Immune Dysfunction as a Cause and Consequence of Malnutrition

Abstract

Trends
Undernourished children principally die of common infections, and immune defects are consistently demonstrated in under- and overnutrition.
Parental malnutrition leads to epigenetic modifications of infant immune and metabolic genes.
Healthy gut development relies on sensing of dietary nutrients, commensal, and pathogenic microbes via immune receptors.
Recurrent infections, chronic inflammation, and enteropathy compound clinical malnutrition by altering gut structure and function.
Immune cell activation and systemic proinflammatory mediator levels are increased in malnutrition.
Malnutrition impairs immune priming by DC and monocytes, and impairs effector memory T cell function.
Immune dysfunction can directly drive pathological processes in malnutrition, including malabsorption, increased metabolic demand, dysregulation of the growth hormone and HPA axes, and greater susceptibility to infection.

Full text

Series:
Lifetime
Immunity
Review
Immune
Dysfunction
as
a
Cause
and
Consequence
of
Malnutrition
Claire
D.
Bourke,
1,
*
James
A.
Berkley,
2,3
and
Andrew
J.
Prendergast
1,4
Malnutrition,
which
encompasses
under-
and
overnutrition,
is
responsible
for
an
enormous
morbidity
and
mortality
burden
globally.
Malnutrition
results
from
disordered
nutrient
assimilation
but
is
also
characterized
by
recurrent
infections
and
chronic
inflammation,
implying
an
underlying
immune
defect.
Defects
emerge
before
birth
via
modifications
in
the
immunoepigenome
of
malnourished
parents,
and
these
may
contribute
to
intergenerational
cycles
of
malnutrition.
This
review
summarizes
key
recent
studies
from
experimental
animals,
in
vitro
models,
and
human
cohorts,
and
proposes
that
immune
dysfunction
is
both
a
cause
and
a
consequence
of
malnutrition.
Focusing
on
childhood
undernutri-
tion,
we
highlight
gaps
in
current
understanding
of
immune
dysfunction
in
malnutrition,
with
a
view
to
therapeutically
targeting
immune
pathways
as
a
novel
means
to
reduce
morbidity
and
mortality.
Malnutrition
as
an
Immunodeficiency
Syndrome
Malnutrition,
which
encompasses
both
under-
and
overnutrition,
is
responsible
for
an
enormous
health
burden
globally
[1,2]
(Box
1).
Although
broadly
defined
as
impaired
nutrient
assimilation,
malnutrition
does
not
simply
arise
from
inadequate
food
intake.
Obesity
can
develop
indepen-
dently
of
poor
diet
and
persist
despite
switching
to
a
healthy
diet
[3–7],
and
stunting
prevalence
is
only
modestly
reduced
by
intensive
feeding
interventions
[8].
Despite
manifesting
as
distinct
physical
defects,
several
observations
implicate
shared
etiological
pathways
in
under-
and
overnutrition:
early-life
undernutrition
increases
the
risk
of
obesity
in
later
life
[4,9];
altered
metabolism
[10–13],
chronic
inflammation
[11,14,15],
and
gut
dysfunction
(enteropathy)
[11,12,16]
are
features
of
both
conditions;
and
excess
energy
and
macronutrient
intake
is
often
coincident
with
micronutrient
deficiencies
in
overweight
individuals
[17,18].
There
is
a
growing
appreciation
that
malnutrition
is
complex,
reflecting
a
suite
of
overlapping
comorbidities
that
are
poorly
understood
[19–21].
Characterizing
pathogenesis
across
the
spectrum
of
malnutrition
is
essential
to
underpin
novel
therapeutic
approaches
to
support
international
goals
to
improve
nutrition,
health,
and
well-being
(https://sustainabledevelopment.un.org).
Undernourished
children
principally
die
of
common
infections
[22,23],
implying
that
mortality
is
related
to
underlying
immunodeficiency,
even
in
mild
forms
of
undernutrition
[24].
Infections
are
more
common
and
more
severe
in
people
with
obesity
[25].
Defects
in
both
the
innate
and
adaptive
arms
of
the
immune
system
have
been
consistently
demonstrated
in
undernourished
children
(Box
2)
[23].
In
this
review
we
explore
the
hypothesis
that
immune
dysfunction
is
both
a
cause
and
consequence
of
malnutrition,
and
summarize
key
recent
evidence
from
experimental
Trends
Undernourished
children
principally
die
of
common
infections,
and
immune
defects
are
consistently
demonstrated
in
under-
and
overnutrition.
Parental
malnutrition
leads
to
epige-
netic
modifications
of
infant
immune
and
metabolic
genes.
Healthy
gut
development
relies
on
sen-
sing
of
dietary
nutrients,
commensal,
and
pathogenic
microbes
via
immune
receptors.
Recurrent
infections,
chronic
inflamma-
tion,
and
enteropathy
compound
clin-
ical
malnutrition
by
altering
gut
structure
and
function.
Immune
cell
activation
and
systemic
proinflammatory
mediator
levels
are
increased
in
malnutrition.
Malnutrition
impairs
immune
priming
by
DC
and
monocytes,
and
impairs
effec-
tor
memory
T
cell
function.
Immune
dysfunction
can
directly
drive
pathological
processes
in
malnutrition,
including
malabsorption,
increased
metabolic
demand,
dysregulation
of
the
growth
hormone
and
HPA
axes,
and
greater
susceptibility
to
infection.
1
Centre
for
Genomics
and
Child
Health,
Blizard
Institute,
Queen
Mary
University
of
London,
London,
UK
2
Kenya
Medical
Research
Institute
(KEMRI)–Wellcome
Trust
Collaborative
Research
Programme,
Centre
for
386
Trends
in
Immunology,
June
2016,
Vol.
37,
No.
6
http://dx.doi.org/10.1016/j.it.2016.04.003
©
2016
The
Authors.
Published
by
Elsevier
Ltd.
This
is
an
open
access
article
under
the
CC
BY
license
(http://creativecommons.org/licenses/by/4.0/).

