Food Allergy, the Brain, and Neurological Symptoms

Food Allergy and the Brain
Attilio Boner
University of
Verona, Italy
attilio.boner@univr.it
Introduction
Micronutrients and Behaviour
Immunity & Ipersensitivity
Food Allergy&Ipersensitivity and Brain
Not only Food Allergy
Which came first?
Possible Mechanisms
Food-based Therapies
Conclusions

Clinically, allergy is
characterized by
symptoms that, by in
large, are secondary to
an altered nervous system
itchy and red eyes;
rhinorrhea, nasal congestion,
and sneezing;
urge to cough, dyspnea,
airway mucus secretion, and
episodic reflex bronchospasm;
dysphagia, altered
gastrointestinal motility;
cutaneous itching and
flare responses.
Allergy as an Immune-Neuronal Disorder

Clinically, allergy is
characterized by
symptoms that, by in
large, are secondary to
an altered nervous system
itchy and red eyes;
rhinorrhea, nasal congestion,
and sneezing;
urge to cough, dyspnea,
airway mucus secretion, and
episodic reflex bronchospasm;
dysphagia, altered
gastrointestinal motility;
cutaneous itching and
flare responses.
Allergy as an Immune-Neuronal Disorder
the immune-driven
inflammation associated
with allergic reactions
might in some cases be
trivial unless transduced
into the neurogenic
symptoms of suffering
(eg, itch, cough,
bronchospasm,
motility disturbance,
pain, sneeze,
skin conditions).

Neuromodulation
during
the
allergic
reaction.
Undem BJ,
JACI
2014;
133:1521
1) sensory (afferent)
nerves sense the local
tissue environment.
2) in the central
nervous system the
signal induces
3) neurotransmitter
release at
nerve’s synapse

Neuromodulation
during
the
allergic
reaction.
Undem BJ,
JACI
2014;
133:1521
1) sensory (afferent)
nerves sense the local
tissue environment.
2) in the central
nervous system the
signal induces
3) neurotransmitter
release at
nerve’s synapse
These symptoms
occur because
mediators
released during an
allergic reaction
can interact with
sensory nerves,
change processing
in the central
nervous system,
and alter
transmission in
sympathetic,
parasympathetic,
and enteric
autonomic nerves.

Neuromodulation during the allergic reaction.
Undem BJ, JACI 2014;133:1521
The allergic response
comprises changes at all
3 levels of the neural arc:
These changes can be subdivided into:
1) acute changes (overt activation of nerves that lasts only as long as
the stimulus is present),
2) longer-lasting changes in neuroexcitability that can outlast the
stimulus by hours or days, and
3) the more persistent phenotypic changes that can last
for weeks and perhaps, when one considers the idea of
developmental ‘‘critical periods,’’ for years.
sensory nerve function,
CNS integration, and
autonomic/enteric
neuroeffector cell function.

C, Mast cells (green) near
MrgA3 expressing
‘‘afferent itch nerves’’
(orange) in mouse skin
Mast cells are found in close proximity to nerves in
virtually all organs. Undem BJ, JACI 2014;133:1521
A, Mast cell tryptase–
positive cells (red) near
PGP9.5-positive nerves
(green) in human intestinal
submucosal plexus.
B, Mast cells (red) near
synapsin-positive neurons
(green) in rat cardiac ventricle.

MrgA3 expressing
submucosal plexus.
the infiltrating eosinophil is also often
associated with nerves.
Thornton MA, Clin Immunol 2013;147:50-7.

MrgA3 expressing
submucosal plexus.
fine nerve terminals in various tissues are also
commonly associated also with other bone marrow–
derived cells, such as plasma cells.
Arizono N, Lab Invest 1990;62:626-34.

Already in 400 B.C., Hippocrates described
the importance of the gastrointestinal
tract in health and disease, by stating
‘bad digestion is the root of all evil’
The enteric nervous system (ENS) discovered
around 1900 is often described as the
‘second brain’ since it consists of a complexity
comparable to the CNS.
Costa M, Gut 2000;47(Suppl. 4):iv15–9.
De Theije CGM, Pediatr Allergy Imm 2014;25:218

Gut feelings: the emerging biology
of gut-brain communication.
Mayer EA. Nat Rev Neurosci
2011:12:453–66
a | Endocrine, immune and neuronal afferent
signalling from the gut to the CNS.
•Information about luminal factors and conditions of
the gut are signalled through extrinsic vagal and spinal
afferents to the brain stem and spinal cord,
respectively.
•Different stimuli can activate spinal, vagal and
intrinsic primary afferents directly, without
intermediary cells such as the enteroendocrine (EE)
cells which act both in an endocrine and paracrine
fashion.
•Enterochromaffin (EC) cells signal to both
intrinsic primary afferents and vagal afferents trough
secretion of serotonin (5-hydroxytryptamine; 5-HT).
Enteroendocrine
cell

La funzione della serotonina è molteplice in quanto regola l’umore, induce al rilassamento, al
piacere ed al benessere, interagisce con il ciclo sonno-veglia, stimola l’interesse sessuale,
aumenta la sensibilità al dolore e condiziona l’aggressività.
La serotonina (neurotrasmettitore) interessa anche il sistema cardio-circolatorio, l’apparato
respiratorio, regola l’attività gastrointestinale (la sua mancanza provoca stitichezza o la
presenza eccessiva diarrea) e la temperatura corporea.
La serotonina (neurotrasmettitore) è implicata nelle emicranie e nelle cefalee, provocate dalla
sua assenza.
La dopamina crea le sensazioni di soddisfazione, gratificazione sessuale, motivazione (o della
punizione), stimolando l’attenzione, la memoria, l’apprendimento (legato al lavoro), il
comportamento, la cognizione ed il movimento volontario. La dopamina Agisce sul sistema
simpatico (sistema nervoso autonomo), causando l’aumento della pressione sanguigna e del
battito cardiaco.

2011:12:453–66
•Information about luminal factors and conditions of
the gut are signalled through extrinsic vagal and spinal
afferents to the brain stem and spinal cord,
respectively.
•Mechanical stimuli (stretch, pressure, distortion and
shearing forces) can activate spinal, vagal and
intrinsic primary afferents (IPANs) directly, without
intermediary cells such as the enteroendocrine (EE)
cells.
•Signalling molecules (including proteases, histamine,
serotonin and cytokines) that are produced by immune
cells in Peyer's patches and within the gut epithelium
can activate their respective receptors on vagal and
spinal afferents.

2011:12:453–66
•Similarly, neuropeptides and hormones
(gut peptides) that are released from enteroendocrine
(EE) cells in response to other luminal factors, such as
nutrients, toxins or antigens, can act both in an
endocrine fashion, reaching targets in the brain
(area postrema, dorsal vagal complex and
hypothalamus), and through receptor activation on
spinal and vagal afferents, in a paracrine fashion.
•Enterochromaffin (EC) cells signal to both
intrinsic primary afferents (IPANs) and
vagal afferents trough secretion of serotonin
(5-hydroxytryptamine; 5-HT).
Enteroendocrine
cell

2011:12:453–66
b | Encoding of multiple luminal signals by
enteroendocrine (EE) cells.
•Different classes of enterochromaffin (EE) cells are
interspersed between gut epithelial cells throughout
the gastrointestinal tract.
•Upon luminal stimulation (or upon activation by
postganglionic sympathetic or vagal nerves), these cells
can release up to 20 different gut peptides from their
basolateral (and possibly luminal) surface.
•Released peptides can activate closely adjacent vagal
afferent nerve terminals in a paracrine fashion, or
when released into the circulation they can exert an
endocrine effect, signalling to various sites in the brain
and other parts of the gastrointestinal tract. Enteroendocrine
cell

2011:12:453–66
•Different types of receptors
have been identified on the
luminal side of EE cells,
including G protein-coupled
taste receptors (GPCRs)
for sweet and bitter tastants,
GPCRs that are responsive
to fatty acids
and
toll-like receptors (TLRs).
Enteroendocrine
cell

2011:12:453–66
•The intestinal taste receptors that are shown are
coupled to a specific Gα protein subunit, gustducin
(Gαgust), and receptor-induced increases in intracellular
calcium result in peptide release from the basolateral
membrane.
[Ca2+]i, intracellular calcium concentration;
DAG, diacylglycerol; GI peptide, gastrointestinal peptide;
GPR40, G protein-coupled receptor 40; InsP3, Inositol-1,4,5-
trisphosphate;. PIP2, aquaporin PIP2 member; PKC, protein
kinase C; PLCβ2, phospholipase Cβ; T1R, taste receptor type 1
member; TRPM5, transient receptor potential cation channel
subfamily M member 5
(specifically linked to taste receptor signalling);
VSCC, voltage-sensitive Ca2+ channel.
Enteroendocrine
cell

2011:12:453–66
Gut–brain signalling related to food
intake
•Nutrient-related signals reach the CNS
through spinal, vagal and endocrine
signalling pathways.
•Endocrine signalling of gut peptides that
are released into the systemic circulation
reach the dorsal vagal complex through
the area postrema where they modulate
the transmission of afferent vagal signals
to the dorsal motor nucleus.
•These gut peptides also reach
specialized neurons within the
hypothalamus.
•Paracrine signals activate function-
specific vagal afferent fibres that
ultimately signal to subregions of the
anterior insula (aINS). area postrema

2011:12:453–66
intake
•The sensory aspect of taste is primarily
encoded in the anterior insula (aINS), but
the multimodal integration of satiety
signals with the sensory properties of
food (including its flavour, palatability
and reward value) as well as the context
of food intake (including food related
visual and auditory signals) occurs in the
orbitofrontal cortex (OFC).

