Probiotics as a Possible Strategy for the Prevention and Treatment of Allergies. A Narrative Review

oods Re iew P obio ics as a Possible S a egy o he P e en ion and T ea men o Alle gies. A Na a i e Re iew A oa Lopez-San ama ina, Es he Gonzalez Gonzalez, Alexand e Lamas , Alicia del Ca men Mond agon, Pa icia Regal and Jose Manuel Mi anda *   Ci a ion: Lopez-San ama ina, A.; Gonzalez, E.G.; Lamas, A.; Mond agon, A.d.C.; Regal, P.; Mi anda, J.M. P obio ics as a Possible S a egy o he P e en ion and T ea men o Alle gies. A Na a i e Re iew. Foods 2021,10, 701. h ps:// doi.o g/10.3390/ oods10040701 Academic Edi o : An onello San ini Recei ed: 17 Feb ua y 2021 Accep ed: 23 Ma ch 2021 Published: 25 Ma ch 2021 Publishe ’s No e: MDPI s ays neu al wi h ega d o ju isdic ional claims in published maps and ins i u ional a il- ia ions. Copy igh : © 2021 by he au ho s. Licensee MDPI, Basel, Swi ze land. This a icle is an open access a icle dis ibu ed unde he e ms and condi ions o he C ea i e Commons A ibu ion (CC BY) license (h ps:// c ea i ecommons.o g/licenses/by/ 4.0/). Labo a o io de Higiene Inspección y Con ol de Alimen os, Depa amen o de Química Analí ica, Nu ición y B oma ología, Uni e sidad de San iago de Compos ela, 27002 Lugo, Spain; [email p o ec ed] (A.L.-S.); es he [email p o ec ed] (E.G.G.); [email p o ec ed] (A.L.); [email p o ec ed] (A.d.C.M.); pa icia. [email p o ec ed] (P.R.) *Co espondence: [email p o ec ed] Abs ac : Alle gies a e an inc easing global public heal h conce n, especially o child en and people li ing in u ban en i onmen s. Alle gies impai he quali y o li e o hose who su e om hem, and o his eason, al e na i es o he ea men o alle gic diseases o educ ion in hei symp oms a e being sough . The main objec i e o his s udy was o compile he s udies ca ied ou on p obio ics as a possible he apy o alle gies. The mos s udied alle gies on which p obio ics ha e been shown o ha e a bene icial e ec a e hini is, as hma, and a opic de ma i is. Mos s udies ha e s udied he adminis a ion o Lac obacillus and Bi idobac e ium spp. in child en and ha e shown bene icial e ec s, such as a educ ion in hype eac i i y and in lamma ion caused by alle gens and a dec ease in cy okine elease, among o he bene icial e ec s. In he case o child en, no clea bene icial e ec s we e ound in se e al s udies, and he po en ial isk om he use o some oppo unis ic bac e ia, such as p obio ics, seems con o e sial. In he s udies ha epo ed bene icial esul s, hese e ec s we e ound o make alle gy symp oms less agg essi e, hus educing mo bidi y in alle gy su e e s. The di e en e ec s o he same p obio ic bac e ia on di e en pa ien s seem o ein o ce he idea ha he e icacy o p obio ics is dependen on he mic obial species o s ain, i s de i ed me aboli es and byp oduc s, and he gu mic obio a eubiosis o he pa ien . This s udy is ele an in he con ex o alle gic diseases, as i p o ides a b oade unde s anding o new al e na i es o he ea men o alle gies, bo h in child en, who a e he main su e e s, and adul s, showing ha p obio ics, in some cases, educe he symp oms and se e i y o such diseases. Keywo ds: alle gic disease; p obio ic; a opic de ma i is; hini is; gu mic obio a 1. In oduc ion An alle gy is de ined as a hype sensi i i y eac ion caused by an immunological esponse o a speci ic an igen, known as an alle gen. Alle gens ac on inna e immune cells. Repea ed con ac wi h an alle gen igge s he ac i a ion o mas cells and basophils and he elease o alle gic media o s, esul ing in symp oms anging om sneezing and i chy ashes o se e e sho ness o b ea h and anaphylaxis [ 1 – 3 ]. Cu en ly, he lis o alle gic diseases published by he WHO includes as hma, hini is, conjunc i i is, hinosinusi is, anaphylaxis, a opic eczema, hi es, and angioedema, as well as seconda y eac ions caused by d ugs, oods, o insec s [4]. Today, app oxima ely 1 billion people wo ldwide su e om alle gies, and hese numbe s a e es ima ed o inc ease o 4 billion in he nex 30–40 yea s [ 1 ]. In ecen yea s, he p e alence o alle gic diseases has inc eased g ea ly, o he poin ha 30–40% o he wo ld’s popula ion now su e s om one o mo e alle gic diseases. I is impo an o no e ha hese diseases a ec all age g oups, bu hey a e mo e equen ly epo ed in childhood [5]. Foods 2021,10, 701. h ps://doi.o g/10.3390/ oods10040701 h ps://www.mdpi.com/jou nal/ oods Foods 2021,10, 701 2 o 19 While no de e minan isk ac o s ha e been iden i ied, i is possible ha en i on- men al ac o s, such as ciga e e smoking, ai pollu ion, and exposu e o alle gens explain he obse ed changes in he p e alence o alle gic diseases [ 6 ]. A common explana ion o he inc eased p e alence o alle gic diseases is he “hygiene hypo hesis”, i s p oposed in 1989 by S achan [ 7 ], in which i is s a ed ha a lack o exposu e in childhood o in ec ious agen s, symbio ic mic oo ganisms, and pa asi es inc eases he child’s suscep ibili y o hese diseases la e in li e [ 6 ]. Dec eased mic obial exposu e due o imp o ed hygiene, changes in die , o