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PERSPECTIVES | MICROBIOLOGY
In humans and other mammals, the first microbes encountered in early life are those
from the maternal microbiota. Despite the foundational nature of this event in human
development, uncertainty persists about the precise timing of this first contact. The
dogmatic belief that fetal development occurs within a sterile intrauterine environment
has been challenged by evidence of bacterial genomic DNA within placental and
chorioamniotic tissues and culturable microbes in newborn meconium (the first feces
passed after birth), raising the controversial possibility that microbial colonization may
begin in utero (1, 2). However, these observations stop short of providing definitive
evidence of colonization during fetal development with a bona fide microbiota (that is,
a live, persistent, and functional community of microorganisms), and thus the concept
of a fetal microbiota remains the subject of debate. In support of this, a recent study
found that the human placenta was devoid of a microbiome although it was found to
contain potential pathogens in a small proportion of samples (3).
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What is clear is that seeding of early-life microbiota with maternal microbes leaves a
lasting imprint on the biology of offspring. Many studies, of both humans and mice,
have found links between the composition of the maternal microbiota and subsequent
risk of childhood illnesses, including infection, asthma, allergy, autoimmunity, and
metabolic diseases such as obesity and diabetes (7). Furthermore, the discovery that
pathological alterations of microbiota composition and diversity (called “dysbiosis”)
can confer susceptibility to a variety of chronic health conditions in adulthood has led
investigators to question whether these dysbiosis-associated phenotypes can be
vertically transmitted from mother to child via the microbiota. For example, a study of
935 mother–infant pairs from Canada found that children of overweight or obese
mothers had a threefold increased risk of becoming obese at 1 year, which increased
to fivefold with cesarian delivery (6). The authors identified taxonomic signatures in
the fecal microbiota of infants during the first months of life that were associated with
a risk of being overweight, supporting the conclusion that the seeding of an “obesity-
associated” microbiota in early life may transmit this phenotype to offspring (6).
Similar data are emerging for a variety of other chronic illnesses including asthma,
allergies, and autoimmunity, not just in childhood but into adulthood as well. This
raises fundamental questions about our understanding of heritable phenotypes,
blurring the lines between inherited familial disease risk and transmissible infection
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given that vertical transmission of microbiota loosely fulfills Koch’s postulates (which
form the criteria for establishing a causative relationship between microbial infection
and disease).
With mounting and compelling data implicating the maternal microbiota of pregnancy
and early life in health and disease, researchers have begun to uncover the
biological mechanisms that allow the maternal and early-life microbiota to influence
host physiology. As exemplified by studies of germ-free mice that are devoid of
microorganisms, colonization by microbes in early life is critical for normal immune
development, including immune cell production (comprising myeloid and lymphoid
lineages), development of lymph nodes, antibody production, T cell polarization, and
immune regulatory functions, as well as innate immunity and epithelial barrier
integrity. Exposure of germ-free mice to commensal bacteria in the gut induces
reprogramming of immune cell function that can reverse many of these immunological
defects, but only (or much more effectively) if microbial exposure occurs at birth, not
later in adulthood (10).
Given that the early-life microbiota is seeded by vertical transmission, the education
of immunity in offspring is critically dependent on maternal commensals. Furthermore,
this relationship among the maternal microbiota, early-life colonization, and immune
development continues to coevolve throughout early life (see the figure). For
example, breastfeeding serves as a continued source of maternal microbes, as well
as supplying nutritional and antimicrobial factors that continuously shape the infant’s
gut microbiota (11). In support of this, an immunological “weaning reaction” in mice
was recently observed at the stage of life when pups are weaned off breastmilk,
consisting of a surge of microbiota-induced immune gene expression in the intestine
together with the generation of immunosuppressive regulatory T cells (12).
Perturbation of this critical developmental window caused long-lasting susceptibility
to immunopathology later in life (12). Although it is clear that maternal microbes and
other factors in breastmilk modulate microbiota composition and immunological
function in offspring, the existence, magnitude, and importance of such a weaning
reaction in humans has not been investigated. The immunological and developmental
impact of the maternal and earlylife microbiota extends well beyond the gut mucosal
immune system, including emerging evidence for a microbiota-mediated gut–brain
axis controlling neuroimmune development and susceptibility to neurodevelopmental
disorders (e.g., autism) and psychiatric illnesses (13).
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GRAPHIC: A. KITTERMAN/SCIENCE
The maternal microbiota of pregnancy also appears to affect fetal development from
afar. Prior to birth, the maternal microbiota is separated from the developing fetus by
both physical barriers of the placenta and chorioamniotic sac and immunological
barriers that are established at the maternal–fetal interface. Nevertheless, data from
animal studies indicate that the composition and metabolic function of the maternal
microbiota are reflected in fetal immune development. Deciphering the impact of the
maternal microbiota during gestation on long-term childhood development has proven
challenging owing to the inherent coupling of the gestational effects of the maternal
microbiota with its role in establishing the early-life microbiota in offspring. For
example, studies of mouse pups born to dams treated with antibiotics during
gestation display abnormal T cell polarization and increased susceptibility to
infections and autoimmunity later in life, but it is not clear whether this is solely a
gestational effect versus a consequence of vertical transmission of a skewed
microbiota to the pups (14, 15).
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Although much has been learned about the maternal microbiota in pregnancy and
early life, many fundamental questions remain. It is unclear if this information can be
used to prevent and treat childhood illnesses. To do so, are live microbial
therapeutics needed, or will specific bacterial products or metabolites suffice (and if
so, which ones)? Further research is needed to determine whether there is a
“normal” maternal and early-life microbiota that should be universally strived for, or
whether microbial therapeutics require individualization. In addition, what are the
ethical considerations of therapeutic modification of an unborn fetus through
manipulation of the maternal microbiota, such as issues of consent and the potential
for unexpected adverse effects? To answer these (and other) outstanding questions,
studies must move beyond observational correlations to define causal relationships,
including the cellular and molecular mechanisms that mediate microbiota–host
interactions in pregnancy and early life. This research must incorporate more than
microbial community structure and instead aim to uncover the functional interactomes
that exist between commensal microbes and the host. This represents an exciting
challenge for scientists to refine the understanding of this fundamental aspect of
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human biology, and an opportunity to apply this science at the cutting edge of health
care to improve maternal and child health.
1Department of Critical Care Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB,
Canada.
2Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of
10.1126/science.aay0618
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