2011:12:453–66
intake
•Further integration with inputs from the
reward system and with interoceptive
memories of previous food ingestion
generates a multidimensional
food-related experience that ultimately
determines ingestive behaviour.
•Prefrontal regions exert cognitive
control over ingestive behaviours.
•Learning about food-related experiences
and the formation of interoceptive
memories is an important aspect of the
cortical circuitry that is involved in this
process.

2011:12:453–66
intake
ACC, anterior cingulate cortex;
AP, area postrema;
ARC, arcuate nucleus;
cNTS, caudal NTS;
HIPP, hippocampus;
LH, lateral hypothalamus;
NAc, nucleus accumbens;
NTS, nucleus tractus solitarius;
PeF, pernifornical hypothalamus;
OLF, olfaction;
PFC, prefrontal cortex;
rNTS, rostral NTS;
VTA, ventral tegmental area

Paracrine signaling is a form of cell-cell
communication in which a cell produces a signal
to induce changes in nearby cells, altering the
behavior or differentiation of those cells.
Signaling molecules known as paracrine factors diffuse over a
relatively short distance (local action), as opposed to endocrine
factors (hormones which travel considerably longer distances via the
circulatory system), juxtacrine interactions, and autocrine signaling.
Cells that produce paracrine factors secrete them into the
immediate extracellular environment. Factors then travel to nearby
cells in which the gradient of factor received determines the outcome.
Paracrine and Endocrine Signaling

Bidirectional communications
between the brain and the gut
occur via various pathways,
involving the vagus nerve,
autonomic nervous system and
neuroimmune interactions both in
the GI tract and in the brain.
Kennedy PJ, Neurosci Biobehav Rev
2012: 36: 310–40.
Over the past few decades,
strong correlations have been
observed between the occurrence
of GI problems and
psychiatric disorders.
Cryan JF, Neurogastroenterol Motil
2011: 23: 187–92

Allergen challenge is often associated with the overt
activation of afferent nerve terminals leading to action
potential discharge of afferent C-fibers
C-fibers
(pain, cough, itch)
are known to
express receptors
for many chemical
mediators that,
present in the
allergically
inflamed tissue,
lead to nerve
membrane
depolarization.
1° mediators
2°receptors
3°depolarization

Neuromodulation takes place also at the level of
gene expression.
The allergic reaction can lead to production and release
of neurotrophic factors from mast cells in the local
environment of the nerve terminals where they
influence nerves’ gene expression.
‘‘nerves phenotypic switch’’
an intense quantitative increase
in action potential volleys at the
central terminals of afferent
C-fibers to the CNS Undem BJ, JACI 2014;133:1521

Allergen-induced modulation of CNS neurons
Undem BJ, JACI 2014;133:1521
Thus allergic reactions may modulate CNS neurons
increasing neurotransmitter/neuropeptide release from the
central terminal of the afferent nerves into the CNS neurons.
increase in the synaptic
efficacy of the CNS neurons,
a process often referred to
as
‘‘central sensitization.”
1°
2°
3°
4°

Undem BJ, JACI 2014;133:1521
as
Allodynia: a normally nonpainful stimulus, such
as gentle brushing of the hair
leads to inappropriate pain.
Allotussivity: the sensation of a persistent
urge to cough is present, even
when there is nothing in the
airways to cough up
Alloknesis: the itchy sensation evoked
by a stimulus that is
normally non-pruriceptive
1°
2°
3°
4°

Undem BJ, JACI 2014;133:1521
as
as gentle brushing of the hair leads
to inappropriate pain.
airways to cough up
A clinically relevant aspect
of central sensitization
is that it provides a
mechanism whereby an
allergic reaction in
one location can influence
the physiology of a
disparate location.
1°
2°
3°
4°

Undem BJ, JACI 2014;133:1521
as
airways to cough up
1) stimulation of C-fibers
in the larynx can enhance
parasympathetic drive to the
peripheral airways.
2) C-fiber activation in the
esophagus (eg, during acid
reflux) can lead to the urge to
cough through enhancing synaptic
activity of A-fibers
in the trachea.
1°
2°
3°
4°

Undem BJ, JACI 2014;133:1521
as
airways to cough up
Allergen challenge in the nose
can lead to central sensitization
of lower airway cough nerves.
This raises the possibility that cough
associated with gastroesophageal reflux is
not secondary to microaspiration of
substances into the airways and that cough
associated with nasal allergy is not
necessarily secondary to ‘‘postnasal drip’’
and the direct activation of cough nerves, as
much as it is due to central sensitization of
the cough pathway by converging esophageal
and nasal nociceptors.
1°
2°
3°
4°

Central sensitization in allergy is supported by studies with young
adult rhesus monkeys.
After sensitization to house dust mite, monkeys were
repeatedly challenged with house dust mite–containing
aerosol.
Approximately 5 to 6 months later, the electrical excitability of
neurons in the nucleus of the solitary tract were found to be strongly
upregulated; their responsiveness to a
given input stimulus was much stronger than that seen
with similar neurons from nonallergic monkeys.
Extended allergen exposure in asthmatic monkeys induces neuroplasticity in
nucleus tractus solitarius. Chen CY, J Allergy Clin Immunol 2001;108:557-62.

Central sensitization
monkeys sensitized to house dust mite
and repeatedly challenged with house
dust mite–containing aerosol
5 to 6 months later
strongly upregulation of
excitability of neurons
in the nucleus of the solitary tract
their responsiveness to a given input stimulus
was much stronger than that seen with
similar neurons from nonallergic monkeys.

A, Photomicrograph of a patch-clamped neuron in a brain slice from the caudomedial nucleus
of the solitary tract, which is where the vagal sensory afferents terminate.
B, recordings of
depolarizing
current pulses C,
Increased
action
potential
discharge in
response to
depolarizing
stimulus

Allergic modulation of efferent enteric nerves
Of particular relevance to food
allergy, immunologic activation of
mast cells in the gut is commonly
associated with alterations in
neurotransmission within the
enteric ganglia, thereby
increasing the synaptic activity
of submucosal neurons.

Allergic modulation of efferent enteric nerves
There is evidence that mast cell activation leads
to more neurotransmitter (typically acetylcholine)
released from the presynaptic terminals per given
amount of stimulus.
Allergen challenge can also lead to an increase in
autonomic neurotransmitter release from the
postganglionic peripheral terminals per a given
amount of stimulus.
(+)
(+)
Undem BJ, JACI 2014;133:1521

Concept of modulation in critical periods: early life
Undem BJ, JACI 2014;133:1521
There may be a potential role of ‘‘critical periods’’ in allergen-induced
neuromodulation because these changes can persist for years or even a
lifetime.
It is well established that the development of sensory systems
often requires use-dependent activity early in life
(experience-dependent plasticity). Berardi N, Curr Opin Neurobiol 2000;10:138.
Thus, for example, if a young animal is deprived of vision by
lid closure, changes occur in the neural circuitry of the visual
cortex, leading to severe and permanent loss in visual acuity.
Even prolonged vision deprivation after the critical period is without
an effect on visual acuity.

Undem BJ, JACI 2014;133:1521
Allergic (or infectious)
inflammation in critical
periods therefore raises
the possibility that the
inflammatory response
might leave behind a
nervous system that is
subtly altered many years
later, such that a mild
inflammatory insult could
lead to overly exaggerated
responses.

Undem BJ, JACI 2014;133:1521
Allergic inflammation in
critical periods
nervous system subtly
altered many years later,
such that a mild
lead to overly
exaggerated responses.
first
1000
days

Undem BJ, JACI 2014;133:1521
Allergic inflammation in
critical periods
nervous system subtly
altered many years later,
such that a mild
lead to overly
exaggerated responses.
first
1000
days
The prevalence of
food allergy peaks in
the first 2 years
of life.
Berin MC, Sampson HA.
Food allergy:
an enigmatic epidemic.
Trends Immunol.
2013; 8:390–397.

2012: 36: 310–40.
of GI problems and psychiatric
disorders.
2011: 23: 187–92
Food allergy is
suggested to be one
of the GI triggers
for various
psychologic
and
psychiatric
conditions

2012: 36: 310–40.
of GI problems and psychiatric
disorders.
2011: 23: 187–92
Allergic reactions to
food are primarily
observed in children,
and an association with
neurodevelopmental
disorders has
therefore been
proposed.
de Theije CG,
Pediatr Allergy Immunol.
2014;25(3):218-26

 A cohort of 9- to 10-
month-old infants.
 The infants were given
oral iron for 3 months.
 Behavioral coding from
videotape at 12 months
Dose-Response Relationships between Iron Deficiency
with or without Anemia and Infant Social-Emotional
Behavior Lozoff, J PED 2008;152:696
There were significant (P <0.05)
linear effects of poorer iron
status for:
• increasing shyness,
• decreasing
orientation/engagement,
• decreasing soothability, and,
• when an examiner attempted to
engage the infants in imitative
play, decreasing positive affect
and engagement.
not only !!!