inc eased use o an ibio ics may be de e minan s o an inc eased p e alence o alle gies [7–9]. Addi ionally, he e is a lo o e idence sugges ing ha li ing in u al a eas in childhood has a p o ec i e e ec agains alle gic disease, such as a opy, alle gic hini is, and as hma [ 10 , 11 ]. This may be ela ed o en i onmen -de i ed ac o s, such as con ac wi h bac e ial endo oxins [ 12 ], con ac wi h animals [ 13 ], o in ake o aw o ligh ly p o- cessed milk [ 13 , 14 ]. In ecen decades, he mig a ion om adi ional a ming o he u ban en i onmen , inc ease in p ocessed ood in ake, lack o con ac wi h animals, and excessi e hygiene has been ela ed o he inc ease in he incidence o alle gic diseases [15,16]. Due o he inc ease in alle gies, hei p e en ion and ea men ha e become a global public heal h p io i y. Fo his eason, new al e na i es a e being sough , one o which could be he use o p obio ics o p e en hese diseases and educe hei symp oms [ 5 ]. “P obio ic” means “ o li e”, and p obio ics a e de ined as “Li e mic oo ganisms ha , when being adminis e ed in app op ia e doses, con e a bene i o he heal h o he hos ” [ 5 ]. The use o p obio ics o ea o p e en speci ic diseases is a b anch o mic obiology known as “ he apeu ic mic obiology” [ 17 – 20 ]. P obio ics exe mul iple heal h e ec s, such as immunomodula o y agen s and ac i a o s o hos de ense pa hways, which educe mo bidi y [ 21 ]. In he con ex o alle gic disease, he p obio ics’ mic obiome is essen ial o he de elopmen o hos immune esponses. E ec i e p obio ics mus be esis an o bile sal s, gas ic enzymes, and a low pH, and hey canno cause mucosal in lamma ion o in ec ion [22]. The popula ion o mic oo ganisms ha inhabi s a de e mined ecological niche o heal hy indi iduals is e med he in es inal mic obio a. I s coloniza ion begins be o e bi h and ma u es slowly, un il i eaches he adul s a e a a ound 3 yea s o age. The human gu mic obio a es ablishes a symbio ic ela ionship wi h he hos and plays a e y impo an ole in human heal h, because dysbiosis in he gu mic obio a o en occu s in he p esence o disease [ 17 , 20 ]. The in es inal mic obio a cons i u e a key ac o in he de elopmen o an adequa e immune esponse, because he con ac be ween gu bac e ial an igens and he pa o he immune sys em associa ed wi h he in es ine ep esen s an impo an componen o he human immune sys em [ 17 ]. The mic obio a play a undamen al ole in he de elopmen o he human immune sys em, especially in he i s yea s o li e. I s main ole is o in e ene in he homeos asis and immuni y o he in es ine [17]. The main objec i e o his s udy is o p o ide a li e a u e e iew o he e ec s o he ad- minis a ion o p obio ics in he p e en ion and ea men o alle gic diseases. This s udy is ele an , because i b oadens he knowledge o new al e na i es o he ea men o hese diseases in bo h child en and adul s, educ ion in he symp oms associa ed wi h alle gies, and p e en ion o he occu ence o alle gen-caused acu e ad e se episodes. 2. Me hodology A na a i e li e a u e sea ch was conduc ed up o 10 Feb ua y 2021 o all he a ailable li e a u e in he ollowing da abases: Web o Science, PubMed, and Scopus. A combina ion o he ollowing sea ch e ms was applied: “p obio ics” and “alle gic diseases”; “gu mic o- bio a” and “alle gic diseases”. The sea ch e ms we e adjus ed o he speci ic da abases and consis ed o a combina ion o ee- ex sea ches. The selec ion o a icles will be limi ed o s udies published in English and Spanish, wi h no es ic ions on he yea o publica ion, al hough he mos p ominen a icles a e hose published a e 2015. A o al o 115 a icles we e selec ed and included in he e iew. The ollowing da a on he s udy cha ac e is ics we e ex ac ed om he included eco ds: au ho and yea o publica ion, ype o s udy, Foods 2021,10, 701 3 o 19 p obio ics used, dosage and ime o adminis a ion, ype o alle gy, and he conclusions o each s udy. The au ho s e iewed he i les and he abs ac s. I he abs ac s epo ed he use o dia ies ha con ained na a i e elemen s, ull ex s we e ead, and i he p e- es ablished eligibili y c i e ia we e me , hey we e included in he e iew. A na a i e app oach con aining summa y ables and g aphs will acili a e he syn hesis o he included s udies. 3. Resul s and Discussion 3.1. Cha ac e is ics o Alle gic Diseases and Mos Common Alle gic Diseases In alle gic diseases, he e is a dis u bance in he balance be ween T helpe (Th)1 and Th2 lymphocy es in a o o Th2 lymphocy es. Th1 lymphocy es a e key o in ec- ion, ac i a ing mac ophages o de end he body p ima ily agains in acellula mic obes. Th2 lymphocy es, on he o he hand, ac i a e eosinophils and mas cells and induce he p o- duc ion o IgE, which is esponsible o alle gies. These alle gies a e caused by he esponse o an inapp op ia e immune esponse o Th2 lymphocy es o di e en an igens, including en i onmen al o ood an igens. The ac i a ion o his esponse leads o he sec e ion o in e leukins (IL)-4, IL-5, and IL-13 and an alle gen-speci ic IgE p oduc ion, which d i es alle gic in