Edi o ial: The Immunological
Implica ions o he Hygiene
Hypo hesis
Pe a Ina P e e le
1
, Idoia Pos igo
2
and Holge Ga n
3
*
1
Medical Facul y, Comp ehensi e Biobank Ma bu g (CBBMR), Membe o he Ge man Biobank Alliance (GBA) and he
Ge man Cen e o Lung Resea ch (DZL), Philipps Uni e si y o Ma bu g, Ma bu g, Ge many,
2
Facul y o Pha macy and
Lasca ay Resea ch Cen e , Pa asi ology and Alle gy Resea ch G oup, Uni e si y o The Basque Coun y (UPV/EHU), Vi o ia,
Spain,
3
Medical Facul y, Biochemical Pha macological Cen e (BPC), T ansla ional Inflamma ion Resea ch Di ision & Co e
Facili y o Single Cell Mul iomics, Membe o he Ge man Cen e o Lung Resea ch (DZL), Philipps Uni e si y o Ma bu g,
Ma bu g, Ge many
Keywo ds: hygiene hypo hesis, inflamma ion, mic obiome, bac e ia, pa asi es, en i onmen
Edi o ial on he Resea ch Topic
The Immunological Implica ions o he Hygiene Hypo hesis
Human beings de eloped in close icini y o hei na u al en i onmen du ing hei long-las ing
his o y. Du ing his ime, a s able ela ionship was es ablished be ween he highly di e se
en i onmen al influences and physiological p ocesses in he human body esul ing in an op imal
adap a ion o humans o he espec i e ecological niches. The eby, en i onmen al ac o s in ol ed
bo h ex e nal impac s including equen (ea ly-li e) mic obial o pa asi ic in ec ions and he
es ablishmen o an in e nal mic obial communi y, he mic obiome. Due o u baniza ion and
indus ializa ion hese ela ionships we e massi ely dis u bed and new in e ac ions de eloped. Ve y
ecen ly, his was imp essi ely shown again by Wibowo e al., who econs uc ed ancien mic obial
genomes om 1.000 –2.000 yea -old s ool samples and showed ha hese paleo ecal mic obiomes
a e simila o hose om people cu en ly li ing in non-indus ialized a eas o he wo ld, bu a e
significan ly di e en om mic obiomes in humans li ing in highly indus ialized coun ies (1).
These a he ecen changes a e conside ed o ha e subs an ially con ibu ed o he de elopmen o
mode n ci iliza ion diso de s, which p edominan ly in ol e non-communicable diseases (NCDs)
such as alle gies, au oimmune and neu ological diseases, and cance . Con empla ing he po en ial
in e se ela ionship o ea ly-li e exposu e o a highly di e se mic obial en i onmen and he
p e alence o NCDs, he Hygiene Hypo hesis was es ablished abou 30 yea s ago. Since hen, se e al
s udies ha e added new e idence and efined he pos ula e jus i ying his Resea ch Topic on
immunological implica ions o he Hygiene Hypo hesis, which now cons i u es an impac ul
collec ion o e iew and o iginal a icles add essing ecen de elopmen s and no el findings
combined wi h e ospec i e and p ospec i e iews in his s ill highly opical field o
scien ific esea ch.
Fi s , on Mu ius, one o he mos p ominen key opinion leade s in he field p o ides a concise
pe sonal s a emen discussing he p o ec i e e ec s o adi ional a m exposu es on he
de elopmen o childhood as hma and alle gies. F om he epidemiological poin -o - iew,
(mic obial) di e si y in he a m en i onmen is key o i s alle gy-p e en i e e ec s (2) and his
is suppo ed by he ac ha no single componen has so a been iden ified ha con e s p o ec ion.
F on ie s in Immunology | www. on ie sin.o g Augus 2021 | Volume 12 | A icle 7321271
Edi ed and e iewed by:
Ian Ma io ,
Uni e si y o No h Ca olina a
Cha lo e, Uni ed S a es
*Co espondence:
Holge Ga n
ga n@s a .uni-ma bu g.de
Special y sec ion:
This a icle was submi ed o
Mic obial Immunology,
a sec ion o he jou nal
F on ie s in Immunology
Recei ed: 28 June 2021
Accep ed: 02 Augus 2021
Published: 17 Augus 2021
Ci a ion:
P e e le PI, Pos igo I and
Ga n H (2021) Edi o ial: The
Immunological Implica ions
o he Hygiene Hypo hesis.
