin.
In2016,Çermanetal. againprobedtherelationshipbetweenglycemicloadandacne,collecting
self-reportedfoodlogsfrom86patients(50withacneand36without)oversevendays. Thestudy
includedmaleandfemalepatientswithmildtosevereacneandtrackedadiponectininadditionto
insulin/insulinresistancemarkers. Adiponectinisaproteininvolvedintheregulationofglucoseand
fattyacidbreakdown. Boththepresenceandtheseverityofacnepositivelycorrelatedwithglycemic
load,butnotwithinsulinorinsulinresistancemarkers. Adiponectinlevelswerelowerinacnepatients
thanincontrols,thoughnotsignificantlydifferentbyseverity. Theglycemicloaddisparitybetween
experimentalandcontrolgroupswaslessthanthatinSmith’sinterventionalstudy(16versus73),
whichmayexplainthedifferencesininsulinmarkersandreflectthenormaldietarydifferencesbetween
youngadultsinTurkeyandinAustralia. Alow-glycemicloaddietbalancescarbohydrateintakewith
dietary fiber, slowing digestion and the release of sugar into the bloodstream. The recommended
dailyallowance(RDA)ofdietaryfiberis25g,basedona2000kilocaloriediet. Dietaryfiberintake
from2001–2010was16.1g/dayforadultsoverage19[55]. Thisdeficientconsumptionofdietary
fiberreflectsthewholegrains,vegetablesandfruitsthataverageAmericansarelackingonadaily
basis. Thoughthemechanismbywhichthisdietimprovesacneisunknown,complexcarbohydrates,
like resistant starch, insoluble fiber, and fructooligosaccharides, have been correlated with greater
insulinsensitivityandlessinflammation[56–60]. Inadditiontoprebioticpolysaccharides,plant-based
foodsarealsosourcesofbioactivepolyphenols,whichwediscusslater.
5.1. Insulin
Insulin is a peptide hormone made by the pancreas that regulates carbohydrate metabolism
throughitsinfluenceonglucose.Evidencefrommultiplestudies,includingSmithetal.,suggestinsulin
andcarbohydratemetabolismmayhavearoleintheetiologyandseverityofacne[54]. Theoccurrence
ofacneaspartofvarioussyndromesassociatedwithinsulinresistancefurthersupportstheassociation
betweeninsulinandacne. Forexample,70%ofpolycysticovarysyndrome(PCOS)caseshaveacne
symptoms. PCOS is characterized by hyperandrogenism, anovulation, polycystic ovaries, insulin
resistance and hyperinsulinemia. Emiroglu et al. investigated the relationship between acne and
insulin resistance in males with acne. All 22 subjects with resistant acne had impaired metabolic
profilesanddecreasedinsulinsensitivity[61].
Themechanismlinkinghighinsulinlevelsandacnemaybethroughthealteredproliferationof
keratinocytesinthepilosebaceousunit.Hyperinsulinemiaincreasesserumlevelsofinsulin-likegrowth
factor-1andreducesserumlevelsofinsulin-likegrowthfactorbindingprotein-3[62]. Bothofthese
factorshavebeenshowntoincreasekeratinocyteproliferationandstimulatehormoneproduction,
whichmaycontributetothepathogenicfactorsofacne[61]. Thegutmicrobiotamayalsocontribute
toinsulinresistance. ADanishstudyof277non-diabeticindividualsfoundincreasedpopulations
of specific gut microbes (Prevotella copri and Bacteroides vulgatus) and an association with insulin
resistance[63]. Insulinresistanceandthegutmayrepresentanewtargetfortherapyinacnepatients.
There are many plant-based foods that can improve insulin sensitivity, thereby reducing
overproduction and stabilizing blood sugar. Many of the compounds responsible appear to be
polyphenols,thoughthemolecularmechanismofactionisgenerallynotunderstoodandmayvary
depending on the molecule. Invitro, berry extract exposure reduced glucose uptake by human
intestinalepithelialcells[20]. Foods/supplementsthatexertapositiveeffectoninsulinsensitivity
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include olive leaf, berries (with the most data on strawberries), grapes and red wine, cinnamon,
and green tea [20]. Green tea extract supplementation has been shown to decrease the number of
acnelesionsinpostpubescentfemaleswithatrendingdecreaseinfastingbloodsugar(p=0.10)and
asignificantdecreaseintotaltriglycerides[21]. Itisimportanttonotethattherearefewstudieson
mostofthesefoodsandtheireffectsonglucosemetabolism;therefore,resultsshouldbecautiously
accepteduntilmore,largerclinicaltrialsareperformed.