Geographic
Medicine
Research,
Kifili,
Kenya
3
Centre
for
Tropical
Medicine
and
Global
Health,
University
of
Oxford,
Oxford,
UK
4
Zvitambo
Institute
for
Maternal
and
Child
Health
Research,
Harare,
Zimbabwe
*Correspondence:
c.bourke@qmul.ac.uk
(C.D.
Bourke).
animal
models,
human
cohorts,
and
in
vitro
studies.
We
regard
malnutrition
as
a
syndrome
in
which
multiple
underlying
processes
are
the
cause
of
elevated
mortality
and
morbidity
[20]
(Box
1);
immune
dysfunction
is
involved
in
many
of
these
pathways
and
is
therefore
a
key
driver
of
the
vicious
cycle
that
leads
to
clinical
malnutrition
(Figure
1).
Our
focus
is
childhood
Box
1.
Epidemiology
and
Clinical
Features
of
Malnutrition
Malnutrition
is
a
clinical
syndrome
that
encompasses
a
spectrum
of
anthropometric
defects
from
wasting
(low
weight-for-
height)
and
stunting
(low
height-for-age)
in
undernutrition
to
overweight
(body
mass
index,
BMI,
of
25–30)
and
obesity
(BMI
>30)
in
overnutrition.
An
estimated
3.1
million
children
under
5
years
die
annually
as
a
result
of
undernutrition,
accounting
for
45%
of
all
child
mortality
[2].
The
global
prevalence
of
overweight
in
the
under
5
year
age
group
increased
by
54%
between
1990
and
2011
[2].
Growth
faltering
in
developing
countries
is
often
evident
at
birth.
Weight-for-age
and
length-for-age
Z
scores
continue
to
decline
over
the
first
2
years
of
life,
with
little
recovery
thereafter
[70].
Maternal
height
and
infant
birthweight
are
consistent
predictors
of
infant
growth
(short
mothers
bear
small
babies
who
become
stunted
adults
themselves)
[20].
Stunting
affects
around
165
million
children
worldwide
(www.who.int/nutgrowthdb/estimates/en)
and
is
associated
with
short-
term
increases
in
infectious
mortality
and
long-term
neurodevelopmental
defects
[20,65,87].
Stunted
children
are
shorter
than
healthy
reference
populations
(height-for-age
Z
score
2)
and
may
exhibit
reduced
exploratory
behavior
and
physiological
arousal
[87],
but
are
otherwise
clinically
well.
Wasting
affects
approximately
52
million
children
(www.who.int/nutgrowthdb/estimates/en)
and
has
a
stronger
associa-
tion
with
case
mortality
than
stunting.
Wasting
is
characterized
by
loss
of
fat
and
muscle
in
the
thighs,
buttocks,
upper
arms,
and
ribs;
severe
acute
malnutrition
(SAM)
is
characterized
by
severe
wasting
(mid-upper
arm
circumference
(MUAC)
<115
mm
for
children
aged
6–59
months
and/or
weight-for-height
Z
score
3;
www.who.int/childgrowth/
standards).
Kwashiorkor
is
a
distinct
SAM
phenotype
typified
by
skin
and
hair
changes,
irritability,
symmetrical
edema,
and
fatty
liver
infiltration.
Children
with
uncomplicated
SAM
(no
apparent
infections
and
good
appetite)
can
be
managed
in
the
community
with
energy-dense
micronutrient-supplemented
foods
[84].
Children
with
complicated
SAM
(clinically
unwell
and/or
refusing
feeds)
are
often
physiologically
unstable,
with
impaired
organ
function,
coinfections,
micronutrient
deficiencies,
and
a
high
risk
of
dying,
which
requires
immediate
hospitalization,
supervised
feeding
and
rehydration,
and
broad-spectrum
antibiotics
even
if
symptoms
of
infection
are
absent
[84].
Early-life
undernutrition
confers
an
increased
risk
of
obesity
in
adulthood
[4,9].
This
‘double
burden’
of
malnutrition
disproportionately
affects
low-
and
middle-income
countries
undergoing
rapid
socioeconomic
changes
[4].
Clinical
symptoms
of
obesity
include
high
percentage
adipose
tissue,
high
circulating
levels
of
triglycerides,
high
blood
pressure
which
can
lead
to
cardiovascular
disease,
and
high
blood
glucose
levels
reflecting
insulin
resistance
which
can
lead
to
type-2
diabetes
[4,6,9,25].
Similarly
to
undernutrition,
overweight
is
associated
with
an
increased
risk
of
all-cause
[1]
and
infectious
mortality
[25].
Box
2.
Immune
Defects
in
Undernourished
Children
A
recent
systematic
literature
review
[23]
identified
245
studies
published
between
1957
and
2014
describing
immune
parameters
in
undernourished
children
(age
0–5
years).
However,
the
review
highlights
that
the
majority
of
studies
were
conducted
several
decades
ago
using
out-dated
immunology
techniques
and
focused
on
hospitalized
children
with
severe
forms
of
malnutrition
and
multiple
coinfections.
Characterization
of
immunodeficiency
was
limited
by
a
lack
of
longitudinal
studies,
particularly
for
mild
and
moderate
malnutrition.
The
precise
nature
of
immunodeficiency
in
under-
nutrition
therefore
remains
uncertain;
however,
the
consensus
from
the
available
evidence
is
that
both
innate
and
adaptive
immunity
are
impaired
by
malnutrition.
Defects
in
innate
immune
function
include
impaired
epithelial
barrier
function
of
the
skin
and
gut,
reduced
granulocyte
microbicidal
activity,
fewer
circulating
dendritic
cells,
and
reduced
complement
proteins,
but
preserved
leukocyte
numbers
and
acute
phase
response.
Defects
in
adaptive
immune
function
include
reduced
levels
of
soluble
IgA
in
saliva
and
tears,
lymphoid
organ
atrophy,
reduced
delayed-type
hypersensitivity
responses,
fewer
circulating
B
cells,
a
shift
from
Th1-associated
to
Th2-associated
cytokines,
and
lymphocyte
hyporesponsiveness
to
phytohemagglutinin,
but
preserved
lymphocyte
and
immunoglobulin
levels
in
peripheral
blood.
Despite
this,
most
malnourished
children
seem
to
respond
adequately
to
vaccination,
although
the
timing,
quality,
and
longevity
of
vaccine-specific
responses
may
be
impaired
[71,72].
There
is
an
evident
need
for
contemporary
studies
of
childhood
undernutrition
incorporating
up-to-date
functional
immunological
methods
in
well-characterized
longitudinal
cohorts
of
children.
Studies
need
to
define
malnutrition
using
current
metrics
of
stunting,
wasting,
or
both
together,
with
appropriate
well-nourished
comparison
groups,
and
evaluate
associations
between
immune
parameters
and
clinical
outcomes.
Development
of
novel
experimental
approaches
to
explore
immune
ontogeny
[88,89],
epigenetics
[5,32–34],
immunometabolomics
[61],
the
gut
microbiome
[49]
and
virome
[90],
enteropathy
[59],
and
nutrient-sensing
[38,39]
also
provide
unprecedented
opportunities
for
translation
into
immunological
studies
of
childhood
undernutrition.
Because
immunodeficiency
is
also
a
feature
of
overnutrition
(reviewed
recently
[6,25]),
immunological
studies
in
overweight
and
obese
children
may
also
be
pertinent
to
understanding
immunopathogenesis
in
undernutrition.
Trends
in
Immunology,
June
2016,
Vol.
37,
No.
6
387