lamma ion [ 1 , 10 ]. In e e on (INF)- γ inhibi s Th1 ac i i y by inducing hese cy okine esponses, hus main aining an alle gic pheno ype [23]. The p e alence o alle gic diseases has doubled in he indus ialized pa s o he wo ld in he las 25 yea s [ 6 ]. These diseases mainly a ec child en and young people, bu as hey age, he se e i y and complexi y o hese diseases inc ease, esul ing in an ad e se impac on hei quali y li e and high cos s o he heal h ca e sys em [ 10 , 24 ]. In gene al e ms, ap- p oxima ely 200–250 million people su e om ood alle gies, one- en h o he popula ion su e s om d ug alle gies, and 400 million su e om hini is [ 24 ]. Wo ldwide, 300 mil- lion people su e om as hma, and his incidence is expec ed o inc ease by 100 million in 2025 [ 25 ]. Food alle gies a e ecognized as he mos common immune diso de s [ 26 ], and hey a e conside ed a wo ld heal h isk, pa icula ly in de eloped coun ies [ 27 ]. The majo isk ac o s o he de elopmen o ood alle gies a e ela ed o gene ics, he en- i onmen , and immune ole ance ailu e. Addi ionally, gu mic obio a composi ion and ac i i y ha e an impo an ole in immunological de elopmen , and hus, gu mic obio a eubiosis is ecognized a key ac o in p e en ing ood alle gies [26,28]. One a iable on which hese alle gic diseases depend is sex. Due o hei cha ac e is ics and speci ic pa e ns in women, women a e mo e suscep ible han men o alle gies due o he o a ian ho mones and hype eac i i y o he ai ways, which may occu du ing he mens ual cycle o p egnancy [ 29 , 30 ]. P e ious s udies showed ha a signi ican pe cen age o women wi h as hma su e wo se symp oms du ing he pe imens ual phase [31,32]. Alle gic hini is (AR) is o emos among he mos common alle gic diseases. I a - ec s be ween 10% and 20% o he o al popula ion and is he e o e he mos p e alen ch onic non-communicable disease in he wo ld [ 33 ]. Howe e , he p e alence o his disease is p obably unde es ima ed because many pa ien s do no ecognize hini is as a disease and he e o e do no seek medical ad ice [ 34 ]. The mos impo an alle gens ha igge AR a e pollens. AR esul s om immunoglobulin (IgE)-media ed in lamma ion o he nasal mucosa, which is cha ac e ized by p u i us, sneezing, hino hea, and nasal conges ion. In addi ion, AR is a po en ial isk ac o o as hma [ 24 ], ano he common alle gic disease and ch onic in lamma o y diso de o he ai ways, which cu en ly a ec s some 300 million people wo ldwide [24,35]. As hma is a he e ogeneous disease, in which in lamma ion o he ai ways occu s and espi a o y symp oms, such as wheezing, ches igh ness, and coughing, along wi h sho ness o b ea h, which a ies in du a ion and in ensi y [36]. U ica ia is a diso de wi h a ious unde lying causes. I is es ima ed ha app oxi- ma ely 25% o people expe ience a leas one episode o u ica ia in hei li e ime, bu only 3% will de elop ch onic u ica ia [ 37 ]. I is cha ac e ized by he appea ance o hi es, las ing Foods 2021,10, 701 4 o 19 be ween 1 and 24 h, and/o angioedema, which can las up o 72 h [ 24 ]. The ac i a ion o mas cells loca ed supe icially in he skin leads o u ica ia, while mas cells in he de mis a e in ol ed in angioedema. His amine is he main media o in u ica ia and in many cases o angioedema [24,38]. The mos common ch onic in lamma o y skin disease is a opic de ma i is (AD). The in- cidence o AD has inc eased 2- o 3- old in ecen yea s in indus ialized coun ies [39,40]. In he las 30 yea s, he p e alence o his disease has inc eased o 10–20% in child en and 1–3% in adul s. This ch onic in lamma o y skin disease is also known as a opic eczema, is e y p u i ic, and is cha ac e ized by e y hema and oedema. In addi ion, AD usually occu s du ing in ancy and childhood [ 41 ]. AD may ha e a mixed IgE-media ed and non-IgE-media ed mechanism [ 10 ]. A opy mani es s as alle gic hini is, b onchial as hma, a opic de ma i is, o e en ood alle gies and is de ined as he de elopmen o an immedia e hype sensi i i y eac ion o en i onmen al and ood an igens due o a ge- ne ic p edisposi ion [ 24 , 35 ]. A a ian o AD is alle gic con ac de ma i is (ACD), which mani es s due o a delayed hype sensi i i y eac ion and is media ed by T-cells in he skin. In his case, he alle gens, which a e called “hap ens”, a e o a low molecula weigh and bind o p o eins in he skin, whe e hey become an igenic [42]. Food-o igin alle gies ha e a high mo bidi y, which a ec s he su e e ’s quali y o li e; in ol e high cos s; and, in he case o anaphylaxis, can lead o dea h. Wo ldwide, 220– 250 million people may su e om ood-o igin alle gies [ 43 ]. The oods mos equen ly implica ed in pedia ic pa ien s a e cow’s milk and eggs. Mo eo e , milk o egg sensi iza- ion in child en is associa ed wi h an inc eased isk o de eloping dus mi e alle gy and e en as hma. In many cases, ood alle gies a e media ed by IgE [ 10 ]. In adul hood, he mos common oods implica ed in alle gies a e legumes, nu s, ui s, and c us aceans [43]. Anaphylaxis is he mos se ious alle gic disease and can be a al. The onse can be wi hin minu es o e en hou s and usually a ec s di e en body sys ems. The ig- ge s o anaphylaxis a y wi h age and geog aphy, and he p e alence is a leas 1% [ 44 ]. Anaphylaxis is usually IgE-media ed and can be due o ood, insec enom, d ugs, o la ex [10]. 