Plants from the family Berberidaceae are commonly used in traditional Chinese medicine for
avarietyofailments,includingthechronicskinconditionseczemaandpsoriasis[15]. Thisfamily
includesthegenusMahoniaandBerberis,whichproduceflowersandedibleberries. Amongmany
bioactivecompoundsintheseplants,berberineisoneofthemostwellstudied. Ithasbeenshown
to relieve insulin resistance in hepatic cells invitro and to be anti-inflammatory [17,64]. Berberine
andothercomponentsareantimicrobialagainstcommonskinmicrobes,likePropionibacteriumacnes,
Staphylococcusspp. andMalasseziaspp.[16]. Oneofthereasonsitmaybeeffectiveintreatingeczema
and psoriasis is an antiproliferative effect on keratinocytes, which may also attenuate acne lesion
development[18]. Additionally,inhamsters,berberineappearedtodecreaselipogenesisbysebaceous
glands, which may translate to human sebaceous glands [19]. Berberine showed strong activity
againstclinicalisolatesofPropionibacteriumacnesisolatedfromacnepatients. AChinesestudyusing
GongLaoQuHuoherbalsupplementscomprisedofMahoniafruitswasusedtotreat92patientswith
acnevulgaris. Ninetyeightpercentofthetreatmentgrouponberberineimprovedcomparedto91%of
thecontrolgrouptakingminocycline. Statisticalanalysissuggestedtherewasnodifferencebetween
the berberine and minocycline groups. This suggests that herbal supplementation may be just as
effectiveasthestandardantibioticswithoutthedrawbacks[15].
FruitsfromthegenusGarciniaarebestknownfortheirantibacterialandweightlosseffects.Weight
lossmaybeduetoleptin-likeactivityandtheresultantdecreasesininsulinandinsulinsensitivity,
inadditiontoappetitesuppression[22].Insucrose-loadedmicefedGarciniacambogiarindextract,there
wasasignificantdecreaseinseruminsulinlevels(3.52versus1.83ng/mL)comparedtocontrols[22].
Male rats consuming a high fat diet showed increased serum leptin levels and decreased glucose
intolerancewhenfedGarciniacambogiaethanolicextract[65]. αandγmangostinandphenolicethers
inGarciniamangostanaimprovedinsulinsensitivityandattenuatedlipopolysaccharide(LPS)-induced
inflammationinvitro[66,67]. Garciniamangostanaextractledtoanincreaseintheinsulin-producing
pancreatic β cells in normal and diabetic rats [67,68]. The loss of β cell number and function is
associated with type I and II diabetes, and increasing the population has been hypothesized as
acure[69]. Althoughtopicallyappliedαmangostinclinicallyimprovedacneseverityandinhibited
growthofbothStaphylococcusepidermidisandP.acnesinvitro[23,70,71],orally-administeredextracts
havenotbeentestedasanacnetreatment. ThevariousactivitiessuggestthatGarciniafruitsmaybe
worthstudyingfortheireffectsonacnewithoralsupplementation.
Aprebioticsupplementcontaininginulin,β-glucan,andblueberrypolyphenolsledtosignificantly
improved glucose tolerance in adult humans, though no statistically-significant difference was
observedininsulinsensitivity[72]. Indiet-inducedobeserats,acombinationprobioticcontaining
Bifidobacterium,Lactobacillus,LactococcusandPropionibacteriumstrainsimprovedinsulinsensitivityand
decreasedbodymass[73].
Turmeric,thegrounddriedrootoftheCurcumalongaplant(Zingiberaceaefamily),isknownforits
prominentroleincurriesandtraditionalmedicalsystemslikeChinesemedicineandAyurveda. Ithas
shownpromisingresultsasanantimicrobial,anti-inflammatory,andantidiabetic,allactivitiesthat
mayimproveacnevulgaris. Ithasbeensuggestedthatturmericcanhelppreventtheonsetofdiabetes
andstabilizebloodsugar[74–76]. Severalstudiesinmicehaveshownthatcurcuminsupplementation
resultsinreducedglucoseintolerance,hypoinsulinemia,andhyperglycemia[75]. Thegrowthofthe
commonskinbacteriaStaphylococcusepidermidisandStaphylococcusaureusisinhibitedbycurcumin,
whichalsoactssynergisticallywithseveralantibiotics[28,29]. Whencurcuminwasphotoactivated,
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itwasalsoabletoinhibitthegrowthofPropionibacteriumacnes,thoughunactivatedcurcumindidnot
inhibitgrowth[27].