undernutrition
in
developing
countries,
where
the
greatest
burden
of
mortality
is
concentrated
[2],
but
we
also
identify
relevant
studies
of
overnutrition.
Throughout
the
review
we
highlight
research
gaps
that
need
to
be
addressed
in
future
studies
and
speculate
on
the
potential
for
immune-targeted
therapies
to
reduce
morbidity
and
mortality
in
undernourished
children.
Immune
Development
in
Malnutrition
The
trajectory
of
infant
immune
development
during
the
first
1000
days
of
life
(Box
3)
is
sensitive
to
nutritional
status,
such
that
impaired
immune
organ
growth
[26–28]
and
thymic
atrophy
[23,29]
can
be
evident
at
birth
in
undernourished
infants.
In
a
rural
Bangladeshi
cohort,
thymic
index
(TI)
at
birth
was
positively
associated
with
birthweight
[27]
and
all-cause
mortality
at
8
weeks
[26].
Compared
to
adequately
nourished
rat
pups,
pups
of
dams
exposed
to
protein
energy
malnutrition
(PEM)
during
lactation
have
smaller
thymuses
[30,31],
increased
thymocyte
apoptosis
[31],
and
a
greater
proinflammatory
thymocyte
response
to
leptin
as
a
result
of
higher
leptin
receptor
expression
[30].
These
observations
suggest
an
interacting
relationship
between
nutrition,
growth,
and
immune
development,
of
which
thymic
size
is
one
indicator.
Infant
infections,
microbial
colonization
of
the
gut,
T
cell
activation,
and
TI
have
also
been
linked
to
Malnutrion
Malabsorpon Stunng and wasng Poor cognion Metabolic syndrome*
Altered body
composion
Altered feeding
behavior
Enteropathy
Altered
microbiota Reduced
IGF-1
Dysregulated adipokine and
HPA signaling
Increased metabolic
demand
Recurrent infecons
Subopmal immune
priming and memory
Chronic inflammaon and
immune acvaon Insufficient regulaon
of immune responses
Immune dysfuncon
(Summarized in Box 2)
Inadequate diet Parental malnutrion
Modified
immunoepigenome
● Caloric restricon
● Micronutrient or macromolecule
deficiencies
● Excess fat or sugar intake
● Dietary transition
● Distinct epigenetic marks on
immune genes
● Heritable changes
● Reduced Iymphoid organ size and development (Box 3
)
● In utero exposure to infection and inflammation (metabolic cost)
● Acquisition of suboptimal microbiota (Box 4
)
● Poor mucosal development (Box 3
)
● Absence of dietary ligands sensed by immune cells
● Reduced passive protection by maternal immune factors
● Low birth weight
● Dysregulation of tolerogenic infant immune environment (Box 3
)
(Box 4)
(Clinically defined in Box 1
)
Figure
1.
Conceptual
Framework
for
Immune
Dysfunction
as
a
Cause
and
Consequence
of
Malnutrition.
Immune
dysfunction
can
arise
before
birth
via
developmental
pathways
(purple),
compounded
by
environmental
and
behavioral
factors
(yellow),
particularly
those
experienced
during
early
life.
Immune
dysfunction
(blue;
as
defined
in
a
recent
systematic
review
[23]
and
summarized
in
Box
2)
can
contribute
both
directly
and
indirectly
to
a
range
of
causal
pathways
(green)
that
lead
to
clinical
malnutrition
(red;
refer
to
Box
1
for
the
clinical
features
of
under-
and
overnutrition
in
humans).
Abbreviations:
HPA,
hypothalamus–pituitary–adrenal
axis;
IGF-1,
insulin-like
growth
factor
1;
*,
refers
to
predisposition
to
metabolic
syndrome
in
adulthood
following
exposure
to
undernutrition
in
infancy.
388
Trends
in
Immunology,
June
2016,
Vol.
37,
No.
6