3.2. The Immune Sys em and P obio ics The human in es inal mic obio a cons i u es a complex ecosys em ha includes, in ad- di ion o bac e ia, ungi, A chaea, i uses, and p o ozoa. The concen a ion o bac e ia inc eases om he s omach he duodenum, bu i is in he la ge in es ine whe e i ises up o 10 11 –10 12 UCF/g [ 45 ]. I has been es ima ed ha he e a e a leas 1800 gene a and be ween 15,000 and 36,000 species o bac e ia in he la ge in es ine [ 17 ]. Fi micu es and Bac e oide es a e he main bac e ial phyla, ollowed by Ac inobac e ia, P o eobac e ia, and Ve ucomic obia. In addi ion, ungi and p o ozoa make up app oxima ely 1% o he species in ou gu mic obio a [45,46]. “P obio ic” means “ o li e”, and p obio ics a e cu en ly used o e e o bac e ia ha ha e bene icial e ec s on human and animal heal h [ 17 ]. In 2001, he Food and Ag icul u e O ganiza ion o he Uni ed Na ions (FAO)/Wo ld Heal h O ganiza ion (WHO) de ined hem as “li e mic oo ganisms which, when adminis e ed in adequa e amoun s, con e a heal h bene i on he hos ” [ 47 ]. This de ini ion was co ec ed in 2014 by he In e na ional Scien i ic Associa ion o P obio ics and P ebio ics, and i now eads “mic oo ganisms o which he e is scien i ic e idence o sa e y and e icacy” and excludes “li e cul u es associa ed wi h e men ed oods o which he e is no e idence o a heal h bene i ” [48]. P obio ics con ibu e a ious bene icial e ec s on human heal h and a e used o ea di e en in ec ious and non-in ec ious diseases. Va ious e ec s ha e been seen in he o m o p o ec ion agains in ec ions, dec eases in i i able bowel symp oms, he inhibi ion o Helicobac e pylo i g ow h and i al in ec ions [ 49 ], he p e en ion o cance , dec eases in gu in lamma o y esponse, and he p e en ion and/o ea men o alle gies, which is he ocus o his e iew [5]. Foods 2021,10, 701 5 o 19 I is belie ed ha he adminis a ion o bene icial mic oo ganisms may be he key o imp o ing heal h and suscep ibili y o disease, as human o ganisms and he gu mic obio a es ablish a symbio ic ela ionship impo an o he main enance o human heal h [ 17 ]. I is likely ha hese mic obio a o ganisms ha e e ol ed along wi h ou immune sys em, hus p omo ing immune ole ance. This includes he induc ion o egula o y T cells (T eg) and he con ol o Th2 and Th1 balance, which may p e en he de elopmen o alle gic and au oimmune diseases [1]. P obio ics can s imula e he immune sys em compounds sec e ed o p esen in he cel- lula ba ie . The e o e, p obio ic use imp o es he body’s de enses by igge ing an im- mune esponse, acco ding o he pa hological s a e, and p omo ing a balance be ween p o- and an i-in lamma o y cy okines ha a e sec e ed by ac i a ed immune cells. P obio ics hence ac as a non-speci ic adju an o he inna e immune esponse [ 50 ]. The e is e idence ha p obio ics p omo e he p oduc ion o some cy okines, including IL-10, ans o ming g ow h ac o (TGF)- β , IL-12, and INF- γ , which egula e he immune esponse and educe alle gic in lamma ion [10]. Many s udies ha e shown ha he gu mic obio a and p obio ic in ake can suppo ma u a ion o he immune sys em du ing he i s yea s o li e due o di e en physiological and me abolic eac ions in he hos . The mos p omising p obio ics in e ms o immune sys em de elopmen a e hose belonging o he gene a Lac obacillus and Bi idobac e ium [ 6 ]. The e ec s o p obio ics a e dose- and s ain-dependen [ 51 , 52 ] and may be in luenced by age-speci ic unc ions, such as he ma u i y o he hos ’s in es inal ba ie . I was sugges ed ha he pe ina al pe iod may ep esen a window o oppo uni y o e ec i e p obio ic in e en ion in alle gic diseases [ 53 ]. In he i s s age o li e, he mic obio a is s ill de eloping, so he adminis a ion o p obio ics leads o a p ope mic obial coloniza ion and esul s in a g ea e e ec i eness in he p e en ion and ea men o di e en diseases [ 17 ]. The immune e ec s o p obio ics, which a e p ima ily media ed h ough he inna e immune sys em, include he p omo ion o epi helial in eg i y, in es inal pe meabili y, and mucus p oduc ion h ough he p oduc ion o an i-in lamma o y cy okines and ole ogenic CD103+ dend i ic cells, in addi ion o he p omo ion o he di e en ia ion and p oli e a ion o egula o y T cells, he inhibi ion o he Th2 cell esponse, and an inc eased elease o IgA om plasma cells [ 54 , 55 ]. The he apeu ic po en ial o p obio ics in alle gic diseases is media ed by a ious mechanisms o ac ion, such as he modula ion o he immune esponse, compe i i e inhibi ion o in asi e lo a in he gu , modi ica ion o pa hogenic oxins and hos p oduc s, and an inc eased epi helial ba ie unc ion [41]. Lac obacillus educes p oin lamma o y esponses by egula ing nuclea ac o kappa B (NF- κ B) signaling. P obio ics also p omo e he ma u a ion o dend i ic cells (DCs) in o an i-in lamma o y cy okines, such as IL-10. In addi ion, human monocy e-de i ed DCs can elease IL-10 when ea ed wi h p obio ics, hus igge ing he di e en ia ion and su i al o T egs [ 23 ]. Bi idobac e ium animalis and Bi idobac e ium longum induce he elease o in e e on gamma (IFN- γ ) and umo nec osis ac o alpha (TNF- α ) by DCs, while only Bi idobac e ium bi idum can ac i a e Th17 cells h ough he elease o IL-17. Di e en s udies ha e indica ed ha p obio ics can modula e he Th1/Th2 balance and, consequen ly, p e en in lamma o y diseases, such as alle gies [23]. 