5.2. SexHormones
Sexhormones,includingandrogensandprogestins,havebeenimplicatedinacnepathogenesis.
Progesterone, which peaks before menstruation and is elevated throughout gestation, has been
correlated with flares of acne, psoriasis, rosacea, herpes lesions, and both atopic and allergic
dermatitis [77]. However, progesterone also inhibits the enzyme 5α-reductase that transforms
testosterone into 5α-dihydrotestosterone (5αDHT), a hormone that has been shown to increase
proliferation of sebocytes in ex vivo sebaceous glands to a greater degree than testosterone [78].
Highlevelsof5αDHThavealsobeencorrelatedwithacnevulgaris[79]. Theeffectofsexhormoneson
acnepathologyislikelymorecomplexthanabsolutelevelsofparticularhormonesandcouldresult
fromanimbalancebetweenseveralorfromtheactivityof5α-reductase.
Femaletomaletranssexualpatientshaveinsomecasessufferedseverechronicacneafterbeginning
testosteronesupplementation[80]. Typicaltreatmentslikedoxycyclineandtopicalretinoidsdidnot
show an improvement, but oral isotretinoin led to clearance followed by a delayed recurrence of
severe acne in both patients [80]. Another study with a larger sample size (n = 70) showed that
acne presence and severity did increase over the first six months on testosterone, but that this
conditionwastemporaryandthatonly~6%ofpatientshadacneafterlong-termsupplementation[81].
One explanation for the development of acne in this population is an overall increase in sebum
production. Giltay and Gooren studied sebum production and hair growth in both female and
maletranssexualpatients,wheretestosteronesupplementationincreasedoverallsebumproduction
and estrogen supplementation decreased sebum production [82]. Several other studies show that
womenwithacnehaveelevatedlevelsoffreetestosteroneandtotaltestosterone,thoughthissame
relationship is not seen in men [83]. Estrogen can counter androgens through negative feedback
loops,suggestingthatincreasingdietaryphytoestrogensmaybeabettersolutionthanattemptingto
decreasetestosterone,whichcanhavenegativeeffectsonmalefertilitysincetestosteroneisnecessary
forspermatogenesis[84–86]. Estrogenseemstohaveabeneficialeffectonskin,decreasingsebaceous
glandsize,sebumproductionandacne[87,88].
Phytoestrogensarepresentinavarietyofedibleplantsandarefamouslyhighinsoyproducts
intheformofisoflavones[89,90]. PlantsfromthegenusVitexhavebeenusedtotreatpremenstrual
acne, menopause symptoms and polycystic ovary syndrome. There are several polyphenols in
Vitexagnus-castus(chasteberry)fruit,whichwereabletostronglybindtoestrogenreceptorsinhuman
breastcancercellsinvitroandarelikelyresponsiblefortheirclinicalresponses/usage[91]. Thewhole
fruit extract of Vitex agnus-castus is thought to act on follicle-stimulating hormone and luteinizing
hormonelevelsinthepituitarytoincreaseprogesteronelevels[92]. Vitexsupplementationappearsto
causeanincreaseinestrogenlevels,aswell[93,94]. Inovariectomizedmice,Vitexsupplementation
attenuatedlearningandmemorylossassociatedwithlowlevelsofestrogen,evencausinganincrease
inestrogenreceptormRNAs[95]. AlongwithVitexagnus-castus,hopsandredcloverwereshown
tobindtoestrogenreceptorsinhumanbreastcancercells. Ginsengandlicoricerootshowedsome
downstreamestrogenicactivity,thoughtheydidnotbindtoestrogenreceptors[91]. Theseplantshave
beencommonlyusedintraditionalChinesemedicineformenopausalsymptoms,buttheirroleas
estrogenanaloguesalsomakethempromisingforattenuationofacne.
5.3. Antimicrobial
Itisacceptedthatacnehassomemicrobialetiology,thoughtheexactpathologyisnotknown.