breast-feeding
practices
(Box
3),
but
the
specific
breast
milk
components
responsible
have
not
been
identified.
It
is
increasingly
apparent
that
malnutrition
can
influence
immune
development
before
conception
because
maternal
malnutrition
confers
epigenetic
modifications
in
her
offspring
[32–34].
Gambian
women
who
conceived
during
periods
of
low
food
availability
had
lower
plasma
concentrations
of
methyl-donor
pathway
substrates
relative
to
women
who
conceived
during
periods
of
higher
food
availability,
and
their
infants
had
distinct
percentages
of
methylation
of
known
metastable
epialleles
at
2–8
months
of
age
[34].
A
randomized,
double-blind,
placebo-controlled
trial
of
pre-
and
periconception
multiple
micronutrient
supplementation
also
found
differences
in
infant
DNA
methylation
between
the
supplemented
and
unsupplemented
groups
[32,33].
Methylation
differ-
ences
in
immune
(SIGLEC5,
CD4,
and
KLRC2)
and
innate
defense
(BPIL1,
CHIT1,
and
DEFB123)
genes
were
evident
at
birth,
and
some
were
still
detectable
9
months
later
[33],
suggesting
that
maternal
micronutrient
supplementation
had
a
lasting
impact
on
the
infant
immune
epigenome.
Distinct
methylation
of
the
IL10
locus
has
also
been
identified
in
Dutch
adults
exposed
to
famine
in
utero
relative
to
their
unexposed
sex-matched
siblings
over
50
years
later
[35].
How
the
perinatal
immune
epigenome
affects
long-term
immune
function
has
not
been
assessed;
however,
the
heritable
impact
of
malnutrition
suggests
that
the
optimal
timing
for
therapeutic
interventions
to
rescue
infant
growth
and
development
may
need
to
be
re-evaluated
[20,29].
The
intimate
association
between
the
nutritional
status
of
infants
and
their
mothers
means
that
the
relative
impacts
of
immune
dysfunction
and
maternal
diet
on
infant
malnutrition
are
difficult
to
extricate.
However,
paternal
malnutrition
has
recently
been
shown
to
impart
heritable
changes
on
infant
metabolism
and
immune
function
without
in
utero
exposure
to
a
marginal
diet
[36,37].
Male
mice
exposed
to
in
utero
PEM
had
distinct
epigenetic
marks
at
the
Lxra
locus
that
were
inherited
by
their
adequately
nourished
offspring
[37].
Lxra
encodes
a
nuclear
receptor
involved
in
inflammation
and
lipid
metabolism,
and
Lxra-dependent
changes
in
liver
lipid-synthesis
genes
Box
3.
Immune
Development
During
the
First
1000
Days
of
Life
The
first
1000
days
of
life
(from
conception
to
2
years)
is
identified
as
a
developmental
window
of
opportunity
for
therapeutic
interventions
for
undernutrition
(www.thousanddays.org/)
and
is
also
a
critical
period
in
immune
development
[91].
Evidence
that
early-life
malnutrition
confers
life-long
immunodeficiency
[4,20,24]
is
consistent
with
a
‘layered’
model
of
immune
ontogeny
in
which
adult
immune
function
relies
on
developmental
steps
at
earlier
ages
(e.g.,
fetal
and
adult
CD4
+
T
cells
derive
from
phenotypically-distinct
hematopoietic
stem
cells
[89]).
Immune
responses
are
more
tolerogenic
in
infancy
than
adulthood,
fetal
naïve
T
cells
differentiate
into
Tregs
more
readily
[89],
Tregs
comprise
higher
proportions
of
CD4
+
T
cells
in
pediatric
(30–40%)
versus
adult
tissues
(1–10%)
[88],
and
maternal
alloantigen-specific
T
cell
expansion
is
suppressed
by
high
Treg
frequencies
in
infant
lymphoid
organs
[92].
GALT
population
by
lymphocytes
begins
in
utero,
but
postnatal
cues
from
environmental
(dietary
and
microbial)
antigens
instigate
optimal
positioning
and
accumulation
of
peripherally
matured
cells
[38,88].
Analysis
of
infant
organ
donor
tissues
showed
that
activated
T
cell
populations
initially
expand
at
mucosal
sites,
likely
due
to
ingested
or
inhaled
antigen
exposure
[88].
Naïve
(CD45RA
+
CCR7
+
)
T
cells
predominate
in
most
infant
tissues
(70–90%)
relative
to
adults
(<50%);
however,
the
gut
and
lungs
had
the
highest
T
EM
(CD45RA