3.3. Use o P obio ics in Alle gic Diseases The inc eased p e alence o alle gies, such as eczema, may be due o al e a ions in he gu mic obio a in ea ly li e, such as a educed abundance o he P o eobac e ia phy- lum and he gene al Bi idobac e ium,Akke mansia,Faecalibac e ium, and Lachnospi a [ 52 , 56 ]. Fo example, an associa ion has been desc ibed be ween gu coloniza ion wi h Clos idium di icile and alle gies in child en. Va ious s udies ha e shown ha child en wi h a opic de ma i is ha e a less di e se gu mic obio a [ 56 , 57 ] and lowe Bi idobac e ium le els [ 57 ] han heal hy child en. In alle gic child en, highe coun s o S aphylococcus au eus and En e - obac e iaceae and lowe Bi idobac e ium coun s we e ound han in heal hy child en [ 58 ]. In addi ion, a lowe coloniza ion o en e ococci du ing he i s mon h o li e and o Bi i- Foods 2021,10, 701 6 o 19 dobac e ium du ing he i s yea o li e ha e been ound in in an s wi h alle gies, compa ed o non-alle gic in an s [58]. I has been p oposed ha p obio ics could po en ially es o e in es inal homeos asis and p e en o alle ia e alle gies by in e ac ing wi h he in es inal immune cells [ 51 ]. Mo eo e , symbio ics, which a e a syne gis ic combina ion o p obio ics and p ebio ics, ha e p o en bene icial o di e en alle gic condi ions, o example, by educing as hma- like symp oms and he use o as hma medica ions [59]. P obio ics a e use ul o he modula ion o alle gic diseases, as hey s imula e he le - els o IgA in he mucosa and he T and B cells o he immune sys em [ 23 ]. The esul s o di e en s udies examining he in luence o p obio ics on alle gic diseases ha e been con adic o y, and as a esul , ew p ac ical ecommenda ions as o he use o p obio ics in alle gic diseases ha e been es ablished [ 60 ]. I is impo an o no e ha , due o mul iple ac o s, he esul s a y be ween s udies (Figu e 1). The impac o p obio ics on humans is highly a iable be ween indi iduals. Fo example, a ecen s udy ound ha indi iduals wi h a heal hie gu mic obio a composi ion esponded in a be e way han o he indi- iduals o he adminis a ion o p obio ics [ 61 ]. This esul is logical, because he ac ion o p obio ics depends on se e al ac o s, including coloniza ion esis ance, acid and sho chain a y acid p oduc ion, he compe i i e exclusion o pa hogens, and bac e iocin p o- duc ion, which can in luence p obio ic pe sis ence [ 62 , 63 ]. Zmo a e al. [ 64 ] demons a ed ha pe sis en pe sonalized gu mucosal esis ance o comme cial p obio ics is associa ed wi h unique hos and mic obiome ea u es. Fo example, a p obio ic’s coloniza ion can be a ec ed by an unde - ep esen a ion o speci ic ca bohyd a e-u iliza ion genes in he gu , hus p e en ing he complex me aboliza ion o polysaccha ides by he p obio ic bac e- ia [ 62 ]. Thus, he e icacy o p obio ics is dependen on bo h he mic obial species o s ain and i s de i ed me aboli es and byp oduc s (commonly named as pos bio ics), as well as he numbe o p obio ic cells and ype o p obio ic ca ie [27]. Figu e 1. Fac o s ha could explain he a ied e ec s o p obio ics unco e ed by di e en s udies. P e ious s udies ha e ound ha supplemen a ion wi h a ious p obio ic p epa a ions can balance he in es inal mic obio a, egula e he immune sys em, and educe alle gies. Fu he , hese s udies ha e explo ed new s ains o p obio ics, p obio ic genomic cha - ac e is ics, and he in i o mechanisms o ac ion, o mula ion p ocesses, and sa e y o p obio ics [ 65 , 66 ]. Cu en ly, s udies a e a emp ing o iden i y p o ec i e ac o s ha Foods 2021,10, 701 7 o 19 egula e he immune sys em and allow o ole ance o di e en alle gens in a speci ic way. One o he mos s udied p obio ics is Lac obacillus GG, which is equen ly s udied in connec ion wi h he managemen o AD, al hough he esul s ha e been qui e incon- sis en [ 8 ]. Fu he , Lac obacillus we e able o educe alle gic symp oms and o educe mo bidi y in child en [67]. Taniuchi e al. [ 68 ] demons a ed ha a Bi idobac e ium species was e ec i e in he ea - men o cow’s milk hype sensi i i y in in an s wi h a opic de ma i is. In addi ion, Enomo o e al. [ 69 ] demons a ed ha p ena al and pos na al supplemen a ion wi h wo species o Bi idobac e ium educed he isk o de eloping eczema and a opic de ma i is in in an s. These di e ences disappea ed a 10 mon hs o age, highligh ing ha he ea ly s age mic o- bio a is pa icula ly impo an o egula ing alle gies in child en. Two sys ema ic e