Science - USA (2022-05-27)

the increasing rates of immune-mediated dis-
eases is the hygiene hypothesis, which was
formulated based on the observation that de-
creasing household sizes (fewer siblings) are
associated with increased rates of hay fever
( 51 ), leading to the proposal that reduced in-
fectious disease exposures explains the increas-
ing rates of immune-mediated diseases. An
alternative to the hygiene hypothesis is the
“old friends”hypothesis, which posits that a
loss of specific microbes with which humans
coevolved led to increased rates of immune-
mediated disease by altering immune-microbe
interactions and immune system regulation
( 52 ). Both of these hypotheses exemplify mis-
matches between ancestral environments in
which humans evolved and modern environ-
mental conditions (Fig. 3A). Such mismatches
between ancestral and modern environments
could involve losses of important microbes
that serve valuable functions as commensals,
loss of specific nutrients with important non-
redundant immunological functions, or new
pollutants and chemical substances that have
never been encountered before and might af-
fect immune system processes.
The reasons for priming the phenotype and
locking certain conditions in place during a
critical period of adaptation early in life must
servesomebenefitovercarryingafullyflex-
ible phenotype throughout life. One likely
benefit in the case of establishing immune-
microbe mutualism is that colonization and

tolerance induction can occur during a period

when the infant is rather immobile, physi-

cally sheltered, fed breastmilk, and immuno-

logically protected by passive immunity and

antimicrobial peptides. Locking certain aspects

of the phenotype during these conditions is

likely more beneficial than allowing a fully

amenable phenotype throughout life and risk-

ing substantial changes upon infections and

other insults. However, the benefit of early-

life priming only holds if the environmental

conditions experienced early in life are rep-

resentative of those encountered later in life.

Interpreting this from the perspective of mis-

matches between ancestral and modern envi-

ronments suggests that a mismatch involving

key factors that shape immune-microbe inter-

actions early in life, such as colonization with

key microbes, formula feeding, cesarean de-

livery, and antibiotic exposure, can have dis-

proportionally large impacts on long-term

health compared with, for example, antibiotic

exposure later in life (Fig. 3A). This framework

is meant to bring together the foundation

offered by evolution with the idea of mis-

matched ancestral and modern environments.

It also separates specific mismatched envi-

ronmental exposures into those that are influ-

ential during the early-life establishment of

immune-microbe interactions and hardwir-

ing of selected elements of the phenotype

versus those environmental exposures that

more directly affect humans later in life, such

as smoking, alcohol consumption, exposure

to sun radiation, and solid food components

(Fig. 3A).

Trade-offs between growth

and immune function

Another evolutionary mechanism that controls

overall immune function is energy allocation

and trade-offs between investments in immu-

nity (maintenance), growth, and reproduction,

as described by life history theory ( 1 ). Humans

are born highly dependent on their parents for

food and protection, and there are strong in-

centives for newborns to grow rapidly. This is

reflected by the impressive growth rates of in-

fants, who often triple their body weight during

the first year of life. Until recently, food supply

has been a limiting factor for nursing mothers,

and the quantity and quality of breastmilk

would lead to trade-offs between investments

in physical growth and immunity. For example,

children who are growth restricted in utero

show stronger anti-helminth IgE responses

compared with nonrestricted children, even

when tested in adolescence ( 53 ). Given that par-

asitic infections are a common cause of mal-

nutrition in mothers and growth restriction in

fetuses, prioritization of Th2 immunity in new-

borns as preparation for likely parasitic exposure

after birth is a rational evolutionary outcome.

In industrialized societies, food supply is

rarely a limiting factor during pregnancy or

lactation. Both breastfed and formula-fed

Brodin,Science 376 , 945–950 (2022) 27 May 2022 4of

Ancestral

environment

Early-life

environment

Adult

environment

Evolution Development

Fully matched

Ancestral mismatch

Ancestral mismatch

in adult environment

Early-life mismatch

Complete mismatch

Homo

sapiens

Antibiotics

Newborn

child

Adult

phenotype

Energy

Tolerance to

the microbiota

Inflammatory responses

against the microbiota

Growth

Immune

responses

Energy

Growth

Immune

responses

A B Nutrition and growth trajectories in the first year of life

C Energy-restricted and unrestricted immune responses

Month after birth

Body weight (kg)

11

10

9 8 7 6 5 4 3

0 1 2 3 4 5 6 7 8 10 11 129

CDC standard

(mostly formula fed)

WHO standard, 2006

(Breastfed)

1916 (Breastfed)

Fig. 3. Mismatch between ancestral and modern environments and altered
trade-offs between growth and immunity.(A) During human evolution, the human
immune system evolved under strong selective pressures from microbes. Given
the substantial recent changes to humanenvironmental conditions, a mismatch
between ancestral and modern environments has occurred. Because of the
particular importance of the critical period early in life, mismatches of key factors
involved during this time (antibiotics, breastfeeding, loss of key commensals) may
affect long-term health and immune-mediated diseases. Using this proposed
framework of mismatched ancestral, early-life, and adult environments, the
consequences of specific environmental changes can be investigated. (B) Trade-offs

between investments in physical growth and immunity are described by life history

theory ( 1 ). Changing growth rates over the past century ( 54 – 58 )anddifferences

between breastfed and formula-fed infantstoday reflect such underlying changes.

(C) One hypothesis from these observations is that changes to environmental

conditions, such as unlimited access to nutrients and energy, can derail evolutionarily

conserved mechanisms for resource allocation, which also affects the immune

system by removing the constraints imposed by resource allocation early in life,

leading to more exuberant inflammatory responses to commensals, dysbiosis, and

intestinal inflammation. This could result in increased rates of both immune-

mediated diseases and obesity and metabolic disorders in the long term. ILLUSTRATION: KELLIE HOLOSKI/

SCIENCE