F on . Immunol. 12:732127.
doi: 10.3389/ immu.2021.732127
EDITORIAL
published: 17 Augus 2021
doi: 10.3389/ immu.2021.732127
Howe e , wo key elemen s o he p o ec i e a m e ec ha e
been desc ibed, exposu e o animal sheds, in pa icula o
cowshed dus , and he consump ion o unp ocessed cow’s
milk. Mo eo e , p egnancy has been ecognized as an ea ly
window o oppo uni y o p e en immune de ia ion and
alle gic ou comes in o sp ing by adi ional a m exposu e
implying a ole o epigene ic imp in ing. Finally i has been
concluded ha a mul iplici y o exposu es, ia di e se ou es,
influence mic obiome composi ion a di e en mucosal si es and
o e all hese impac s a e associa ed wi h a lowe isk o as hma in
a m popula ions. In a subsequen mini e iew, we p o ide a
sho ch onological o e iew on landma k findings ha
de eloped and u he shaped he Hygiene Hypo hesis o e
ime. We discuss mic obial and nu i ional aspec s wi h ega d
o hei associa ion o he hypo hesis and p o ide insigh s in o ou
cu en unde s anding on unde lying immunological mechanisms
(P e e le e al.). While he Hygiene Hypo hesis was o iginally
es ablished in he con ex o alle gic diseases, Jean-F ancois Bach
expanded i s applica ion o o he condi ions such as au oimmune
diseases in he ea ly 2000s (3). In his Resea ch Topic, he
con ibu es a sophis ica ed e iew a icle e isi ing he Hygiene
Hypo hesis in he con ex o au oimmune diso de s. Simila o
alle gies, hese diseases ep esen complex mul i ac o ial and
polygenic ch onic condi ions and hus he unde lying
mechanisms o disease ini ia ion and pe pe ua ion a e mul iple
and complex as well. This e iew summa izes he cu en
epidemiological e idence o he in e se associa ion o in ec ions
and au oimmune diso de s and p o ides insigh s in o he cu en
immunological mechanisms hough o be in ol ed in hese
in e ac ions (Bach). Expanding he ocus owa ds a mo e holis ic
iew, Fiuza e al. p esen hei concep o conside ing humans and
hei en i e associa ed mic obial communi ies as e olu iona ily
de eloped holobion s. They discuss he in e ac ions be ween he
en i e y o human-associa ed mic obial communi ies and he
de eloping immune sys em du ing on ogenesis, and how shi s
in en i onmen al condi ions may impac hese well-balanced
in e ela ionships. Fu he , in line wi h he Hygiene Hypo hesis,
he au ho s desc ibe epigene ic modifica ions as undamen al
mechanisms in gene-en i onmen -in e ac ions and as d i ing
o ces o he ma u a ion o he immune sys em.
A be e unde s anding o he mechanisms unde lying he
Hygiene Hypo hesis may lead o new concep s o alle gy
p e en ion. In his con ex , Sa a e e al. demons a e ha
exposu e o con en ional o gno obio ic mo he mice wi h he
p obio ic bac e ium Esche ichia coli Nissle 197 may dec ease
polysensi iza ion o bi ch and g ass pollen alle gens and alle gic
inflamma ion in he o sp ing. In e es ingly, ecombinan a ian s
o he bac e ial s ain exp essing bi ch and g ass pollen alle gens
did no esul in he same ex en o alle gy p e en ion. The e iew
by on Mu ius al eady poin ed o ß-lac oglobulin (BLG) as an
abundan componen in aw cow’s milk and he ambien ai o
cowsheds. Based on hese findings, Afifi e al. hypo hesized ha
BLG may exe ole ogenic e ec s he eby con ibu ing o he
alle gy-p e en i ing a m e ec s. Using a mouse model, hey we e
able o show ha p ophylac ic p e ea men wi h he ligand-filled
holoBLG, bu no he emp y apoBLG, educed alle gen-specific
an ibody i e s, ea u es o an igen p esen a ion, and alle gic T cell
esponses, in alle gen-specific ( owa ds apoBLG) as well as an
alle gen-non-specific ( owa ds bi ch pollen alle gen) manne . In
an ambi ious la en class analysis (LCA) app oach, Hose e al.
analyzed daily ood consump ion pa e ns in ela ion o he gu
mic obiome o child en by one yea o age and a school age ( ime
poin o as hma ini ia ion). The au ho s ound excessi e mea
consump ion o be associa ed wi h la e as hma de elopmen
while consump ion o milk p oduc s compensa ed o such an
e ec . In e es ingly, mic obiome analyses indica ed ha his
associa ion migh be ela ed o he “i on ba le field”in he gu .
F ee i on is a limi ing nu i ional ac o o he me abolism o bo h
he hos and bac e ia. Unbalanced mea consump ion os e s
accumula ion o gu -associa ed bac e ial s ains equipped wi h
side opho es ha a e highly capable o aking up ee i on om
he gu lumen. Since milk p oduc s in gene al, and unp ocessed
milk in pa icula , con ain la ge amoun s o i on-binding be a-
lac oglobulin, his milk compound migh e ec i ely comba he
g ow h o such bac e ial i on compe i o s.