iews and me a-analyses show ha p obio ic supplemen a ion be- o e and a e bi h can p e en alle gic diseases, pa icula ly eczema [ 70 , 71 ]. On he o he hand, when p obio ics a e adminis e ed only a e bi h, hey may no be e ec i e in p e- en ing alle gic diseases [71,72]. Many animal s udies, mainly in mice, in which di e en p obio ics in isola ion o mix u es o hem we e used o ea o p e en alle gic diseases, show an e ec . Ob iously, expe imen al animals di e widely om humans in key aspec s, such as he gu mic obio a composi ion, immune unc ion, o me abolism [ 45 ]. Thus, ex apola ing he esul s ob ained om animal models o humans may no be alid and should always be conside ed as p elimina y o limi ed. The p obio ics mos o en used in hese s udies a e he Lac obacillus and Bi idobac e ium gene a and, o a lesse ex en , En e ococcus [ 73 ]. The use o En e ococcus as p obio ics p esen s some in insic isks ha makes hem poo ly sui ed o use as p obio ics, especially he E. aecium and E. aecalis species. As oppo unis ic pa hogens, bo h en e ococci possess an a ay o i ulence ac o s and an ibio ic esis ance de e minan s, which ende hem con o e sial. E en in a i ulen en e ococci, when hey each he in es inal ac , hey can in e ac wi h endogenous en e ococci and o he commensals ha could lead o bi- di ec ional gene ic exchange [65,66]. In e ms o alle gies, he mos s udied a e hose ela ed o he ai ways, such as as hma, bu also a opic de ma i is [ 74 , 75 ] and ood alle gies [ 6 , 76 ]. The bene icial e ec s o p obio ics on alle gies include a educ ion in hype eac i i y and in lamma ion due o he p esence o alle gens, a dec ease in in e leukins and eosinophils, and a educ ion in TNF and INF, e c. In addi ion o he animal s udies, he e ha e also been many s udies wi h humans, especially child en (Table 1). As in he s udies wi h mice, in his case, he p obio ics mos o en used we e o he gene a Bi idobac e ium and Lac obacillus, o mix u es o hem. To a lesse ex en , P opionibac e ium [ 77 ] o Esche ichia coli and En e ococcus aecalis [ 8 ] we e used, and hese p obio ics we e adminis e ed in doses o 10 7 o 10 10 colony- o ming uni s (CFU)/day. Today, he consensus s a emen s conside a numbe o iable cells o 1 × 10 9 CFU/day in ood and ood supplemen s as he minimum numbe o be e ec i e [ 48 ]. To a lesse ex en , ood and espi a o y alle gies ha e been s udied. The bene icial e ec s ound in hese s udies we e a educ ion in in lamma o y cells, dec ease in in e leukins, educ ion in TNF and INF, and, abo e all, educ ion in symp oms and imp o emen in he quali y o li e o people su e ing om hese alle gies. Resea che s, such as Simpson e al. [ 78 ] and Loo e al. [ 79 ], ollowed up hei s udies o se e al yea s o obse e he e ec s o p obio ics o e ime. S udies wi h a ollow-up o 5 yea s o longe show ha he g ea es p o ec i e e ec o p obio ics agains AD occu s in ea ly childhood and ha his e ec is less likely o be sus ained un il school age [78]. Foods 2021,10, 701 8 o 19 Table 1. Use o p obio ics o ea o p e en alle gic diseases in in an s. Type o S udy P obio ic Dosage and Time o Exposu e Alle gic Disease Main Findings Re e ence Randomized, double-blind s udy wi h 27 in an s wi h a opic disease Bi idobac e ium lac is Bb-12 and Lac obacillus hamnosus GG (LGG) O al adminis a ion o 3 ×108CFU o LGG and 109CFU o B. lac is o 4 weeks A opic eczema A e 2 mon hs, a signi ican imp o emen in he skin condi ion occu ed in he p obio ic g oup. The Sco ing A opic De ma i is (SCORAD) and concen a ion o soluble CD4+ dec eased in he p obio ic g oups [80] Double-blind, placebo-con olled, c osso e s udy wi h 58 child en Lac obacillus hamnosus 19070-2 and Lac obacillus eu e i DSM 122460 A dose o 1010 CFU wice daily o 6 weeks A opic de ma i is The du a ion o eczema dec eased du ing p obio ic adminis a ion. The ea men esponse was mo e p onounced in alle gic pa ien s, and he SCORAD sco e dec eased [81] Randomized, double-blind, placebo-con olled s udy wi h 230 in an s wi h suspec ed cow’s milk alle gy (CMA) LGG, L. hamnosus LC705, B. b e e Bb99 and P opionibac e ium euden eichii ssp she manii JS O al adminis a ion o LGG (5 ×109CFU) o a mix u e o LGG (5 ×109CFU), L. hamnosus LC705 (5 ×109), B. b e e Bb99 (2 ×108), and P opionibac e ium euden eichii spp. she manii JS (2 ×109) wice daily o 4 weeks. A opic de ma i is ela ed o cow’s milk alle gy T ea men wi h LGG may alle ia e symp oms o a opic eczema and/o de ma i is synd ome in IgE-sensi ized in an s [77] Randomized, double-blind, placebo-con olled s udy wi h 56 child en Lac obacillus e men um VRI-033 PCC 1×109CFU wice daily o 8 weeks A opic de ma i is A educ ion in he SCORAD index was seen in he p obio ic- ea ed g oup. A he end o he s udy, mo e child en ea ed wi h his p obio ic had milde a opic de ma i is [82] Randomized, placebo-con olled s udy wi h 59 child en wi h AD L. hamnosus and B. lac is A dose o 2 ×1010 CFU daily o 12 weeks A opic de ma i is A combina ion o L. hamnosus and B. lac is imp o ed a opic de ma i is