CCR7

)
proportions
in
the
infant
tissues
analyzed
[88].
A
role
for
immune
receptor
interactions
with
environmental
antigens
in
murine
gut
development
has
been
conclusively
demonstrated
[48,93].
Vascularization
of
the
ileum,
epithelial
cell
proliferation,
and
colonic
mast
cells
are
perturbed
in
neonatal
mice
lacking
the
TLR
and
IL-1
receptor-associated
signaling
molecules
MyD88
and
TRIF
[48].
Mice
weaned
onto
macromolecule-depleted
chow
devoid
of
dietary
antigens
lack
peripherally
generated
Treg
(pTreg)
cells
required
for
oral
tolerance
[93].
These
effects
were
distinguishable
from
those
of
the
microbiota
because
MyD88-
and
TRIF-deficient
animals
had
similar
fecal
microbiota
compositions
to
co-housed
littermates
[48].
Comparison
of
intestinal
tissue
from
macromolecule-deficient
mice,
germ-free
mice
and
mice
exposed
to
a
normal
diet
and
microbial
colonization
showed
that
diet-induced
and
microbiota-induced
pTreg
populate
distinct
locations
[93].
Infant
diet
shapes
environmental
antigen
exposure,
and
weaning
alters
mucosal
development
[48].
Exclusive
breastfeeding
is
recommended
for
the
first
6
months
of
life
in
developing
countries,
thereby
providing
essential
nutrients
and
maternal
immune
factors
[91].
Early
introduction
of
non-breast
milk
foods
increases
risk
of
diarrhea
[94],
which
coincides
with
growth
faltering
[20,55].
Breast
milk
also
contains
microbes
[95]
which
engage
immune
receptors
and
seed
the
gastrointestinal
tract
[96].
Birth
mode
(vaginal
or
caesarean)
[96]
and
breastfeeding
duration
[95]
shape
the
infant
microbiota.
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2016,
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No.
6
389

were
evident
in
second-generation
offspring
[37].
The
sperm
epigenome
of
obese
men
has
also
been
shown
to
respond
to
weight
loss
after
bariatric
surgery
[36].
Gut
Immune
Responses
in
Malnutrition
The
gut
is
the
primary
interface
between
diet
and
the
immune
system,
and
a
range
of
postnatal
cues
from
the
microbiota,
pathogens,
and
dietary
components
are
required
for
healthy
devel-
opment
of
gut-associated
lymphoid
tissue
(GALT;
Box
3).
Direct
Nutrient
Sensing
A
range
of
micronutrients
and
nutrient
metabolites
act
as
direct
immune
stimuli
[38],
but
isolating
their
independent
effects
has
been
largely
restricted
to
murine
models
in
which
diet
can
be
carefully
controlled.
The
aryl
hydrocarbon
receptor
(AhR),
which
binds
to
metabolites
of
cruciferous
vegetables,
is
abundantly
expressed
on
murine
intraepithelial
lymphocytes
(IEL;
TCRgd
+
CD44
int
CD25

CD69
+
CCR6

)
and
intrinsic
AhR
signaling
is
essential
for
their
localization
in
the
gut
and
skin
[39].
Lymphoid
tissue-inducer
cells
(a
type
of
innate
lymphoid
cell,
ILC3,
involved
in
lymphoid
development)
express
AhR
and
retinoic
acid
receptor
(RAR)-
related
orphan
receptor
(ROR)
gt,
which
interacts
with
the
vitamin
A
metabolite
retinoic
acid,
demonstrating
a
mechanistic
link
between
nutrient
sensing
and
immune
development
[39–41].
Murine
dendritic
cell
(DC)
subsets
vary
in
their
relative
expression
of
retinoid
and
rexinoid
receptor
isoforms,
leading
to
selective
loss
of
splenic
CD11b
+
CD8/

Esam
high
DC
and
the
associated
gut-homing
CD11b
+
CD103
+
DC
subset
in
vitamin
A-deficient
mice
[40].
An
analo-
gous
population
of
CD103
+
DC
has
been
isolated
from
human
mesenteric
lymph
nodes
[42],
although
their
micronutrient
receptor
profiles
and
functions
have
not
been
investigated
in
malnutrition.
DCs
can
also
synthesize
retinoic
acid,
which
influences
subsequent
T
cell
trafficking
(reviewed
in
[43])
and
promotes
T
regulatory
cell
(Treg)
induction
in
the
lamina
propria
(reviewed
in
[44]).
Peyers
patch
follicular
DCs,
a
specialized
cell
type
promoting
high-affinity
antibody
responses,
also
express
RARs
and
Toll-like
receptors
(TLRs)
in
mice
[45].
Both
vitamin
A
and
MyD88
deficiencies
result
in
reduced
IgA
production
in
murine
Peyers
patch
germinal
centers
and
lower
B
cell
chemoattractant
CXCL13
and
B
cell
activating
factor
expression
[45],
impli-
cating
sensing
of
both
micronutrients
and
bacteria
in
mucosal
B
cell
function.
Importantly,
nutrient-sensing
pathways
such
as
AhR
and
RAR
signaling,
directly
influence
clear-
ance
of
gastrointestinal
infections
in
murine
models
[39,41].
Direct
nutrient
sensing
may
also
enable
the
gut
immune
system
to
adapt
to
adverse
environmental
conditions,
including
micronutrient
deficiencies.
For
example,
mice
subjected
to
vitamin
A
deficiency
exhibit
profound
reductions
in
ILC3
and
antibacterial
responses,
with
a
compensatory
expansion
in
IL-13-producing
ILC2,
leading
to
increased
anti-helminth
responses
[41].
Collectively
these
experiments
refute
the
idea
that
undernutrition
leads
to
a
generalized
reduction
in
immune
responsiveness,
supporting
instead
a
model
of
phenotypic
plasticity
in
mucosal
immunity
that
responds
to
nutrient
availability.
These
murine
models
highlight
mechanisms
that
may
be
pertinent
to
human
malnutrition
because
vitamin
A
deficiency
is
one
of
the
most
common
micronutrient
deficiencies
globally.
Meta-analysis
of
43
clinical
trials
of
oral
vitamin
A
supplementation
in
infancy
demonstrated
a
consistent
reduction
in
diarrheal
incidence
and
mortality
[46];
however,
no
trials
assessed
mucosal
immune
responses.
All-trans
retinoic
acid
supplementation
led
to
slight
elevations
in
lipopolysaccharide
(LPS)-
and
vaccine
peptide-specific
IgA
in
the
whole
gut
lavage
fluid,
but
not
the
serum,
of
Zambian
adults
in
a
small
typhoid
vaccination
study
[43,47],
highlighting
the
benefit
of
investigating
both
peripheral
and
mucosal
immune
responses
in
future
studies.
Microbiota
In
addition
to
nutrient
sensing,
microbiota
sensing
via
pathogen-recognition
receptors
(PRR)
is
also
required
for
GALT
development
[48]
(Box
3).
The
configuration
of
commensal
micro-
organisms
(microbiota)
detectable
in
feces
is
altered
in
malnutrition
(Box
4),
and
fecal
transplants
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2016,
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6