 A cohort of 9- to 10-
month-old infants.
 The infants were given
oral iron for 3 months.
 Behavioral coding from
videotape at 12 months
Dose-Response Relationships between Iron Deficiency
with or without Anemia and Infant Social-Emotional
Behavior Lozoff, J PED 2008;152:696
There were significant (P <0.05)
linear effects of poorer iron
status for:
• increasing shyness,
• decreasing
orientation/engagement,
• decreasing soothability, and,
• when an examiner attempted to
engage the infants in imitative
play, decreasing positive affect
and engagement.
not only !!!
Infant
social-emotional
behavior appears
to be adversely
affected by Iron
Deficiency
with or without
anemia.

Iron Deficiency Anemia and Cognitive Function
in Infancy Carter Pediatrics 2010;126;e427
 Effects of iron deficiency anemia
(IDA) on specific domains of
infant cognitive function
 IDA was defined as hemoglobin
level<110 g/L with/or ≥2 abnormal
iron deficiency indicators
(mean corpuscular volume,
red cell distribution width,
zinc protoporphyrin,
transferrin saturation, ferritin)
 At 9 and 12 months, the Fagan
Test of Infant Intelligence
(FTII); A-not-B task; Emotionality,
Activity, and Sociability
Temperament Survey; and
Behavior Rating Scale
 Infants with IDA showed
poorer recognition memory
The Behavior Rating Scale
orientation/engagement
measure
partially
mediated
these effects

Iron-Deficiency Anemia in Infancy and Social Emotional
Development in Preschool-Aged Chinese Children
Chang Pediatrics 2011;127:e927
 Children with iron-deficiency
anemia (IDA) in infancy whose
anemia was not corrected before
24 months (chronic IDA) (n=27).
 Children with IDA in infancy
whose anemia was corrected
before 24 months (corrected
IDA) (n=70).
 Children who were non-anemic in
infancy and at 24 months (n =64).
Children who had
chronic IDA in infancy
at age 4 yrs displayed:
1.less positive affect
and frustration
tolerance;
2.more passive
behavior and physical
self-soothing in the
stranger approach;
3.delay of
gratification.

Iron-Deficiency Anemia in Infancy and Social Emotional
Development in Preschool-Aged Chinese Children
Chang Pediatrics 2011;127:e927
In contrast,
the behavior and affect
of children whose
anemia was corrected
before 24 mo of age
were comparable
to those of children who
were non-anemic
throughout infancy.
 Children with iron-deficiency
anemia (IDA) in infancy whose
anemia was not corrected before
24 months (chronic IDA) (n=27).
 Children with IDA in infancy
whose anemia was corrected
before 24 months (corrected
IDA) (n=70).
 Children who were non-anemic in
infancy and at 24 months (n =64).

Iron-deficiency anemia in infancy and poorer cognitive
inhibitory control at age 10 years.
Algarín C, Dev Med Child Neurol. 2013;55(5):453-8.
132 Chilean children
(mean age 10 y):
69 children had IDA in infancy
and 63 comparison children who
did not have IDA
Go/No-Go task with
event-related potentials
Relative to comparison participants,
children who had IDA in infancy
showed:
1) slower reaction time (mean [SE],
528.7 ms vs 485.0 ms);
2) lower accuracy (95.4% vs 96.9%);
3) longer latency to N2 peak (378.9
ms vs 356.9 ms);
4) and smaller P300 amplitude

Functional Significance of Early-Life Iron Deficiency:
Outcomes at 25 Years Lozoff J Ped 2013;163:1260
 At 25 years, 33 subjects
with chronic iron deficiency
in infancy vs 89 who were
iron-sufficient before
and/or after iron therapy.
 Education, employment,
marital status, and physical
and mental health.
•Anemia was defined as Hb ≤105 g/L
non-anemia as Hb ≥120 g/L,
Hb concentration 106-119 g/L
considered intermediate.
•Iron deficiency was defined as
- serum ferritin <12 ng/mL and
- free erythrocyte protoporphyrin
≥1.77 µmol/L (100 µg/dL) of
red blood cells and/or
- transferrin saturation <10%

% subjects who did not
complete secondary school
58.1%
chronic iron
deficiency
iron
sufficient
60 –
50 –
40 –
30 –
20 –
10 –
0
19.8%
p=0.003
and mental health.

% subjects who were single
83.9%
chronic iron
deficiency
iron
sufficient
23.7%
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00
p=0.03
and mental health.

83.9%
chronic iron
deficiency
iron
sufficient
23.7%
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00
p=0.03
They reported poorer emotional health
and more negative emotions and
feelings of dissociation/detachment.
and mental health.
% subjects who were single

indirect paths for chronic iron
deficiency and not completing
secondary school via
poorer cognitive functioning in
early adolescence
more negative emotions via
behavior problems in
adolescence, indicating a
cascade of adverse outcomes.
and mental health.

Neuropsychosocial Deficits Associated with
Iron Deficiency: How Long Do They Last? Editorial
Trimm J Ped 2013;163:1242
 Iron deficiency anemia (IDA) is more prevalent
in pregnant women and young children.
 Brain development in utero through early childhood
requires adequate availability of iron.
 Insufficient quantities of iron interfere with neuronal and glial
development, neurotransmitter production, and myelination.
 The consequences of these disturbances include
cognitive, motor, and emotional dysfunction.

 From studies that focus on early and prompt treatment of iron
deficiency anemia . It is not evident that iron supplementation
reverses the disruption to brain development.
 The persistence of cognitive, motor, emotional, academic, and
social concerns suggests long-term or permanent disruption.
 A recent systematic review of daily iron supplementation in
2-to 5- year-old children identified increases in hemoglobin and
ferritin. However, improvement in clinically important outcomes
like cognitive development was not found.
Trimm J Ped 2013;163:1242

What has to be done
Promoting access to and intake of adequate nutrition
by women prior to and during pregnancy.
Once born, children at risk of developing iron deficiency should be
identified as soon as possible.
1) inadequate access to age-appropriate balanced diet,
2) low intake of protein paired with high intake of cereals/legumes,
3) preterm delivery or
4) low birth weight.
Trimm J Ped 2013;163:1242

Iron supplementation in infancy contributes to more
adaptive behavior at 10 years of age.
Lozoff B, J Nutr. 2014 Jun;144:838-45.
Healthy Chilean infants free
of Iron Deficiency Anemia
at age 6 mo were randomly
assigned to
iron supplementation or no
added iron (formula with
iron/powdered cow milk,
vitamins with/without iron)
from ages 6 to 12 mo.
Follow-up at age 10 yrs
Compared with the no-added-iron
group children in the
iron-supplemented group were:
1) more cooperative, confident,
persistent after failure, coordinated,
2) direct and reality-oriented
in speech,
3) working harder after praise,
4) spent more time laughing and
smiling together with their mothers
and started smiling more quickly.

Higher prevalence of iron deficiency as strong predictor
of attention deficit hyperactivity disorder in children.
Bener A, Ann Med Health Sci Res. 2014;4(Suppl 3):S291-7.
case-control study
630 children with ADHD
aged 5-18
630 controls
aged 5-18 years old
low serum:
1. iron,
2. magnesium,
3. vitamin D
may be
associated
with

Magnesium in man: implications for health and disease.
de Baaij JH. Physiol Rev. 2015;95(1):1-46.
Magnesium (Mg(2+) is the second
most abundant intracellular cation
after potassium, it is involved in over
600 enzymatic reactions including
energy metabolism and protein
synthesis.
Mg(2+) supplementation has been
shown to be beneficial in treatment
of, among others, preeclampsia,
migraine, depression, coronary artery
disease, and asthma.

Maternal Long-Chain Polyunsaturated Fatty Acid
Status during Early Pregnancy and Children's Risk of
Problem Behavior at Age 5-6 Years
Loomans EM, J Ped 2014;164;762-768
•Essential fatty acids and particularly their long-chain polyunsaturated
derivatives eicosapentaenoic acid (EPA; omega-3), docosahexaenoic acid
(DHA; omega-3), and arachidonic acid (AA; omega-6) are important to
neurodevelopmental processes such as neurogenesis, cell proliferation,
membrane functioning, and, potentially, myelination.
•To enable optimal fetal brain development, both a sufficient and
balanced supply of omega-3 and omega-6 long-chain polyunsaturated fatty acids
(LCPUFAs) from the maternal circulation (ie, placental transfer) are crucial.
•Hence, deficiencies in maternal LCPUFA or an imbalance in the
omega-6:omega-3 LCPUFA (ie, AA/[DHA + EPA]) during gestation
might affect fetal brain development and influence subsequent
long-term behavioral outcomes.