only in ood-sensi ized child en [83] Randomized, double-blind, placebo-con olled s udy wi h 50 in an s L. hamnosus L h and LGG Adminis e ing 1, 5, 25 and 125 mL o cow’s milk o mula a 30 min in e als (5 ×109CFU/mL o mula) A opic de ma i is ela ed o cow’s milk alle gy No clea e ec s we e seen on he SCORAD, sensi iza ion, in lamma o y pa ame e s, o cy okine p oduc ion [84] Randomized ial wi h newbo ns o 231 women wi h alle gies Lac obacillus acidophilus LAVRI-A1 3×109CFU/day o he i s 6 mon hs o li e A opic de ma i is A opic de ma i is a es we e simila in he p obio ic and placebo g oups. A 12 mon hs, he a e o sensi iza ion was signi ican ly highe in he p obio ic g oup [85] Randomized, double-blind, placebo-con olled s udy wi h 193 in an s diagnosed wi h cow’s milk alle gy (CMA) Lac obacillus casei CRL431 and Bi idobac e ium lac is BB-12 107CFU/g o each o he p obio ic bac e ia o 6 mon hs Cow’s milk alle gy (CMA) Supplemen a ion wi h Lac obacillus and Bi idobac e ium in an ex ensi ely hyd olyzed o mula did no accele a e cow’s milk ole ance in in an s wi h CMA [86] Double-blind, placebo-con olled, andomized ial wi h 253 in an s B. longum BL999 and L. hamnosus LPR O al supplemen a ion wi h 1 ×107CFU/g/day o B. longum and 2 ×107CFU/g/day o L. hamnosus o he i s 6 mon hs A opy and eczema No signi ican e ec on he p e en ion o eczema o alle gen sensi iza ion in he i s yea o li e [87] Double-blind, placebo-con olled, andomized ial wi h 179 in an s Lac obacillus F19 1×108CFU/day o 4–6 mon hs Eczema The cumula i e incidence o eczema a 13 mon hs was lowe in he p obio ic g oup. A 13 mon hs, he INF-y/IL-4 a io was highe in he p obio ic g oup. No di e ences in se um concen a ions o IgE [88] Randomized, double-blind ial o child en om 415 mo he s LGG, B. animalis ssp. lac is Bb-12 and L. acidophilus La-5 Milk con ained 5 ×1010 CFU/day o L. hamnosus and Bb-12. 5 ×109CFU o L. acidophilus o 4 mon hs, om 36 weeks o ges a ion o 3 mon hs pos na ally A opic de ma i is and as hma In he p obio ic g oup, he cumula i e incidence o a opic de ma i is was educed bu he e was no e ec on sensi iza ion [89] Randomized, double-blind s udy wi h 39 in an s wi h AD LGG A daily in ake o 3.4 ×109CFU o 3 mon hs A opic de ma i is The p opo ions o IgA- and IgM-sec e ing cells dec eased in he p obio ic g oup, and he p opo ions o CD191+ and CD27+ B cells inc eased [90] Foods 2021,10, 701 9 o 19 Table 1. Con . Type o S udy P obio ic Dosage and Time o Exposu e Alle gic Disease Main Findings Re e ence Randomized, placebo-con olled ial wi h 606 newbo ns Esche ichia coli DSM 17252 and En e ococcus aecalis DSM 1644 O al bac e ia lysa e con aining hea -killed nonpa hogenic 1.5–4.5 ×107bac e ia/mL (3 × 0.7 mL/day) A opic de ma i is A signi ican e ec was obse ed in a subg oup o he p obio ic g oup wi h single he edi y o a opy, which was mos p onounced o in an s wi h a opic a he s [8] Double-blind, placebo-con olled, andomized pa allel s udy wi h 100 child en Mix u e o L. casei, L. hamnosus, L. plan a um, and B. lac is O al adminis a ion a 2 ×109CFU in each s ain, wice daily o 6 weeks A opic de ma i is The p obio ic mix u e did no supp ess he g ow h o o he s ains, bu no di e ences in clinical imp o emen we e seen be ween he ea ed and placebo g oups [41] Double-blind, p ospec i e, andomized, placebo-con olled s udy wi h 2020 child en L. pa acasei GMNL-133 and/o L. e men um GM090 2×109CFU/day o L. pa acasei,L. plan a um, o 4×109CFU o a mix u e o 3 mon hs A opic de ma i is Child en gi en ei he p obio ics alone o a mix u e o bo h showed a dec ease in he se e i y o a opic de ma i is sco es. Lowe es sco es we e also eco ded o people wi h skin diseases. IgE, TNF-α, and INF-y inc eased in he p obio ic g oup [91] Randomized, con olled, double-blind s udy wi h 159 newbo ns LGG 1010 CFU/day o he i s 6 mon hs o li e Eczema and as hma The es ima ed cumula i e incidence o eczema and as hma was lowe in he p obio ic g oup a 2 yea s o age [92] P ospec i e, double-blind, placebo-con olled, andomized s udy wi h 40 child en B. longum BB536, Bi idobac e ium in an is M-63, and B. b e e M-16 V O al supplemen a ion con aining B. longum BB536 (3 ×109CFU), B. in an is M-63 (1 ×109 CFU), and B. b e e M-16 V (1 ×109CFU) as powde in a 3 mg sache . Adminis e ed e e y day o 8 weeks Seasonal alle gic hini is and in e mi en as hma A signi ican imp o emen o symp oms and quali y o li e in he p obio ic g oup [67] Double-blind, 2-a m, placebo-con olled s udy wi h 50 child en wi h AD B. lac is CECT 8145, B. longum CECT7347, and L. casei CECT 9104 109CFU/day o a mix u e o he 3 p obio ic s ains A opic de ma i is A educ ion in IL-4, IL-5, and IL-13 and a dec eased ac i i y o Th2 in he p obio ic g oup. The SCORAD index and use o co icos e oids we e also educed in he p obio ic g oup [93] A mul i-cen e , double-blind, placebo-con olled, andomized ial wi h 1099 e y p e e m in an s B. in an is BB-02, S ep ococcus he mophilus TH-4, and B. lac is BB-12 A combina ion o B. in an is BB-02 (300 ×106 