The balance o he local mic obiological en i onmen in
mucosal issues is igh ly con olled by a a ie y o inna e and
adap i e de ense sys ems. Among hem, an imic obial pep ides
such as he human b-de ensin 2 (hBD-2) play a key ole and hus
dis u bances in hei p oduc ion may a o he de elopmen o
alle gic and/o au oimmune diso de s. In hei manusc ip ,
Bo che s e al. clea ly demons a e ha gene ic a ia ions
associa ed wi h insu ficien hBD-2 p oduc ion may ep esen a
isk ac o o he de elopmen o such diseases. Acco dingly,
p ophylac ic adminis a ion o hBD-2 was able o educe
pulmona y inflamma ion and imp o e lung unc ion
pa ame e s in a mouse model o alle gic ai way inflamma ion.
In he con ex o gene-en i onmen -in e ac ions, gene ic
p edisposi ion may also ep esen a decisi e ac o in shaping
ea ly immune mechanisms in he p esence o pa asi ic in ec ion
and in as hma de elopmen . In a genome-wide associa ion s udy
(GWAS) on Asca is lumb icoides-in ec ed child en, Ca nei o
e al. associa e WSB1 and IL21R gene ic a ian s wi h ma ke s
o ype-2 immune esponses. WSB1 bu no IL21R gene
exp ession was supp essed in in ec ed child en and inc eased
me hyla ion was concomi an ly obse ed in he WSB1 p omo e
egion. The WSB1/IL21R pa hways may hus ep esen po en ial
a ge s o he ea men o ype-2-media ed diseases. In he same
esea ch a ea, Ko b e al. p esen an expe imen al app oach ha
unde lines he ole o glycosyla ion o pa asi e-de i ed ex ac s in
an i-alle gic immunomodula ion. Using an o albumin-model o
alle gic ai way inflamma ion, in which sensi ized mice we e
in anasally ea ed wi h na i e Toxoplasma gondii lysa es, hey
obse ed a enua ion o expe imen al as hma pa ame e s. In
con as , applica ion o deglycosyla ed lysa es was shown o
exe no p o ec i e e ec indica ing ha he ca bohyd a e
modifica ionsa e ele an o hes ongan i-inflamma o y e ec s
p o ided by T. gondii-de i ed ex ac s. The po en ial ole o suga s
and ela ed ecep o s in he egula ion o immune mechanisms a e
u he highligh ed in a mini e iew p o ided by Pe e s and Pe e s
who emphasize he ole o ca bohyd a e lec in ecep o s (CLRs) in
alle gic ai way inflamma ion. Di e se alle gen glyco-epi opes may
P e e le e al. Edi o ial: Implica ions o he Hygiene Hypo hesis
F on ie s in Immunology | www. on ie sin.o g Augus 2021 | Volume 12 | A icle 7321272
bind o such CLRs, he eby acili a ing hei up ake and
p esen a ion. Howe e , CLRs ha e also been shown o media e
inhibi o y signals and a numbe o s udies ha e demons a ed an i-
inflamma o y e ec s a e binding ca bohyd a e ligands o mic obial
o igin. The au ho s discuss he in ol emen o suga moie ies in
immune egula ion and how CLRs and hei ligands may con ibu e
o alle gy and as hma p o ec ion.
This Resea ch Topic is comple ed by a o wa d-looking mini-
e iew by Ga n e al. ocusing on new de elopmen s and insigh s
in immunological and alle gy esea ch and how hese cu en
pe cep ions u he fine une ou unde s anding on mechanisms
unde lying he Hygiene Hypo hesis. Finally, he applica ion o
he Hygiene Hypo hesis o explain he inc easing incidence o
condi ions o he han alle gies and au oimmune disease is also
discussed, unde sco ing he endu ing impo ance o
his scien ific concep .
AUTHOR CONTRIBUTIONS
All au ho s con ibu ed o he a icle and app o ed he
submi ed e sion.
REFERENCES
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Recons uc ion o Ancien Mic obial Genomes F om he Human Gu . Na u e
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2. Ege MJ, Maye M, No mand A-C, Genunei J, Cookson WO, B aun-Fah lände
C, e al. Exposu e o En i onmen al Mic oo ganisms and Childhood As hma.
N Engl J Med (2011) 364:701–9. doi: 10.1056/NEJMoa1007302
3. Bach J-F. The E ec o In ec ions on Suscep ibili y o Au oimmune and Alle gic
Diseases. N Engl J Med (2002) 347:911–20. doi: 10.1056/NEJM a020100
Conflic o In e es : The au ho s decla e ha he esea ch was conduc ed in he
absence o any comme cial o financial ela ionships ha could be cons ued as a
po en ial conflic o in e es .
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endo sed by he publishe .
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