 Maternal long-chain
polyunsaturated fatty acid
(LCPUFA) status and ratio
during pregnancy
(4336 women)
 Children’s risk of problem
behavior at 5 years of age
rated by
their mother (n = 2502) and
teacher (n = 2061)
0.75
Greater concentrations of Ώ-3
fatty acid docosahexaenoic acid
OR for children’s
emotional symptoms
at age 5 years
1.0 –
0.5 –
0.0
Loomans EM, J Ped 2014;164;762-768

 Maternal long-chain
polyunsaturated fatty acid
(LCPUFA) status and ratio
during pregnancy
(4336 women)
 Children’s risk of problem
behavior at 5 years of age
rated by
their mother (n = 2502) and
teacher (n = 2061)
0.75
1.0 –
0.5 –
0.0
Loomans EM, J Ped 2014;164;762-768
Lower eicosapentaenoic
acid (EPA) and a greater
omega-6:omega-3 LCPUFA
tended to increase the risk
for emotional symptoms
and the risk of
hyperactivity/
inattention problems
Greater concentrations of Ώ-3
fatty acid docosahexaenoic acid
OR for children’s
emotional symptoms
at age 5 years

Dietary long chain n-3 polyunsaturated fatty acids
prevent impaired social behaviour and normalize brain
dopamine levels in food allergic mice.
de Theije CG, Neuropharmacology 2015;90:15-22
Whey sensitive mouse
Whey
Impaired social behaviour
X

Impaired social behaviourWhey sensitive mouse
Whey
n-3 LCPUFA-enriched diet
before and during
sensitization with whey
(-)
X

Whey
before and during
(-)
n-3 LCPUFA
supplementation
increased
docosahexaenoic acid
(DHA) incorporation
into the brain and
restored reduced levels
of prefrontal dopamine
(DA) and its
metabolites
(reward-motivated
behavior).
X

Whey
before and during
(-)
In addition to these
brain effects,
n-3 LCPUFA
supplementation reduced
the allergic skin response
and restored decreased
intestinal levels of
serotonin
metabolite
(regulation of mood,
appetite, and sleep).
X

High Folate Intake Is Related to Better Academic
Achievement in Swedish Adolescents
Nilsson, Pediatrics 2011;128:e358
An increased plasma total homocysteine (tHcy)
serves as a marker for functional deficiency of certain B vitamins,
such as B12, B6, riboflavin, and, in particular, folate.
The genetic model disease homocystinuria is characterized by
high plasma tHcy levels, mental retardation, and a range of
psychiatric symptoms, in addition to premature atherosclerosis.
In more recent studies, links have been found between
impaired homocysteine metabolism and a wide range of
neuropsychiatric conditions such as depression,
cognitive impairment, and dementia in adult populations
and in the elderly.

 386 Swedish adolescents
aged 15 yrs.
 The sum of school grades in
10 core subjects obtained
in the final semester of
compulsory 9 years of
schooling used as outcome
measure of academic
achievement.
Adolescents are vulnerable
to increased plasma total
homocysteine (tHcy) and to
insufficient folate status.
Academic achievement
was
strongly correlated to
tertiles of tHcy
(negatively; P=0.023)
and to
tertiles of folate intake
(positively; P<0.001).

 386 Swedish adolescents
aged 15 yrs.
 The sum of school grades in
10 core subjects obtained
in the final semester of
compulsory 9 years of
schooling (6 to 14 yrs) as
outcome measure of
academic achievement.
Adolescents are vulnerable
to increased plasma total
homocysteine (tHcy) and to
insufficient folate status.
tertiles of folate intake
Academic achievement at
primary and secondary
school yrs (6-14 yrs)
P<0.001
positive correlation

Plasma nutrient status of patients with Alzheimer's
disease: Systematic review and meta-analysis.
Lopes da Silva S, Alzheimers Dement. 2014;10(4):485-502
≥ 5 studies for folate,
vitamin A, vitamin B12,
vitamin C, vitamin D,
vitamin E, copper, iron,
and zinc
< 5 studies for vitamins
B1 and B6, long-chain
omega-3 fatty acids,
calcium, magnesium,
manganese, and selenium
in AD patients.significantly lower
plasma levels of:
1) Folate,
2)vitamin A,
3)vitamin B12,
4)vitamin C,
5)vitamin E.
nonsignificantly lower levels of:
1) zinc (P = 0.050)
2) vitamin D (P = 0.075)
P < 0.001

and zinc
calcium, magnesium,
plasma levels of:
1) Folate,
2)vitamin A,
3)vitamin B12,
4)vitamin C,
5)vitamin E.
1) zinc (P = .050)
2) vitamin D (P = .075)
P < .001
No significant
differences were
observed for plasma
levels of
copper
and
iron.

and zinc
calcium, magnesium,
plasma levels of:
1) Folate,
2)vitamin A,
3)vitamin B12,
4)vitamin C,
5)vitamin E.
1) zinc (P = .050)
2) vitamin D (P = .075)
P < .001
The lower plasma nutrient
levels indicate that patients
with AD have impaired
systemic availability of
several nutrients.
This difference appears to
be unrelated to the classic
malnourishment that is well
known to be common in AD,
suggesting that compromised
micronutrient status may
precede protein and
energy malnutrition

Immunology of allergic reactions
Under physiologic conditions the body develops
oral tolerance
a consequence of complex
immune cell interactions, among
which dendritic cells (DCs) and
regulatory T cells (Tregs)
produce
Transforming Growth Factor β
and Interleukin 10.
Pabst O, Mowat AM.
Oral tolerance to food protein.
Mucosal Immunol 2012: 5: 232–9.
T-cell anergy and
the production of
antigen-specific
IgA antibodies.
Clonal deletion.
X X
X

Food allergy is generally characterized by T helper (Th) 2 skewing of
the immune system and is accompanied by reduced Treg function
Pabst O, Mucosal Immunol 2012: 5: 232–9.
The majority of food-allergic reactions is mediated by IgE inducing
mast cell degranulation and secretion of inflammatory mediators such
as cytokines, histamine, leukotrienes, and prostaglandin.
Onset of symptoms evolves within several minutes to several hours
after contact with the allergen
Non-IgE-mediated reactions response can be
mediated by Ig-free light chains or by cells.
Onset of symptoms is observed from one hour
to many days after ingestion of the food protein.
Schouten B, J Allergy Clin Immunol 2010: 125: 1308–14.

Food allergy is generally characterized by T helper (Th) 2 skewing of
the immune system and is accompanied by reduced Treg function
Pabst O, Mucosal Immunol 2012: 5: 232–9.
The majority of food-allergic reactions is mediated by IgE inducing
mast cell degranulation and secretion of inflammatory mediators such
as cytokines, histamine, leukotrienes, and prostaglandin.
Onset of symptoms evolves within several minutes to several hours
after contact with the allergen
Non-IgE-mediated reactions response can be
mediated by Ig-free light chains or by cells.
Onset of symptoms is observed from one hour
to many days after ingestion of the food protein.
Schouten B, J Allergy Clin Immunol 2010: 125: 1308–14.
Cell-mediated food allergy is
classified as
‘delayed type hypersensitivity’
and is mediated by
Th1 and Th17 cells.

For systemic clinical symptoms to occur, food allergens
must first cross from the lumen through the epithelial
barrier to the intestinal mucosa.
Kim JS, Curr Opin Gastroenterol. 2012;28:99–103.
During IgE-mediated reactions, allergens crossing the
epithelial barrier then bind to IgE found on mast cells, causing
them to degranulate and release allergic mediators, such as
histamines.
Conversely, non–IgE-mediated reactions likely involve antigens being
presented to Th1, Th17 cells in the intestinal mucosa. These in turn
release cytokines that can lead to long-term changes to epithelial cells
and the intestinal mucosa.
Jyonouchi H. Inflamm Allergy Drug Targets. 2008;7:173–180.

IgE-mediated food allergy can be diagnosed by
skin prick test and allergen-sIgE levels.
Unfortunately, no standardized test is available for detection of
non-IgE-mediated food allergy, and diagnosis is based on
elimination of the suspected allergenic food for weeks.
A challenge test can be used to confirm the diagnosis.
Clinical symptoms of food-allergic reactions are not restricted to the
GI tract, but also involve the skin and airways. In addition to these
non-GI symptoms, it has also been suggested that behavioral and
psychologic symptoms can be evoked by allergic reactions
Costa-Pinto FA, Neural and behavioral correlates of food allergy.
Chem Immunol Allergy 2012: 98: 222–39.

