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
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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
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A ibu ion (CC BY) license (h ps://
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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
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