CFU), S. he mophilus TH-4 (350 ×106CFU), and B. lac is BB-12 (350 ×106). To al: 1 ×109 CFU pe 1.5 g in a powde once daily, un il discha ged om hospi al o e m-co ec ed age Eczema, a opic sensi iza ion, ood alle gy, and wheezing The e was no di e ence in eczema incidence be ween he wo g oups. Addi ionally, he incidence o a opic eczema, ood alle gy, wheezing, and a opic sensi iza ion we e simila in bo h g oups [52] Foods 2021,10, 701 16 o 19 32. Mendes, E.; Ace u i, B.G.; Thomas, A.M.; Ma ins, F.D.S.; C isma, A.R.; Mu a a, G.; B aga, T.T.; Camâ a, N.O.S.; F anco, A.L.D.S.; Se ubal, J.C.; e al. P ophylac ic Supplemen a ion o Bi idobac e ium longum 51A P o ec s Mice om O a iec omy-Induced Exace ba ed Alle gic Ai way In lamma ion and Ai way Hype esponsi eness. F on . Mic obiol. 2017,8, 1732. [C ossRe ] 33. G eine , A.N.; Hellings, P.W.; Ro i o i, G.; Scadding, G.K. Alle gic Rhini is. Lance 2011,378, 2112–2122. [C ossRe ] 34. Bousque , J.; an Cauwenbe ge, P.; Khal ae , N. Alle gic Rhini is and I s Impac on As hma. J. Alle gy Clin. Immunol. 2001 ,108, S147–S334. [C ossRe ] [PubMed] 35. Bje me , L. Time o a Pa adigm Shi in As hma T ea men : F om Relie ing B onchospasm o Con olling Sys emic In lamma ion. J. Alle gy Clin. Immunol. 2007,120, 1269–1275. [C ossRe ] [PubMed] 36. Lai, C.K.W.; Beasley, R.; C ane, J.; Foliaki, S.; Shah, J.; Weiland, S.; he ISAAC Phase Th ee S udy G oup. Global a ia ion in he p e alence and se e i y o as hma symp oms: Phase Th ee o he In e na ional S udy o As hma and Alle gies in Childhood (ISAAC). Tho ax 2009,64, 476–483. [C ossRe ] 37. Chu ch, M.K.; Welle , K.; S ock, P.; Mau e , M. Ch onic spon aneous u ica ia in child en: I ching o insigh . Pedia . Alle gy Immunol. 2011,22, 1–8. [C ossRe ] 38. Zube bie , T.; Ase o, R.; Bindsle -Jensen, C.; Canonica, G.W.; Chu ch, M.K.; Giménez-A nau, A.; G a an, C.E.H.; Kapp, A.; Me k, H.F.; Rogala, B.; e al. EAACI/GA2LEN/EDF/WAO Guideline: De ini ion, Classi ica ion and Diagnosis o U ica ia. Alle gy 2009,64, 1417–1426. [C ossRe ] 39. A ena-Woods, C. O e iew o A opic De ma i is. Am. J. Manag. Ca e 2017,23, S115–S123. [PubMed] 40. Langan, S.M.; I ine, A.D.; Weidinge , S. A opic De ma i is. Lance 2020,396, 345–360. [C ossRe ] 41. Yang, H.-J.; Min, T.K.; Lee, H.W.; Pyun, B.Y. E icacy o P obio ic The apy on A opic De ma i is in Child en: A Randomized, Double-blind, Placebo-con olled T ial. Alle gy As hma Immunol. Res. 2014,6, 208–215. [C ossRe ] [PubMed] 42. Mo z, C.G.; Ande sen, K.E. New Aspec s in Alle gic Con ac De ma i is. Cu . Opin. Alle gy Clin. Immunol. 2008 ,8, 428–432. [C ossRe ] 43. Nwa u, I.B.; Hicks ein, L.; Panesa , S.S.; Mu a o, A.; We el, T.; Ca dona, V.; Dubois, A.E.J.; Halken, S.; Ho mannsomme g ube , K.; Poulsen, L.K.; e al. The Epidemiology o Food Alle gy in Eu ope: A Sys ema ic Re iew and Me a-Analysis. Alle gy 2014 ,69, 62–75. [C ossRe ] 44. Panesa , S.S.; Ja ad, S.; De Sil a, D.; Nwa u, B.I.; Hicks ein, L.; Mu a o, A.; Robe s, G.; Wo m, M.; Bilò, M.B.; Ca dona, V.; e al. The Epidemiology o Anaphylaxis in Eu ope: A Sys ema ic Re iew. Alle gy 2013,68, 1353–1361. [C ossRe ] [PubMed] 45. Lopez-San ama ina, A.; Mi anda, J.M.; Mond agon, A.D.C.; Lamas, A.; Ca delle-Cobas, A.; F anco, C.M.; Cepeda, A. Po en ial Use o Ma ine Seaweeds as P ebio ics: A Re iew. Molecules 2020,25, 1004. [C ossRe ] 46. Lynch, S.V.; Pede sen, O. The Human In es inal Mic obiome in Heal h and Disease. N. Engl. J. Med. 2016 ,375, 2369–2379. [C ossRe ] 47. FAO/WHO Food and Ag icul u e O ganiza ion o he Uni ed Na ions/Wo ld Heal h O ganiza ion. Guidelines o he E alua ion o P obio ics in Food. Repo o a Join FAO/WHO Wo king G oup on D a ing Guidelines o he E alua ion o P obio ics in Food; FAO/WHO Food and Ag icul u e O ganiza ion o he Uni ed Na ions/Wo ld Heal h O ganiza ion: Rome, I aly, 2002. 48. Hill, C.; Gua ne , F.; Reid, G.; Gibson, G.R.; Me ens ein, D.J.; Po , B.; Mo elli, L.; Canani, R.B.; Flin , H.J.; Salminen, S.; e al. The In e na ional Scien i ic Associa ion o P obio ics and P ebio ics Consensus S a emen on he Scope and App op ia e Use o he Te m P obio ic. Na . Re . Gas oen e ol. Hepa ol. 2014,11, 506–514. [C ossRe ] 49. Lopez-San ama ina, A.; Lamas, A.; Mond agón, A.D.C.; Ca delle-Cobas, A.; Regal, P.; Rod iguez-A ila, J.A.; Mi anda, J.M.; F anco, C.M.; Cepeda, A. P obio ic E ec s agains Vi us In ec ions: New Weapons o an Old Wa . Foods 2021 ,10, 130. [C ossRe ] [PubMed] 50. Ana iello, E.; Cunha, M.; Noguei a, J.; Ca alho, J.L.; Sá, A.K.; Mi anda, M.; Cas o-Fa ia-Ne o, H.; Kelle , A.C.; Aimbi e, F. O al Feeding o Lac obacillus Bulga icus N45.10 Inhibi s he Lung In lamma ion and Ai way Remodeling in Mu ine Alle gic As hma: Rele ance o he Th1/Th2 Cy okines and STAT6/T-be . Cell. Immunol. 2019,341. [C ossRe ] 51. Ezendam, J.; De Kle k, A.; G emme , E.R.; Van Lo e en, H. E ec s o Bi idobac e ium Animalis Adminis e ed du ing Lac a ion on Alle gic and Au oimmune Responses in Roden s. Clin. Exp. 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