Certain foods contain pharmacologically active substances, such as
caffeine, histamine, serotonin, and tyramine, which can affect
behavior in all individuals to a greater or lesser extent.
•Ingestion of the amino acids glutamic acid and tryptophan have been known to cause the disturbances of cognition and
myalgia characteristic of the Chinese restaurant syndrome and the eosinophilia myalgia syndrome, respectively.
•Certain ingested foods and food substances, such as strawberries, tomatoes, pineapple, and alcohol, produce an increase
in circulating histamine that is known to be associated with hyperactive behavior.
•Excessive intake of sugar or highenergy foods, e.g., “squash,” leads to the development of reactive hypoglycemia several
hours after ingestion, which, in turn, produces an aberration in behavior and cognitive performance.
Bellanti JA, Allergy Asthma Proc. 2005;26(1):19-28

'exorphins' are derived from the incomplete digestive breakdown of dairy and grain
derived foods.
Exorphins are small protein or peptides that have an action like morphine.
Endorphins, exorphins and morphine all work by way of opioid receptors.
Five exorphins have been discovered in digests of gluten and eight others in digests
of milk.
The discovery of these psychoactive exorphins offers a possible explanation for
some of the reported psychiatric reactions to these proteins including the sense of
"brain fog" that often accompanies immune reactions to dairy and grain foods.
Exorphins may also modulate mood by depressing serotonin, dopamine and
norepinephrine in the central nervous system.

Chinese restaurant syndrome
Chinese restaurant syndrome is a set of symptoms that some people have after eating
Chinese food. A food additive called monosodium glutamate (MSG) has been blamed for the
condition. However, this has not been proven to be the cause.
Symptoms include:
Chest pain
Flushing
Headache
Numbness or burning in or around the mouth
Sense of facial pressure or swelling
Sweating
The following signs may also be used to aid in diagnosis:
Abnormal heart rhythm observed on an electrocardiogram
Decreased air entry into the lungs
Rapid heart rate

The psychosocial impact of food allergy and food
hypersensitivity in children, adolescents and their
families: a review. Cummings AJ, Allergy. 2010;65:933–945.
psychological distress, including
anxiety, depression and stress in
the both the sufferer and the
parents.
Food allergy or
hypersensitivity
•Assessment of quality of life in children with peanut allergy.
Avery NJ, Pediatr Allergy Immunol 2003;14:378–382.
•Impact of peanut allergy on quality of life, stress and anxiety in the family.
King RM, Allergy 2009;64:461–468.
•Food allergy in young adults: perceptions and psychological effects.
Lyons AC, J Health Psychol 2004;9:497–504.
•The impact of childhood food allergy on quality of life.
Sicherer SH, Ann Allergy Asthma Immunol 2001;87:461–464

Self-reported allergies and their relationship to several
Axis I disorders in a community sample.
Patten SB, Int J Psychiatry Med 2007;37:11–22
Axis I refers broadly to the principal disorder that needs immediate attention; e.g., a major depressive
episode, an exacerbation of schizophrenia, or a flare-up of panic disorder. It is usually (though not
always) the Axis I disorder that brings the person "through the office door."
Axis II lists any personality disorder that may be shaping the current response to the Axis I problem.
Axis II also indicates any developmental disorders, such as mental retardation or a learning disability,
which may be predisposing the person to the Axis I problem. For example, someone with severe mental
retardation or a paranoid personality disorder may be more likely to be "bowled over" by a major life
stressor, and succumb to a major depressive episode.
Axis III lists any medical or neurological problems that may be relevant to the individual's current or
past psychiatric problems; for example, someone with severe asthma may experience respiratory
symptoms that are easily confused with a panic attack, or indeed, which may precipitate a panic attack.
Axis IV codes the major psychosocial stressors the individual has faced recently; e.g., recent divorce,
death of spouse, job loss, etc.
Axis V codes the "level of function" the individual has attained at the time of assessment, and, in some
cases, is used to indicate the highest level of function in the past year. This is coded on a 0-100 scale,
with 100 being nearly "perfect" functioning (none of us would score that high!).

 Canadian Community
Health Study in 2002.
 Self-report data
about food allergies.
food
allergies
1.80
2.0 –
1.5 –
1.0 –
0.5 –
0.0
OR for major depression
Axis I refers broadly to the principal disorder that needs
immediate attention; e.g., a major depressive episode, an
exacerbation of schizophrenia, or a flare-up of panic disorder.
in subjects reporting
other
allergies
1.50

 2002 Canadian
Community Health
Study.
food
allergies
1.80
2.0 –
1.5 –
1.0 –
0.5 –
0.0
other
allergies
1.50
 Associations of
comparable strength were
observed for bipolar
disorder and for panic
disorder/agoraphobia.
 The association with
social phobia was
statistically significant,
but not as strong.

 2002 Canadian
Community Health
Study.
food
allergies
1.80
2.0 –
1.5 –
1.0 –
0.5 –
0.0
other
allergies
1.50
This article is
cross-sectional in nature
and
relies on selfreport of
food allergy and so results
should be treated with
caution and causality
cannot be inferred.

Changes in distress over time
1) A great deal of anxiety is experienced by
patients and families around the time of diagnosis of food allergy.
Primeau MN, Clin Exp Allergy 2000;30:1135–1143.
2) Following diagnosis, parents and children will often follow a period
of psychosocial adjustment. Mandell D, Health Soc Work 2005;30:325–335.
3) Once parents understand the risks associated with their child’s
food allergy, fear begins to emerge as a predominant emotion.
Gillespie CA, J Pediatr Nurs 2007;22:30–42.

Changes in distress over time
1) A great deal of anxiety is experienced by
patients and families around the time of diagnosis of food allergy.
Primeau MN, Clin Exp Allergy 2000;30:1135–1143.
2) Following diagnosis, parents and children will often follow a period
of psychosocial adjustment. Mandell D, Health Soc Work 2005;30:325–335.
3) Once parents understand the risks associated with their child’s
food allergy, fear begins to emerge as a predominant emotion.
It is likely to be this fear that promotes patients
and parents to develop coping strategies
to manage allergy and minimize risk.

The period of starting school is also a concern for parents.
Mothers often find it difficult to completely relax when
their children are attending school, away from their supervision.
As children grow into teenagers, parents have reported anxiety
in handing over the responsibility to their child for their risk
assessment, avoidance strategies and management of their
food allergy, and it is suggested there is a risk that they may
transfer their anxieties to their children.
Akeson N, Clin Exp Allergy 2007;37:1213–1220.

parental modelling of anxious
behaviour to activities such as
administering emergency treatment
increased
anxiety in the child.
high levels of anxiety experienced by food allergic children,
although impacting adversely upon QoL, could be interpreted
as protective if it encourages them to comply with adequate
avoidance measures and management plans.
Mandell D, Health Soc Work 2005;30:325–335.

parental modelling of anxious
behaviour to activities such as
administering emergency treatment
increased
anxiety in the child.
high levels of anxiety experienced by food allergic children,
although impacting adversely upon QoL, could be interpreted
as protective if it encourages them to comply with adequate
avoidance measures and management plans.
Mandell D, Health Soc Work 2005;30:325–335.
However, high levels of anxiety may be
maladaptive, for example, if it places
unrealistic restrictions
on an individual’s life

Anxiety and depression: a common feature of health care
seeking patients with irritable bowel syndrome and food
allergy. Addolorato G, Hepatogastroenterology 1998:45:1559–64
 The % of subjects with
high levels of state anxiety,
trait anxiety and depression
was significantly higher in IBS
than in both LI and healthy
controls.
 Psychological findings in
patients with FA were very
similar to those of IBS.
 66 pts with irritable bowel
syndrome (IBS).
 44 with food allergy (FA).
 48 with lactose intolerance (LI).
 52 healthy controls
 State and Trait Anxiety
Inventory and the
Zung depression scale.

Association between childhood allergic disease,
psychological comorbidity, and injury requiring medical
attention.Garg N, Ann Allergy Asthma Immunol. 2014;112(6):525-32
Conduct/oppositional
defiant disorder
2.97
3.0 –
2.0 –
1.0 –
00
In children with allergic
disorders OR for
2.49
Learning delay
 Data from the 2007 to
2008 National Survey
of Children's Health
(27,556 children
0 to 5 years old).
(angry and irritable mood,
argumentative or
vindictiveness)

Conduct/oppositional
defiant disorder
2.97
3.0 –
2.0 –
1.0 –
00
In children with allergic
disorders OR for
2.49
Learning delay
(27,556 children
0 to 5 years old).
(angry and irritable mood,
argumentative or
vindictiveness)
Children with food
allergies, had higher
odds of sustaining
injuries (OR = 2.0).

In children with
allergic disorders OR for
(27,556 children
0 to 5 years old).
Depression Anxiety ADHD
6.03
7.0 –
6.0 –
5.0 –
4.0 –
3.0 –
2.0 –
1.0 –
0.0
5.54
4.75

Are children and adolescents with food allergies at
increased risk for psychopathology?
Shanahan L, J Psychosom Res. 2014;77(6):468-73.
Adolescents (N=1420)
were recruited from the
community, and interviewed
up to 6 times between ages
10 and 16 years.
N=5165 pairs of
interviews.
Cross-sectionally, food allergies
were associated with more
symptoms of:
1) separation and generalized
anxiety
2) attention deficit and
hyperactivity disorder (ADHD),
Longitudinally, adolescents with
food allergy experienced increases
in symptoms of:
1) generalized anxiety disorder
2) depression
from one assessment to the next.