from
undernourished
children
recapitulate
weight
loss
in
gnotobiotic
mice
[13],
suggesting
that
the
microbiota
may
contribute
to
malnutrition
[49].
The
immune
system
has
been
implicated
in
this
relationship
by
IgA
profiling
studies
demonstrating
that
a
portion
of
the
fecal
microbiota
from
Malawian
infants
with
SAM
is
directly
bound
by
mucosal
antibodies
[50].
Importantly,
the
IgA-
targeted
consortia
transferred
enteropathy
to
adult
germ-free
mice,
but
the
bacterial
species
less
often
targeted
by
IgA
did
not
[50].
Pathological
changes
in
the
microbiota
and
nutrient
metabolite
levels
in
overweight
adults
were
associated
with
increased
epithelial
proliferation
rates,
IEL
numbers,
and
CD68
+
macrophages
in
colonic
biopsies
[12].
Notably,
the
16S
ribosomal
RNA-detectable
fecal
community
analyzed
in
these
studies
represents
only
a
subset
of
the
microbial
load
present
in
the
gut.
Future
studies
incorporating
less-accessible
microbes
and
immune
cells
from
gut
tissue
will
be
necessary
to
delineate
their
relative
roles
in
undernutrition.
Infections,
Enteropathy,
and
Inflammation
Healthy
gut
function
requires
a
large
surface
area
for
nutrient
absorption,
made
possible
by
the
complex
villous
architecture
of
the
intestinal
epithelium,
and
an
intact
intestinal
barrier
to
prevent
pathogen
translocation
into
extraintestinal
tissues.
Both
are
markedly
impaired
in
malnourished
individuals
[51–53],
and
there
is
an
almost
universal
abnormality
of
gut
structure
and
function
among
individuals
inhabiting
impoverished
conditions,
termed
environmental
enteric
dysfunction
(EED)
[19,51,52].
Repeated
exposure
to
enteric
pathogens
is
hypothesized
to
be
the
predomi-
nant
cause
of
EED
in
conditions
of
poor
sanitation
[20,51,52],
but
multiple
causes
of
enteropathy
are
likely
in
developing
countries
[51].
Microarray
of
fecal
samples
from
Malawian
children
with
EED
identified
a
range
of
mRNA
transcripts
for
immune
genes
significantly
correlated
with
intestinal
permeability
(percentage
lactulose
recovery
following
a
dual-sugar
absorption
test),
an
indicator
of
EED
severity
[54].
These
findings
implicate
immune
pathways
in
gut
dysfunction,
and
future
studies
will
be
necessary
to
explore
their
relationship
with
malabsorption,
particularly
in
children
with
SAM
who
were
excluded
from
microarray
analysis
[54].
Box
4.
The
Microbiota
in
Malnutrition
The
microbiota
plays
a
direct
role
in
digestion
by
metabolizing
nutrients
that
the
human
gut
cannot
[38,49].
Without
signals
from
microbial
components,
mucosal
immune
development
and
digestion
are
markedly
impaired
[48,93,97],
and
reciprocal
immune
signals
shape
microbiota
composition
[97].
Unlike
intestinal
epithelial
cells,
which
are
segregated
from
the
gut
lumen
by
a
mucus
layer
and
innate
defense
mechanisms,
the
microbiota
is
in
intimate
contact
with
ingested
food
and
environmental
contaminants,
and
the
emerging
view
is
that
the
microbiota
is
a
sensor
of
dietary
change
[11,38,49].
This
hypothesis
has
been
confirmed
through
systematic
modifications
of
dietary
protein,
fat,
polysaccharide,
and
simple
sugars
in
gnotobiotic
mice
populated
with
10
defined
human
gut
bacterial
species,
in
which
each
nutrient
governed
distinct
microbial
compositions,
and
protein
changes
accounted
for
the
largest
variations
[98].
16S
ribosomal
RNA
sequencing
of
bacteria
in
human
fecal
samples
from
developing
countries
has
highlighted
the
specific
contribution
of
the
microbiota
to
undernutrition
in
children
[13,16,50,90],
and
complementary
murine
models
can
be
generated
via
fecal
transplantation
from
children
with
SAM
into
gnotobiotic
mice
[13,16,90].
Cohorts
of
twins
and
triplets
discordant
for
malnutrition,
and
detailed
longitudinal
characterization
of
healthy
microbial
colonization
in
healthy
‘exemplar’
infants
inhabiting
similar
environments,
have
allowed
a
range
of
common
confounders
in
human
malnutrition
studies
to
be
controlled
for,
including
age-dependent
microbial
plasticity;
environmental
factors
such
as
diet,
pathogen
exposure,
and
WASH;
and
host
genetic
variation.
Relative
to
age-matched
adequately
nourished
children,
children
with
SAM
have
defects
in
the
diversity
and
composition
of
commensal
microbes
[13,16,90],
termed
‘microbiota
immaturity’
[16].
Although
therapeutic
feeding
interventions
ameliorate
changes
in
the
bacterial
microbiota
of
children
with
SAM
[16],
the
virome
is
unaffected
[90],
and
the
bacterial
microbiome
returns
to
its
pre-intervention
composition
after
feeding
interventions
have
ceased
[13,16].
Healthy
fecal
metabolite
profiles
in
gnotobiotic
mice
transplanted
with
the
microbiota
from
undernourished
children
were
also
restored
when
animals
were
fed
nutrient-rich
chow,
but
regressed
once
mice
returned
to
a
nutrient-poor
‘Malawian’
diet,
reflecting
the
direct
impact
of
microbial
changes
on
digestion
[13].
Microbiota
composition
and
fecal
and
urinary
metabolite
profiles
also
shifted
in
rural-
dwelling
South
Africans
fed
a
high-fat,
low-fiber
‘Westernized’
diet
[12].
These
observations
demonstrate
that
microbiota
composition
and
the
quality
of
nutrient
digestion
are
rapidly
reconfigured
by
dietary
interventions,
but
these
changes
are
not
sustained,
either
owing
to
underlying
defects
in
gut
immune
function,
reintroduction
of
an
inadequate
diet,
or
continued
exposure
to
unfavorable
environmental
selection
pressures
(e.g.,
poor
WASH).
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391

