Science - USA (2022-05-27)

the timing and location of intestinal antigen

exposure is an important determinant of the

responses elicited and the establishment of

tolerance to commensals ( 39 ). During the first

10 days of postnatal life (the neonatal phase),

antigens are kept separate from intestinal im-

mune cells by a tight barrier, but from day 11

until weaning (day 21), luminal antigens are

encountered mostly by immune cells in the

colon. Thereafter, in the postweaning phase,

antigens are encountered almost exclusively

by immune cells in the small intestine ( 40 ).

Encounters in the preweaning phase (window

of opportunity) are more likely to lead to to-

lerance by induction of Tregs expressing the

transcription factor retinoic acid–related or-

phan receptorgt (RORgt), influencing sub-

sequent exposures to the same antigens later

in life ( 40 )(Fig. 2). The timing and location of

antigen sensing is regulated by goblet cell–

associated antigen passages ( 41 ), which are

inhibited by epidermal growth factor (EGF)

in breastmilk, thereby allowing for a care-

fully timed and localized sensing of luminal

antigens ( 40 ) (Fig. 2). At the time of weaning

in mice, there is a transient intestinal immune

response toward members of the microbiota,

which is modulated by dietary and microbial

factors such as retinoic acid and short-chain

fatty acids that further promote Tregs ex-

pressing RORgt( 42 ). In the absence of such

environmental factors, RORgt+Tregs failed

to develop, and experimental colitis induced

by dextran sulfate sodium and allergic in-

flammation induced by oxazolone were more

pronounced ( 42 ). Tregs induced before and

during the time of weaning persist, but con-

tinuous antigen delivery is required to main-

tain Treg numbers and tolerance to a particular

antigen.

Timing is also important for food allergy

development, in which early exposure to po-

tential allergens reduces the risk of developing

allergies toward these same antigens ( 43 ). This

effect is enhanced in breastfed infants by

maternal IgG-antigen complexes, maternal

EGF, and transforming growth factorbin

breastmilk ( 44 ) (Fig. 2). Members of the micro-

biota also contribute and exert modulatory

effects ( 45 ), and when specific microbes iden-

tified to be overrepresented in nonallergic

childrenaretransferredintomice,theysup-

press experimental allergic inflammation by

inducing RORgt+Tregs ( 46 ).

The window of opportunity for tolerance

induction is less well defined in humans, but

antibiotic exposure during the first 100 days of

life has been associated with increased risk

of atopy ( 31 ). This is a period when the cir-

culating immune system in human newborns

is particularly dynamic ( 35 ) and when CD4+

T cells carrying gut-homing markers are ex-

panding in the blood, suggestive of immune

reactivity to the microbiota ( 34 ). In contrast

to mice, this reaction is less tightly linked to

weaning, but breastmilk and its components

exert an important influence on the nature of

early-life immune responses during microbial

colonization. HMOs in the breastmilk are me-

tabolized by microbes carrying the necessary

genetic machinery, leading to the production of

metabolites such as indole-3-lactic acid, which

likely mediates some of the beneficial effects of

breastmilk early in life ( 34 , 47 ). IgA antibodies

in breastmilk have been shown to promote

colonization by selected microbes in mice by

anchoring them to the mucus layer in the in-

testine ( 48 ). It is becoming increasingly clear

that homeostatic B cell responses in the intes-

tine are dominated by IgA. Conversely, more

inflammatory IgG responses to commensal

microbes are rare but are more abundant when

tolerance is lost, as in inflammatory bowel

disease ( 49 ). Presumably, maternal antibodies

in breastmilk and thosetransferred across the

placenta help to tip the balance toward tole-

rance and immune-microbe mutualism while

providing passive immunity to defend from

invasive bacteria. Breastfeeding and the ex-

pansion of HMO-metabolizing bacteria such

as Bifidobacteriumlongumsubspeciesinfantis

(B. infantis) induce skewing of T cells both

in vivo and in vitro, away from T helper type 17

(TH17) and TH2andtowardTH1celldiffer-

entiation, and exert a dampening effect on

systemic and intestinal inflammation ( 34 )

(Fig. 2).

Whether these differences in early-life re-

sponses to the microbiota and modulation

by breastmilk will also translate into dif-

ferent rates of atopy development and other

immune-mediated diseases remains to be

seen. Clearly, there are numerous evolution-

arily conserved mechanisms that promote

colonization by beneficial microbes, immune

tolerance to these microbes and food com-

ponents, and the establishment of healthy

immune-microbe mutualism early in life.

So why do these increasingly fail in industrial-

ized societies, leading to increasing rates of

immune-mediated diseases?

Mismatched environments

Immune systems have evolved under strong

selective pressure from microbes since the

first appearance of humans in Africa 200,

to 300,000 years ago, dispersal across the con-

tinents from 100,000 years ago, and through

major lifestyle changes such as agricultural-

ism ~10,000 years ago ( 50 ). One way to explain

Brodin,Science 376 , 945–950 (2022) 27 May 2022 3of

Maternal

IgG-Ag

complexes

Breastmilk TGF-β

Breastmilk

EGF

Breastmilk HMO

Bifidobacteria

SCFA

Breastmilk sIgA

Antigen

GAP

IL-10,

TGF-b

Treg

Window of opportunity Immunematuration

Fig. 2. Tolerance-promoting factors during a window of opportunity early in life.The induction of

tolerance toward commensal microbes and harmless food antigens in the gut is promoted during a window of

opportunity whereby regulated antigen sampling through goblet cell–associated antigen passages (GAPs)

is regulated in time and space by the EGF provided by breastmilk ( 40 ). Transforming growth factorb(TGFb)

in breastmilk also promotes the differentiation of Tregs expressing the transcription factor RORgt, and

HMOs provide a growth advantage to beneficial microbes such asB. infantis, which express all of the genes

necessary for HMO metabolism. This process of HMO metabolism and microbial expansion leads to the

production of specific metabolites such as indole-3-lactic acid, which skew CD4+T cells away from

inflammatory TH17 and TH2 and toward TH1 and the prevention of inflammatory responses to the microbiota

( 34 ). Maternal IgA in breastmilk can selectively promote colonization by specific microbes by anchoring

them to the mucus layer, and maternal IgG prevents invasive infections.

THE SYSTEMIC MICROBIOME

ILLUSTRATION: KELLIE HOLOSKI/

SCIENCE