10 and 16 years.
N=5165 pairs of
interviews.
Food allergies were
not, however,
associated with a
higher likelihood of
meeting diagnostic
criteria for a
psychiatric disorder.
symptoms of:
anxiety
in symptoms of:
2) depression

10 and 16 years.
N=5165 pairs of
interviews.
adolescents'
increased symptoms
of psychopathology
in the context of
food allergy likely
reflects an adaptive
increase in vigilance
rather than
cohesive syndromes
of psychopathology.
symptoms of:
anxiety
in symptoms of:
2) depression

10 and 16 years.
N=5165 pairs of
interviews.
Support and guidance
from health care
providers is needed to
help adolescents with
food allergies and
their caregivers
achieve an optimal
balance between
necessary vigilance
and hypervigilance
and unnecessary
restriction.
symptoms of:
anxiety
in symptoms of:
2) depression

Diet restriction in migraine, based on IgG against foods:
a clinical double-blind, randomised, cross-over trial.
Alpay K, Cephalalgia 2010:30:829–37
1) There is evidence of a profound role of
meningeal inflammation in migraine
pathogenesis.
2) Many contributing factors may trigger the
occurrence of migraine attacks and food
is one of the most well-known.
3) IgE-specific food allergy has been shown to
be related with migraine supported by the success
of individualised diet in controlling migraine attacks.
4) IgG mediated hypersensitivity to foods is also possible.

In the
6 weeks
baseline
9.0
Number of migraine attacks
in 6 weeks
6.2
 Diet restriction, based
on IgG antibodies
against food antigens.
 30 patients diagnosed
with migraine.
 6-week diet either
excluding or including
specific foods with
raised IgG antibodies.
In the 6 weeks
elimination diet
period
10 –
09 –
08 –
07 –
06 –
05 –
04 –
03 –
02 –
01 –
00
P<0.001

9.0
6.2
 Diet restriction, based
on IgG antibodies
against food antigens.
 30 patients diagnosed
with migraine.
 6-week diet either
excluding or including
specific foods with
raised IgG antibodies.
10 –
09 –
08 –
07 –
06 –
05 –
04 –
03 –
02 –
01 –
00
P<0.001
Diet restriction
based on IgG
antibodies is an
effective strategy
in reducing the
frequency of
migraine attacks.
In the
6 weeks
baseline
In the 6 weeks
elimination diet
period
Number of migraine attacks
in 6 weeks

The food categories from most frequent IgG positivity to least
(+)
(-)

Non coeliac gluten sensitivity –
A new disease with gluten intolerance.
Czaja-Bulsa G. Clin Nutr. 2014 Aug 29. pii: S0261-5614(14)00218-0.
Non-celiac gluten sensitivity (NCGS) is a new syndrome of gluten intolerance.
In literature some other names have been suggested for this disorder, such as
gluten sensitivity (GS), gluten hypersensitivity or non-celiac gluten intolerance.
The typical presentation of NCGS is a combination of:
- IBS-like symptoms: abdominal pain, nausea, bloating, flatulence, diarrhoea or
constipation, and
-systemic manifestations such as: headache, joint and muscle pain,
muscle contractions, leg or arm numbness,
chronic fatigue, “foggy mind”, body mass loss and
anaemia or they can include behaviour
disturbances such as the disturbance in
attention and depression.

Czaja-Bulsa G. Clin Nutr. 2015;34:189-194.
Symptoms of non-celiac gluten sensitivity disorders (NCGS).
Gluten is comprised of
the proteins
gliadin and glutelin
a 347 patients treated at the
Center for Celiac Research
University of Maryland in
2004e2010

Characteristics of gluten-dependent disorders.
The diagnosis by elimination diet cannot be made until Coeliac Disease and Wheat Allergy
have been eliminated.
The diagnosis is confirmed by a food provocation test.

Pathogenesis
Aetiologically NCGS is a disorder with poorly recognised pathogenesis.
It has not been determined yet what grain ingredients are responsible for
the symptoms of the disease.
A major role as triggers of the innate immune response leading to NCGS can
be played by the poorly absorbed carbohydrates in wheat grains - fructo-
oligosaccharides, fructans.
During fermentation gas is produced and short-chain fatty acid are formed.
What is more, changes in microbiota take place resulting in gastrointestinal
symptoms.
In the NCGS patients TGFβ1 and the FoxP3 markers for regulatory
lymphocytes 3 are significantly reduced, which indicates the likelihood of the
recruitment of the regulatory T lymphocytes to the small intestine to be
smaller than in healthy people.

Classification of
gluten-related
disorders.

Chronic Fatigue Syndrome (CFS)
CFS may be defined as a disorder characterized by
debilitating fatigue lasting for at least 6 months, associated with multiple
other symptoms in which other causes of fatigue have been excluded
feverishness,
chills and night sweats,
recurrent sore throat,
lymph node pain and enlargement,
myalgia, arthralgia,
headache,
postexertional weakness and fatigability,
sleep disorders, and
various neuropsychological complaints.
Fukuda K, Ann Intern Med 1994;121:953–959.

CFS may be defined as a disorder characterized by
debilitating fatigue lasting for at least 6 months, associated with multiple
other symptoms in which other causes of fatigue have been excluded
Fukuda K, Ann Intern Med 1994;121:953–959.

hypofunction of the immune system
chronic viral infections, e.g.,
Epstein-Barr virus (EBV)
allergic disease (food allergy) that is
recognized and not well controlled
neurally mediated hypotension
What Are Possible Causes of CFS?
abnormally fatigued
populations, including those
with the CFS and
overlapping disorders.

Fibromyalgia (FM)
FM currently is
defined as a
disorder with
many of the
features of
Chronic Fatigue
Syndrome
but with the
presence of both
chronic
widespread pain
and the finding
of 11/18 tender
points on
examination.
Clauw DJ, Best Pract Res Clin Rheumatol 2003;17:685–701.
Examples of chronic regional pain syndromes where ‘peripheral’
factors (e.g. inflammation or damage to tissues) play
a minor or no role in pain.
Patients have pain that is “central” (i.e., not caused by inflammation
or damage of structures) rather than peripheral in nature.

Fibromyalgia (FM)
Examples of
overlapping systemic
syndromes
characterized by
otherwise unexplained
chronic pain and
fatigue.
Clauw DJ, Best Pract Res Clin Rheumatol 2003;17:685–701.

Are attention deficit hyperactivity disorder and chronic
fatigue syndrome allergy related? what is fibromyalgia?
Bellanti JA, Allergy Asthma Proc. 2005;26(1):19-28
There are a group of diseases that the allergist immunologist may be called
on to manage in which their precise etiologies have not been identified but
that appear to be initiated or exacerbated by allergic mechanisms.
Attention deficit hyperactivity disorder (ADHD), chronic fatigue syndrome
(CFS), and fibromyalgia (FM) fall into this category of disorders.
Although the precise etiology of ADHD still remains unknown, the most
prevalent theory is that it represents a developmental disability leading to
inadequate production of the neurotransmitter dopamine.
In patients with CFS, there appears to be a fundamental dysfunction of the
neuroendocrine-immunological system with deficiencies of immunological and
neurological function, which, together with chronic viral infection, may lead
to a sequence of events responsible for the symptoms of this disorder.

Gastrointestinal inflammation and associated immune
activation in schizophrenia.
Severance EG, Schizophr Res 2012:138:48–53
 IgG antibodies to
Saccharomyces cerevisiae
(ASCA, a marker of intestinal
inflammation),
bovine milk casein,
wheat-derived gluten.
 193 with non-recent
onset schizophrenia
(Non-RO SZ).
 67 with recent onset
schizophrenia (RO SZ)
 207 non-psychiatric controls.
Quantitative ASCA IgG levels
in individuals with schizophrenia
compared to controls.

inflammation),
bovine milk casein,
onset schizophrenia
(Non-RO SZ).
compared to controls.ASCA markers were
significantly elevated
and correlated with
food antigen antibodies
in recent onset and
non-recent onset
schizophrenia
compared
to controls.

inflammation),
bovine milk casein,
onset schizophrenia
(Non-RO SZ).
compared to controls.
Gastrointestinal
inflammation is a
relevant pathology
in schizophrenia.

Food allergy in autism spectrum disorder
Autism spectrum disorder
is a heterogeneous cluster of
neurodevelopmental disorders
characterized by
impairments in communication
and social interaction and
by repetitive behavior .
American-Psychiatric-Association.
Diagnostic and Statistical Manual of
Mental Disorders (4th ed).
Washington, DC:
American-Psychiatric-Association,
2000

Autism spectrum disorder
is a heterogeneous cluster of
neurodevelopmental disorders
characterized by
impairments in communication
and social interaction and
by repetitive behavior .
American-Psychiatric-Association.
Diagnostic and Statistical Manual of
Mental Disorders (4th ed).
Washington, DC:
American-Psychiatric-Association,
2000
De Theije CGM, Peditr Allergy Imm 2014;25:218
The gut-brain axis
is an emerging
field of
research on
ASD.