EED
may
affect
the
immune
system
through
several
mechanisms:
(i)
altered
nutrient-sensing
pathways
required
for
GALT
development,
(ii)
mechanical
gut
tissue
damage
releasing
host-
derived
immune-activating
damage-associated
molecular
patterns
(DAMPs)
and
upregulating
epithelial
repair
[54],
and
(iii)
loss
of
gut
barrier
function
leading
to
systemic
leakage
of
microbes
and
pathogen-associated
molecular
patterns
(PAMPs)
from
the
gut
lumen
(a
process
termed
microbial
translocation).
Few
studies
have
examined
human
gut
biopsy
samples,
leaving
these
overlapping
mechanisms
poorly
distinguished.
However,
gut
damage
is
evident
early
in
life
in
developing
countries,
and
incremental
acquisition
of
enteric
infections
[55],
circulating
PAMPs,
and
systemic
inflammation
are
linked
to
poor
linear
growth
[14,15,56].
Proinflammatory
medi-
ators
may
contribute
to
stunting
by
dysregulating
growth
hormone
signaling,
consistent
with
murine
models
showing
that
genetic
overexpression
of
IL-6
negatively
regulates
insulin-like
growth
factor-1
(IGF-1)
levels
[57].
Zimbabwean
infants
who
became
stunted
by
18
months
of
age
had
significantly
higher
plasma
concentrations
of
proinflammatory
markers
(C-reactive
protein,
CRP,
and
/1-acid
glycoprotein,
AGP)
and
lower
plasma
levels
of
IGF-1
than
their
non-stunted
counterparts
[14].
IGF-1
levels
negatively
correlated
with
CRP,
AGP,
IL-6
and
soluble
CD14
in
this
cohort
[14],
and
with
CRP,
IFN-g,
IL-1/,
and
MIP-1/
in
a
smaller
cohort
of
Kenyan
infants
with
SAM,
stunting,
and
chronic
inflammation
[56].
Plasma
LPS
levels
were
negatively
associated
with
linear
growth
in
the
latter
study
[56].
Dysregulation
of
growth
factor
signaling
is
also
evident
in
type
1
diabetic
enteropathy
where
high
circulating
IGF-1
binding
protein
levels
impair
the
in
vitro
growth
and
differentiation
of
IGF-1
receptor
+
colonic
stem
cells
[58];
thus
chronic
inflammation
in
undernutrition
could
plausibly
exacerbate
enteropathy
through
simultaneous
epithelial
damage
and
dysregulation
of
IGF-1-dependent
stem
cell-mediated
mucosal
repair.
A
better
understanding
of
immunopathogenesis
in
malnutrition
has
arisen
from
a
murine
model
of
EED
[59].
C57BL/6
mice
fed
fat-
and
protein-reduced
diets
developed
mild
stunting
and
wasting
and,
consistent
with
observations
in
human
EED
[15,51,52],
poor
growth
was
accom-
panied
by
reduced
gut
integrity
and
an
altered
microbiota
[59].
The
EED
gut
had
more
duodenal
gd
IELs,
higher
jejunal
proinflammatory
cytokine
responses
to
oral
doses
of
bacteria,
and
higher
jejunal
and
cecal
Salmonella
typhimurium
loads
post-challenge
than
adequately
nourished
animals
[59].
Collectively,
this
model
demonstrates
that
infection-driven
dysregulation
of
muco-
sal
immune
function
can
cause
EED,
systemic
inflammation,
and
growth
failure.
Alternative
murine
models
provide
proof-of-concept
that
chronic
immune
activation,
as
seen
in
EED,
can
drive
wasting
and
infection
susceptibility
independently
of
dietary
deficiency.
Transgenic
mice
constitutively
expressing
the
activation-induced
costimulatory
ligand
CD70
exhibited
progres-
sive
CD27-dependent
expansion
of
T
effector
memory
cells
(T
EM
)
and
reciprocal
depletion
of
naïve
T
cells
in
secondary
lymphoid
organs,
resulting
in
weight
loss
and
premature
death
from
opportunistic
Pneumocystis
carinii
infection
[60].
The
CD70–CD27
pathway
is
postulated
to
be
overactive
in
human
HIV
[60]
and
may
also
compound
infectious
mortality
in
undernutrition.
Immunometabolic
Signatures
of
Malnutrition
Immunometabolism
refers
to
the
chemical
reactions
required
for
immune
function,
and
the
reciprocal
effects
of
metabolic
products
on
immune
cells
[61].
Cell
activation
results
in
a
metabolic
shift
to
meet
the
high
energy
requirements
of
anabolism
(de
novo
molecule
synthesis)
and
energy
generation
via
catabolism
[61].
Cytokine
signaling
and
T
cell
receptor
engagement
can
trigger
upregulation
of
amino
acid,
iron,
and
glucose
transporters
to
fuel
the
increased
metabolic
demands
of
activated
immune
cells
(reviewed
in
[62,63]).
Immunometabolism
has
emerged
as
an
important
mechanistic
pathway
in
malnutrition
from
observations
that
altered
energy
usage
in
obesity
and
metabolic
syndromes
drives
immune
activation
[6],
and
that
systemic
proinflammatory
cytokines
are
elevated
together
with
free
fatty
acids
and
ketones
in
SAM
[10].
Inflammation
is
reduced
in
children
with
SAM
following
therapeutic
feeding
[10],
and
short-term
shifts
in
fecal
and
urinary
metabolites
occur
following
dietary
alterations
in
under-
and
392
Trends
in
Immunology,
June
2016,
Vol.
37,
No.
6

