infants follow substantially different growth
trajectories today compared with newborns
only ~100 years ago ( 54 – 56 ) (Fig. 3B). In 1916,
breastfed infants had a more constant growth
rate during their first 8 months of life, which
thereafter leveled off at a decreasing growth
rate in the following months ( 57 )(Fig.3B).His-
toric growth rates further back during human
evolution are not known but were likely even
more different from the current ones. In 2006,
growth charts from the US Centers for Disease
Control and Prevention (CDC) showed that
mostly formula-fed infants had initial growth
rates that were slower than exclusively breast-
fed infants in the World Health Organization
(WHO) standard curve, but superseded breast-
fed infants from 6 months onward, leading to
higher average weights compared with breast-
fed infants at 1 year of age ( 58 ) (Fig. 3B). Breast-
feeding is associated with reduced risks of
immune-mediated diseases later in life ( 59 ).
One hypothesis from these observations is that
an additional cause of the increasing rates of
immune-mediated diseases linked to exuberant
inflammatory reactions to commensals and
harmless allergens could be a decoupling of
normal physiological mechanisms of immune
regulation and inhibition based on resource
allocation and trade-offs between growth and
immune function (Fig. 3C). Such decoupling
could contribute further to explaining un-
restricted inflammatory responses early in
life, impaired immune-microbial mutualism,
and increasing rates of childhood obesity as
seen in many industrialized societies today.
To further explore this possible explanation, we
need to take growth rates into account when
assessing immune-mediated diseases and fur-
ther investigate the mechanisms of resource
allocation for growth versus immunity to better
identify at-risk children and test new inter-
ventions to optimize individual trajectories
for growth and immunological health.
A global view
Immune-mediated diseases differ worldwide,
with high and increasing incidences of asthma,
allergies, and autoimmune diseases in indus-
trialized societies, often in urban areas far
away from animals and where repeated anti-
biotic exposures and cleanliness have depleted
many previously common microbes. One im-
portant example isB. infantis,whichdomi-
nates the gut microbiomes of young, breastfed
children in Bangladesh ( 60 )andMalawi( 61 ),
but is nearly absent in children in Europe ( 62 )
and North America ( 63 ). This exemplifies a
mismatch between ancestral and modern en-
vironments with particular importance during
early-life immune system development and
consequently long-term effects on diseases
such as type 1 diabetes ( 64 ), atopy, and asthma
( 31 ). Efforts to restore beneficial microbes and
prevent immune-mediated diseases after the
initial window of opportunity have proven
challenging, and one reason for this could be
that immune-microbe interactions and tissue-
specific niches are less amenable to change
after this initial period. The proposed poten-
tial importance of life history theory and the
trade-off between investments in physical
growth and immune function is an additional
possible mechanism, established during human
evolution, of restraining exuberant responses
to colonizing microbes early in life. If true, then
this additional layer of regulation, which was
lost because of virtually unrestricted access to
calories in modern industrialized societies,
could further explain parallel increases in
childhood obesity and immune-mediated dis-
eases in many countries. Antibiotic steward-
ship, promotion of breastfeeding whenever
possible, and compensatory nutritional strat-
egies when breastfeeding is not possible will
likely be important in reducing the escalat-
ing burden of immune-mediated diseases
in the future. By learning the mechanisms
of immune system regulation and trade-offs
between investments in growth and immu-
nity, we might be better able to restrain im-
mune responses to commensals and harmless
food components and thus restore tolerance
and reduce risks of disease, perhaps even later
in life.
Although unlimited access to energy might
derail evolutionary mechanisms for restrained
immunity, energy malnutrition and scarcity
also have detrimental consequences for both
immunity and growth. Some of these mech-
anisms might be mediated by altered immune-
microbe interactions, as shown by transfers
of microbes from malnourished children to
germ-free mice, which led to growth restric-
tion ( 65 ). In such situations, normal trade-offs
are also derailed and immune function im-
paired, leading to repeated infections, chronic
inflammation, and worsened malnutrition ( 66 ).
In a recent clinical trial of 2- to 6-month-old
children in Bangladesh with acute malnutri-
tion, supplementation withB. infantiswas
able to break this vicious cycle by reducing
markers of intestinal inflammation and im-
proving weight gain ( 67 ).
In the context of healthy immunometabolic
regulation, increased investigation into the
evolutionary mechanisms of resource allo-
cation for growth and immunity are needed
in the hope of achieving a healthier balance.
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THE SYSTEMIC MICROBIOME