The diagnostic category pervasive developmental disorders (PDD), as opposed to specific
developmental disorders (SDD), refers to a group of five disorders characterized by delays in
the development of multiple basic functions including socialization and communication.
PDD-NOS: Pervasive Developmental Disorder, Not Otherwise Specified

Symptoms of PDD may include behavioral and communication problems
such as:
1) Difficulty using and understanding language
2) Difficulty relating to people, objects, and events; for example, lack
of eye contact, pointing behavior, and lack of facial responses
3) Unusual play with toys and other objects
4) Difficulty with changes in routine or familiar surroundings
5) Repetitive body movements or behavior patterns, such as hand
flapping, hair twirling, foot tapping, or more complex movements
6) Inability to cuddle or be comforted
7) Difficulty regulating behaviors and emotions, which may result in
temper tantrums, anxiety, and aggression.

Autistic-like behavioural and neurochemical changes
in a mouse model of food allergy.
de Theije CG, Behav Brain Res. 2014;261:265-74.
Food allergic reaction to
cow's milk protein, induced
shortly after weaning
1) Reduced social behaviour
2) Increased repetitive behaviour
Xincreased levels of serotonin in the intestine
reduced dopaminergic activity in the prefrontal cortex

1) This food allergic reaction increased levels of serotonin
(5-hydroxytryptamine; 5-HT) and the number of 5-HT positive
cells, and decreased levels of 5-hydroxyindoleacetic acid
(5-HIAA) in the intestine.
2) Behavioural changes in food allergic mice were
accompanied by reduced dopaminergic activity in the
prefrontal cortex. The dopamine system is strongly associated with the
reward system of the brain.
3) Neuronal activation (c-Fos expression) was increased in the
prefrontal cortex and reduced in the paraventricular nucleus of the
hypothalamus after exposure to a social target.

1) This food allergic reaction increased levels of serotonin
(5-hydroxytryptamine; 5-HT) and the number of 5-HT positive
cells, and decreased levels of 5-hydroxyindoleacetic acid
(5-HIAA) in the intestine.
2) Behavioural changes in food allergic mice were
accompanied by reduced dopaminergic activity in the
prefrontal cortex. The dopamine system is strongly associated with the
reward system of the brain.
3) Neuronal activation (c-Fos expression) was increased in the
prefrontal cortex and reduced in the paraventricular nucleus of the
hypothalamus after exposure to a social target.
We hypothesize that an intestinal allergic
response regulates complex, but critical,
neuroimmune interactions, thereby affecting
brain circuits involved in social interaction,
repetitive behaviour and cognition.

How do we measure permeability?
It is easy to measure one's intestinal permeability by way of simply measuring the passive permeability
using a dual sugar technique utilising lactulose and mannitol.
The IP test may well be the most useful, precise and low-invasive way for assessing mucosal integrity in
the small bowel. Mannitol (a monosaccharide) and lactulose (a disaccharide) are water soluble molecules
that are not metabolised by the body. Mannitol is readily absorbed, and lactulose is only absorbed slightly.
Testing procedure
The patient is given an oral dose containing 5gr of lactulose and 3gr of mannitol in a base of 10gr of
glycerol. A timed urine sample is analysed and the ratios are assessed for the permeation of the water-
soluble molecules (lactulose and mannitol) through the intestinal mucosa. Accurate information is obtained
regarding gut integrity and function.
What do the results mean?
The permeation of the sugars through the intestinal mucosa can occur either through cells or between
cells lining the small intestine wall. Small molecules (mannitol) readily penetrate cells and passively diffuse
through them. Larger molecules (lactulose) normally are excluded by the cells in a normal, healthy
functioning gut. The rate limiting barrier in this case is the "tight junction" between cells, which are only
one layer thick. Tight junctions are important to maintain healthy epithelial integrity.
Lactulose, being only slightly absorbed, serves as a marker for mucosal integrity.
Mannitol is readily absorbed and serves as a marker for trans-cellular uptake.
Low levels of mannitol and lactulose indicate malabsorption.
Elevated levels of mannitol and lactulose indicate general increased permeability and are indicative of
"leaky gut"syndrome.
The lactulose/mannitol ratio is a useful parameter.
Elevated ratios indicate that the effective pore size of the gut mucosa has increased, allowing access (to
the body) of larger, and possibly antigenic molecules.

Parents of autistic children report more
often that their child suffered from food
allergies than parents of healthy children or
children with special education needs.
Gurney JG, Arch Pediatr Adolesc Med 2006:160:825–30.
Chandler S, J Autism Dev Disord 2013;43(12):2737-47
Indeed, serum levels of immunoglobulins IgA, IgG, and IgM specific
for cow’s milk derived allergens and total IgE are increased in children
with ASD compared with healthy controls.
Lucarelli S, Panminerva Med 1995:37:137–41.

Parental report of health conditions and health care use
among children with and without autism:
National Survey of Children’s Health.
Gurney JG, Arch Pediatr Adolesc Med 2006:160:825–30
 Cross-sectional analysis of
the 2003 to 2004 National
Survey of Children's
Health.
 More than 100 000 parents.
 Response to the question:
"Has a doctor or health
professional ever told
you that your child has
autism?“.
 Autism prevalence
among children
aged 3 to 17 years
5.3 per 1000

4.5
5.0 –
4.0 –
3.0 –
2.0 –
1.0 –
0.0
OR for food allergy
in children
with autism
 Cross-sectional analysis of
the 2003 to 2004 National
Survey of Children's
Health (NSCH).
 More than 100 000 parents.
 Response to the question:
"Has a doctor or health
professional ever told
you that your child has
autism?“.

depression or
anxiety problems
behavioral or
conduct problems
food allergies ADHD
Prevalence in children with Autism vs Controls of
38.9%
45.1%
14.1%
58.9%
60 –
50 –
40 –
30 –
20 –
10 –
0
4.2%
3.2%
5.2% 7%
OR=4.5

Shared heritability of attention-deficit/hyperactivity
disorder and autism spectrum disorder.
Rommelse NN, Eur Child Adolesc Psychiatry 2010:19:281–95
1) Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum
disorder (ASD) are both highly heritable neurodevelopmental disorders.
2) Evidence indicates both disorders co-occur with a high frequency.
meeting criteria for ASD
50 –
40 –
30 –
20 –
10 –
00
children with ADHD
20%
50%
meeting criteria for ADHD
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00
children with ASD
30%
80%
A
D
H
D
ASD

Food allergy and infantile autism.
Lucarelli S, Panminerva Med 1995:37:137–41
 Efficacy of a cow's milk
free diet (or other foods
which gave a positive
result after a skin test).
 36 autistic patients.
 20 healthy children.
1) Levels of sIgA for casein,
lactalbumin and β lactoglobulin
and IgG and IgM for casein
higher than in healthy
controls.
2) A marked improvement in
the behavioural symptoms of
patients after 8 weeks
on an elimination diet.

Food allergy and infantile autism.
Lucarelli S, Panminerva Med 1995:37:137–41
 Efficacy of a cow's milk
free diet (or other foods
which gave a positive
result after a skin test).
 36 autistic patients.
 20 healthy children.
1) Levels of sIgA for casein,
lactalbumin and β lactoglobulin
and IgG and IgM for casein
higher than in healthy
controls.
2) A marked improvement in
the behavioural symptoms of
patients after 8 weeks
on an elimination diet.
Our results
lead us to hypothesise
a relationship between
food allergy and
infantile autism as has
already been suggested
for other disturbances
of the central nervous
system.

Peripheral blood mononuclear cells of ASD children produce more
TNF-a and IL-12 in response to cow’s milk-derived allergens than
those from control subjects. Jyonouchi H. J Pediatr 2005:146:605–10.
Milk intake by autistic patients was a significant predictor of
constipation and led to the worsening of some of the behavioral
symptoms specific for ASD. Afzal N, Pediatrics 2003:112:939–42.
Lucarelli S, Panminerva Med 1995:37:137–41.
Gluten intake has also been suggested to exacerbate autistic behavior
although no association between gluten sensitivity or celiac disease
and ASD has been reported. Barcia G, J Autism Dev Disord 2008:38:407–8
Genuis SJ, J Child Neurol 2010:25: 114–9.
Batista IC, Arq Neuropsiquiatr 2012:70:28–33.

Evaluation of an association between gastrointestinal
symptoms and cytokine production against common dietary
proteins in children with autism spectrum disorders.
Jyonouchi H. J Pediatr 2005:146:605–10
PBMCs from ASD children
with gastrointestinal
symptoms
 Peripheral blood mononuclear
cells (PBMCs) from
109 autism spectrum disorders
(ASD) children with
or without GI symptoms
(GI [+] ASD, N = 75
and GI (-) ASD, N = 34],
from children with
non-allergic food hypersensitivity
(NFH) (N = 15),
and control subjects (N = 19).
cow's milk and gliadin
more TNF-α and IL-12

Evaluation of an association between gastrointestinal
symptoms and cytokine production against common dietary
proteins in children with autism spectrum disorders.
Jyonouchi H. J Pediatr 2005:146:605–10
PBMCs from ASD children
with gastrointestinal
symptoms
 Peripheral blood mononuclear
cells (PBMCs) from
109 autism spectrum disorders
(ASD) children with
or without GI symptoms
(GI [+] ASD, N = 75
and GI (-) ASD, N = 34],
from children with
non-allergic food hypersensitivity
(NFH) (N = 15),
and control subjects (N = 19).
cow's milk and gliadin
more TNF-α and IL-12
A high prevalence of
elevated TNF-α/IL-12
production by GI (+) ASD
PBMCs with cow's milk
proteins and its major
components indicates
a role of non-allergic food
hypersensitivity in GI
symptoms observed in
children with ASD.