overnutrition
[11,13].
Chronic
immune
activation
in
malnutrition
therefore
appears
to
place
high
demands
on
nutrient
metabolism,
which
are
likely
intensified
by
recurrent
infection,
microbiota
perturbations,
and
enteropathy
(Figure
1).
Specific
nutrient
deficiencies
may
influence
T
cell
metabolism
via
cytoplasmic
nutrient
sensors
including
the
glucose
sensor
AMP-activated
protein
kinase
(AMPK/1),
which
regulates
cell
survival
post-activation,
and
the
mammalian
target
of
rapamycin
serine/threonine
kinase
com-
plex
(mTORc1)
[62,63].
Neither
AMPK/1
nor
mTORc1
activity
has
been
assessed
in
T
cells
from
undernourished
children;
however,
both
sensors
can
influence
T
EM
maintenance
(reviewed
by
[63]),
which
is
impaired
in
murine
PEM
[64].
Malnutrition
also
alters
levels
of
energy
homeostasis
mediators,
including
glucocorticoid
hormones
of
the
hypothalamic–pituitary–adrenal
(HPA)
axis
[65]
and
adipokines
released
predominantly
from
adipose
tissue
[6,7].
Glucocorticoid
hormones
regulate
inflammation
and
promote
thymic
and
neurocognitive
development
[65],
which
are
impaired
in
undernourished
children
(Box
1).
Glucocorticoids
are
also
implicated
in
obesity
because
they
simultaneously
affect
adipocyte
metabolism
and
proinflammatory
immune
medi-
ators.
For
example,
human
adipose
tissue
treated
in
vitro
with
dexamethasone
(a
glucocorticoid)
upregulates
genes
associated
with
lipid,
carbohydrate,
and
amino
acid
metabolism,
alongside
leptin
and
acute
phase
response
genes,
but
downregulates
IL-6,
IL-8,
and
MCP-1,
compared
to
untreated
tissue
[66].
Despite
marked
changes
in
adipose
tissue
composition,
no
studies
have
investigated
the
relationship
between
the
HPA
axis
and
inflammation
in
undernutrition.
Of
the
adipokines,
leptin
is
the
most
extensively
studied
because
it
transmits
signals
directly
to
the
immune
system
through
leukocyte
leptin
receptors
[30,67]
and
delivers
feedback
signals
to
the
HPA
axis
via
mTORc1
activation
to
indicate
satiety
[7,67,68].
Ugandan
children
hospitalized
for
SAM
had
higher
serum
leptin
levels
following
nutritional
rehabilitation,
which
coincided
with
increased
insulin
and
IGF-1,
and
decreased
proinflammatory
cytokines
[10].
Infants
who
survived
hospitalization
had
significantly
higher
baseline
leptin
levels
than
those
who
died
[10],
highlighting
the
potential
importance
of
leptin
signaling
for
survival
in
undernutrition.
Mutations
in
the
leptin
signaling
pathway
are
risk
factors
for
human
obesity
[7,67],
and
homozygous
leptin
or
leptin
receptor
deficiency
results
in
excessive
eating,
early-onset
obesity,
and
an
elevated
risk
of
childhood
infections,
that
occur
in
parallel
with
T
cell
hyporesponsiveness,
low
cytokine
production,
and
reduced
CD4:CD8
T
cell
ratios
(reviewed
in
[67]).
High-fat
diets
have
been
shown
to
block
mTORc1
activation
by
leptin
in
the
hypothalamus,
which
may
explain
continued
hyperphagia
in
overnutrition
[68].
One
hypothesis
for
the
paradoxical
link
between
early-life
undernutrition
and
obesity
in
adult-
hood
(Box
1)
is
that
broad
metabolic
trajectories
become
fixed
in
infancy
to
reflect
environmental
conditions
at
the
time,
but
can
lead
to
subsequent
metabolic
maladaptation
if
the
adult
environment
changes
[4].
Observations
from
the
Dutch
Hunger
Winter
of
1944–1945
corrobo-
rate
this
hypothesis
because
infants
of
mothers
exposed
to
the
famine
had
a
higher
risk
of
glucose
intolerance,
coronary
disease,
and
obesity
than
their
unexposed
siblings,
despite
returning
to
a
pre-famine
diet
after
1945
[9].
Similar
to
epigenetic
programming
of
infant
immunodeficiency
by
parental
malnutrition,
the
risk
of
metabolic
syndrome
may
be
epigenetically
programmed.
For
example,
maternal
malnutrition
during
the
Dutch
Hunger
Winter
modified
the
infant
IL10
locus
as
well
as
genes
associated
with
growth
hormones,
cholesterol
transport,
lipid
metabolism,
and
the
HPA
axis
that
persisted
decades
later
[35].
Infant
gender
and
CpG
methylation
of
the
retinoid-X
receptor
/
(RXRA)
and
endothelial
nitric
oxide
synthase