Typical treatments, like benzoyl peroxide and antibiotics, target this component of the condition.
However, there are several plant-based antimicrobials that could be viable alternatives, especially
incombinationwithother dietarychangesthataddress insulinresistanceandhyperandrogenism.
A randomized, double-blind, placebo-controlled clinical trial in India with fifty-three patients
Int.J.Mol.Sci.2017,18,1070 10of16
between 14 and 28 years old tested Ayurvedic plant extracts for safety and efficacy. Study
subjects had mild to moderately severe acne exhibiting a minimum of 10 inflammatory lesions
(papulesandpustules) and five non-inflammatory lesions (blackheads). Plant extract tablets
containing a mixture of Aloe barbadensis, Azadirachta indica, Curcuma longa, Hemidesmus indicus,
Terminalia chebula, Terminalia arjuna and Withania somnifera were formulated. The study found the
combinedtreatmentoftabletsandtopicalformulationoftheplantextractsshowedbetterresultsthan
thetabletsalone,buttheoralpreparationwasmoreefficaciousthanthetopicalalone[14].
TheAyurvedicformulationwasalsoevaluatedforinvitroantibacterialandanti-inflammatory
activity. Azadirachtaindica(alsoknownasneem)containsmanyessentialoilsthathaveantipyretic
and anthelmintic properties [96]. Additionally, it was shown to help control biliary secretion.
SomeIndianfoodsincludingCurcumalonga(turmeric)andAzadirachtaindicahavebeenshowntohave
anti-inflammatoryeffectsbysuppressingPropionibacteriumacnes-inducedreactiveoxygenspeciesand
pro-inflammatorycytokines[26]. Thisdirectanti-inflammatorypropertyisconsideredtobethebasis
fortheclinicaleffectoftheseplantsintreatingacne. SunderVatiisanAyurvedicherbalformulation
containingvariousherbssuchasHolarrhenaantidysenterica,Emblicaofficinalis,andZingiberofficinale.
Adouble-blindplacebo-controlledtrialoforalSunderVatisuggestedthattheformulationisefficacious
forthetreatmentofacne. SubjectstreatedwithoralSunderVatihada60%reductionintheirlesion
count(p<0.01)[26].
GugulipidismadefromthesapoftheCommiphoramukultree,whichisnativetoIndia. Gugulipid
has been traditionally used alone or combined with other herbs for the treatment of a variety of
ailments, includingrheumatism,arthritis, skindiseases, andobesity. Arandomizedstudytreated
twentypatientswithnodulocysticacnewitheithertetracycline500mgorgugulipid25mgforthree
months. The results of the study demonstrated that both groups had a reduction in acne lesions
(65.2%tetracyclinevs. 68%gugulipid) (p > 0.05). Interestingly, patients with oily faces responded
remarkablybettertogugulipid[24].Thisstudysuggeststhatgugulipidextractmayreplacetetracycline
inthetreatmentofacnegivenitsequivalentefficacy,improvedsafetyprofileandlackofantibiotic
resistance. Gugulipidisapotenthypolipidemicagent. Apartfromitshypolipidemicactivity,alarge
number of therapeutic activities like antimicrobial, anthelmintic, anti-inflammatory, anti-arthritic,
andantioxidanthavebeenreported[25].
6. Conclusions
Acne is a multifactorial condition, but one that has been treated successfully through dietary
interventions. Whethertheseplant-basedfoodsprimarilyaffectthemicrobiomeorthehumandirectly
isunclear. Itisimportanttonotethatmanyoftheseplant-basedfoodsandspicesmayaffectmorethan
onefactorinacnepathogenesis(e.g.,insulinresistance,microbiomemodulation,sexhormonebalance),
sowithouttargetedevaluations,itisdifficulttosaywhichmechanismwasmostclinicallyrelevant
(Figure1). Inadditiontotheparticulareffectsofspecificplantfoods,adiethighinplantmatterand
lowinsimplecarbohydratesshouldcauseasignificantimprovementofacnevulgaristhroughavariety
of mechanisms. Some have suggested that acne is a visible manifestation of a systemic problem,
forexampleinsulinresistance,inflammation,gutdysbiosis,andpoornutrition. Plant-basedfoods
andsupplements,especiallythoserichinfiberandpolyphenols,couldprovideanatural,low-risk
interventionforacnevulgaris.