Parent-reported gastro-intestinal symptoms in children
with autism spectrum disorders.
 132 children with autism
spectrum disorders (ASD)
and 81 with special
educational needs (SEN)
but no ASD,
aged 10-14 years.
 82 typically developing
(TD) children.
% children with past and current
gastro-intestinal (GI) symptoms
46.5%
29.2%
21.8%
50 –
40 –
30 –
20 –
10 –
.0
ASD SEN TD
autism
spectrum
disorders
typically
developing
special
educational
needs

Parent-reported gastro-intestinal symptoms in children
with autism spectrum disorders.
 132 children with autism
spectrum disorders (ASD)
and 81 with special
educational needs (SEN)
but no ASD,
aged 10-14 years.
 82 typically developing
(TD) children.
% children with past and current
gastro-intestinal (GI) symptoms
46.5%
29.2%
21.8%
50 –
40 –
30 –
20 –
10 –
.0
ASD SEN TD
The ASD group had
significantly increased
past vomiting
and diarrhoea
and more abdominal
pain more current
constipation.
autism
spectrum
disorders
typically
developing
special
educational
needs

Constipation with acquired megarectum in children with
autism. Afzal N, Pediatrics 2003:112:939–42
 103 autistic children referred
for gastroenterological
assessment.
 29 control radiographs from
referred to the emergency
department, with abdominal pain.
 Radiographs and a radiologist.
The severity of constipation
was determined using a validated
index.
Autistic
36%
% children with moderate
or severe constipation
10%
Controls
p=0.011
40 –
30 –
20 –
10 –
.0

assessment.
index.
Autistic
36%
% children with moderate
or severe constipation
10%
Controls
p=0.011
40 –
30 –
20 –
10 –
.0
Multivariate regression
analysis showed
consumption of milk
to be the strongest
predictor of
constipation in the
autistic group.

Autistic
54.4%
% children with
moderate/severe
rectosigmoid loading or
acquired megarectum
21.1%
Controls
p<0.001
60 –
50 –
40 –
30 –
20 –
10 –
.0
assessment.
index.

Accumulating evidence strongly suggests that Gastro Intestinal
dysfunctions and abdominal pain are often present in children with
ASD.
The reported prevalence of gastrointestnal symptoms ranges from
9% to 91%, an immense range probably due to varying
interpretations of GI problems, inability of ASD children to
express their discomfort and the heterogeneity of the disorder.
Pathways underlying the gut-to-brain connection in
autism spectrum disorders as future targets for disease
management.de Theije CG, Eur J Pharmacol 2011: 668:S70–80.

Autism and coeliac disease.
Barcia G, J Autism Dev Disord 2008:38:407–8
subjects:
- 150 with autistic disorder (AD),
- 49 pervasive developmental
- disorder not otherwise specified,
- 4 childhood disintegrative disorder,
- 6 Asperger disorder.
Serologic screening for CD through
anti-endomysial and anti-tissue
transglutaminase anti-body assays,
and intestinal biopsy when serologic
tests were positive.
3.3%
5.0 –
4.0 –
3.0 –
2.0 –
1.0 –
0.0
% children diagnosed
with coeliac disease

subjects:
The diagnostic category pervasive
developmental disorders (PDD), as opposed
to specific developmental disorders (SDD),
refers to a group of five disorders
characterized by delays in the development of
multiple basic functions including
socialization and communication.
The pervasive developmental disorders are:
1) Pervasive developmental disorder not
otherwise specified (PDD-NOS), which
includes atypical autism, and is the most
common;
2) Autism, the best-known, now understood to
be part of a spectrum;
3) Asperger syndrome;
4) Rett syndrome; and
5) Childhood disintegrative disorder (CDD).

subjects:
3.3%
5.0 –
4.0 –
3.0 –
2.0 –
1.0 –
0.0
This is significantly higher
(p = 0.014) in comparison to
CD prevalence for the
general paediatric population
of 0.94% (1:106).

subjects:
3.3%
5.0 –
4.0 –
3.0 –
2.0 –
1.0 –
0.0
of 0.94% (1:106).
After gluten-free diet
for at least 6 months;
improvement of
gastrointestinal symptoms
was detected while
behavioural improvement
was not.

subjects:
3.3%
5.0 –
4.0 –
3.0 –
2.0 –
1.0 –
0.0
of 0.94% (1:106).
Screening for CD is
recommended in all
children with autism,
even if no
gastrointestinal
symptoms are present.

Celiac disease presenting as autism.
Genuis SJ, J Child Neurol 2010:25: 114–9
Investigations revealed inadequate levels of fat-soluble vitamins,
including notable deficiencies of vitamins A, D, and E as well as low
coenzyme Q10 and folate.
Plasma levels of Ώ-3 fatty acids including a-linolenic acid and
docosahexanoic acid were also very low.
In addition, polyunsaturated Ώ-6 fatty acids including linoleic acid
and γ-linolenic acid were noted to be markedly deficient.
Amino acid status and mineral status were unremarkable other than
a low zinc level.
These findings along with low saturated fat status
(despite regular consumption of saturated fats in his diet)
were suggestive of difficulty with fat absorption.

Autism spectrum disorder and celiac disease: no evidence
for a link. Batista IC, Arq Neuropsiquiatr 2012:70:28–33.
Occurrences of CD determined
in a group of children and
adolescents affected by ASD
and, conversely, occurrences of
ASD assessed in a group of
biopsy-proven celiac patients.
levels of antigliadin antibodies
to asses gluten sensitivity (GS) in
ASD patients compared with the
levels in a group of non-celiac
children.
1) The prevalence of Coeliac
Disease or Gluten Sensitivity
in ASD patients was not
greater than in groups
originating from the same
geographical area.
2) Similarly the prevalence of
ASD was not greater than in
a group of biopsy-proven CD
patients.

A 5-year-old boy diagnosed
with severe autism at a
specialty clinic for autistic
spectrum disorders.
After initial investigation
suggested underlying celiac
disease and varied nutrient
deficiencies, a gluten-free
diet was instituted along
with dietary and supplemental
measures to secure
nutritional sufficiency.
With gluten-free diet the
patient’s gastrointestinal
symptoms rapidly resolved,
and
signs and symptoms
suggestive of autism
progressively abated.

This case is an example of
a common malabsorption
syndrome associated with
central nervous system
dysfunction
and
suggests that in some
contexts, nutritional
deficiency may be a
determinant of
developmental delay.
spectrum disorders.
measures to secure

This case is an example of
a common malabsorption
syndrome associated with
central nervous system
dysfunction
and
suggests that in some
contexts, nutritional
deficiency may be a
determinant of
developmental delay.
spectrum disorders.
measures to secure
It is recommended that
all children with
neurodevelopmental
problems be assessed
for
nutritional deficiency
and
malabsorption
syndromes.

Alterations of the intestinal barrier in patients with autism
spectrum disorders and in their first-degree relatives.
de Magistris L, J Pediatr Gastroenterol Nutr 2010:51:418–24
 Intestinal permeability
(IPT) by means of the
lactulose/mannitol test.
 Faecal calprotectin in
patients with autism,
either with or without
gastrointestinal
symptoms, and in their
first-degree relatives.
Mannitol is a small molecule that normally
passes through easily and serves as a marker
of how well nutrients are being absorbed.
Lactulose is a larger molecule that doesn't
normally pass through very well and serves
as a marker for whether there are large
holes in the lining.
To perform the test, the patient mixes pre-
measured amounts of lactulose and mannitol
and drinks it.
The test measures the amount of lactulose
and mannitol recovered in a 6-hour urine
sample.

patients with
autism
36.7%
21.2%
4.8%
their
relatives
normal
subjects
40 –
30 –
20 –
10 –
.0
% subjects with abnormal
intestinal permeability
gastrointestinal

gastrointestinal
patients with
autism
36.7%
21.2%
4.8%
their
relatives
normal
subjects
40 –
30 –
20 –
10 –
.0
Patients with autism on
a reported gluten-casein-
free diet had significantly
lower intestinal
permeability (IPT) values
compared with those who
were on an unrestricted
diet and controls.

gastrointestinal
patients with
autism
36.7%
21.2%
4.8%
their
relatives
normal
subjects
40 –
30 –
20 –
10 –
.0
The results obtained
support the leaky gut
hypothesis and indicate
that measuring IPT
could help to identify
a subgroup of patients
with autism who could
benefit from a
gluten-free diet.

gastrointestinal
% of children with autism
and gastrointestinal symptoms
constipation
45.5%
34.1%
15.9%
diarrhoea
alternating
diarrhoea-
constipation,
abdominal pain
50 –
40 –
30 –
20 –
10 –
.0

Food Allergy, the Brain, and Neurological Symptoms

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