REVIEW
Immune-microbe interactions early in life:
A determinant of health and disease long term
Petter Brodin1,2,
Research on newborn immunity has revealed the importance of cell ontogeny, feto-maternal tolerance, and
the transfer of maternal antibodies. Less is known about postnatal adaptation to environmental exposures.
The microbiome and its importance for health have been extensively studied, but it remains unclear
how mutually beneficial relationships between commensal microbes and human cells first arise and are
maintained throughout life. Such immune-microbe mutualism, and perturbations thereof, is most likely a
root cause of increasing incidences of immune-mediated disorders such as allergies and autoimmunity
across many industrialized nations during the past century. In this Review, I discuss our current understanding
of immune development and propose that mismatches among ancestral, early-life, and adult environments
can explain perturbations to immune-microbe interactions, immune dysregulation, and increased risks of
immune-mediated diseases.
Y
oung children face a daunting task at
birth and shortly thereafter, when sub-
stantial physiological adaptation must
occur to initiate respiration, thermoreg-
ulation, and nutrition. At the same time,
the child transitions from a sheltered envi-
ronment in utero to the outside world, the
most profound change in environmental ex-
posures during the human lifetime. Facing
this new world poses challenges for the im-
mune system, which must protect the new-
born from invasive pathogens while at the
same time ensuring tolerance to beneficial
microbes that are important for health. Many
diseases that are increasingly prevalent in
industrialized societies, such as asthma, aller-
gies, autoimmune diseases, metabolic disor-
ders, and neurodevelopmental alterations,
have all been associated with perturbed early-
life immune-microbe relationships. Immune-
microbe mutualism, i.e., a mutually beneficial
relationship between different species, must
be established after birth because microbial
colonization first happens during delivery and
thereafter. To help her offspring, a mother
provides passive immunity, antigen exposure
in utero, selected microbes that seed and col-
onize the infant, and optimized, energy-dense
nutrition in the form of breastmilk. Breastmilk
also contains antibodies, antimicrobial pep-
tides, and human milk oligosaccharides (HMOs)
that further promote colonization by beneficial
microbes and limit invasion by pathogens.
Life history theory offers a framework for
explaining the long-term consequences of early-
life events whereby different investments in or
priorities on key traits such as reproduction,
growth, and maintenance—of which immu-
nity is a critical component—can have durable
effects ( 1 ). Throughout evolution, the immune
system has been shaped under strong selec-
tion pressure imposed by infectious agents,
and this forms the basis for adaptive changes.
Mismatches between ancestral and current
environmental conditions must also be con-
sidered when trying to explain immune-
mediated diseases that are influenced by the
microbiota. Perturbations to evolutionary prin-
ciples that govern immune system adaptation
to environmental factors could provide a uni-
fying explanation to recent changes in infant
growth rates, obesity, immune-microbe dysreg-
ulation, and immune-mediated diseases such
as atopy (development of allergies) and auto-
immune diseases in industrialized societies.
In this Review, I discuss conditions during
prenatal, perinatal, and postnatal phases of
development that are relevant to our under-
standing of the establishment of immune-
microbe mutualism. I also discuss how a life
history perspective and mismatches between
ancestral and modern environments, as well
as early-life perturbations, can have long-term
consequences for health and disease.Prenatal preparation
Balanced interactions between human cells and
tissues and commensal microbes are important
for metabolism, prevention of infection, mat-
uration of lymphoid tissues, and functional
development of immune cells. Several evolu-
tionarily conserved mechanisms through which
the mother prepares her offspring for post-
natal life and colonization are also in opera-
tion. During pregnancy, the human immune
system develops in a layered fashion ( 2 )in
which different populations of stem cells sup-
port immune cells poised toward feto-maternal
tolerance early during fetal development and
increasingly poised toward pathogen resist-
ance in the later stagesof pregnancy. Naïve
T cells taken from mesenteric lymph nodes of
fetuses in gestational weeks 18 to 22 are highlyresponsive to allogeneic cells and readily up-
regulate the transcription factor forkhead box
P3 (FoxP3) and differentiate into regulatory
T cells (Tregs) upon stimulation ( 3 ). Even
before Tregs were described, higher frequencies
of CD25-expressing memory phenotype CD
T cells were noted in fetal versus adult spleen
( 4 ). Feto-maternal tolerance is further ensured
by chimeric maternal cells that cross the pla-
centa, further promoting the differentiation of
fetal FoxP3+Tregs ( 5 ) and seeding fetal organs
where these maternal cells can persist into
adulthood ( 6 ).
The exact timing of when fetal hematopoi-
esis shifts to adult hematopoiesis is variable
amongchildrenandgradualinnature( 7 )but
is influenced by prenatal exposures such as
maternal stress and infection (Fig. 1A). In mice,
a transient spike in type I interferons (IFNs)
late in the prenatal period triggered the grad-
ual switch toward adult hematopoiesis ( 8 ).
Although the trigger for this prenatal IFN-I
spike is unknown [and it was observed even
under germ-free conditions ( 8 )], the fact that
such cytokines are readily induced during in-
fections and can cross the placenta suggests
that prenatal infections in the mother and/or
the fetus could initiate a switch from fetal to
adult hematopoiesis and repurpose offspring
immunity toward resistance to infections in
preparation for microbial encounters (Fig. 1A).
Another recent study in mice showed that
mild intestinal infection of pregnant dams with
the food-borne pathogenYersinia pseudo-
tuberculosisdid not spread to the fetus but
did trigger adaptive changes in fetal intestinal
epithelial cells. This was mediated by maternal
interleukin-6 (IL-6), which conferred increased
resistance to intestinal infection later in life, but
also predisposition to inflammatory responses
in the intestine, with possible negative conse-
quences for health ( 9 ).
Similarly, maternal stress in pregnant mice
recalibrates the hypothalamic-pituitary-adrenal
axis of fetuses and impairs CD8+T cell re-
sponses in the offspring long after birth ( 10 ).
Not only do pathogenic microbes induce
adaptations in the fetus but so do symbiotic
microbes. Symbiotic microbes transiently
colonizing pregnant mice have been shown to
prime fetal intestinal epithelia and recruit im-
mune cells to ready the offspring for postnatal
colonization ( 11 ). The priming of fetal immu-
nity by maternal microbes in these mice was
shown to be dependent on immunoglobulin G
(IgG)–mediated transfer of microbial compo-
nents across the placenta, allowing the dams
to prime the fetus for exposure to the same
microbes to which passive immunity, and con-
sequently protection from invasive infection,
is also provided (Fig. 1B) ( 11 ).
Thepresenceofviablebacteriainuterohas
been a hotly debated topic, with conflicting
results and different low-abundance strainsTHE SYSTEMIC MICROBIOMEBrodin,Science 376 , 945–950 (2022) 27 May 2022 1of
(^1) Department of Immunology and Inflammation, Imperial
College London, London, UK.^2 Imperial College Healthcare
NHS Trust, London, UK.^3 Department of Women’s and
Children’s Health, Karolinska Institutet, Uppsala, Sweden.
*Email: [email protected]