The role of IgG hypersensitivity in the pathogenesis and therapy of depressive disorders

Abstract

Depressive episodes are associated not only with changes in neurotransmission in the central nervous system, but also may lead to structural changes in the brain through neuroendocrine, inflammatory, and immunological mechanisms. The aim of this article is to present a new hypothesis connecting the inflammatory theory of depression with IgG food hypersensitivity and leaky gut syndrome. This new potential pathway that may mediate the pathogenesis of depression implies the existence of subsequent developmental stages. Overproduction of zonulin triggered, for example, by gliadin through activation of the epidermal growth factor receptor and protease-activated receptor causes loosening of the tight junction barrier and an increase in permeability of the gut wall ('leaky gut'). This results in a process allowing larger molecules that would normally stay in the gut to cross into the bloodstream and in the induction of IgG-dependent food sensitivity. This condition causes an increased immune response and consequently induces the release of proinflammatory cytokines, which in turn may lead to the development of depressive symptoms. It seems advisable to assess the intestinal permeability using as a marker, for example, zonulin and specific IgG concentrations against selected nutritional components in patients with depression. In the case of increased IgG concentrations, the implementation of an elimination-rotation diet may prove to be an effective method of reducing inflammation. This new paradigm in the pathogenesis of depressive disorders linking leaky gut, IgG-dependent food sensitivity, inflammation, and depression is promising, but still needs further studies to confirm this theory.

Full text

The role of IgG hypersensitivity in the
pathogenesis and therapy of
depressive disorders
Hanna Karakuła-Juchnowicz1, Patrycja Szachta2, Aneta Opolska3,
Justyna Morylowska-Topolska1, Mirosława Gałęcka2,
Dariusz Juchnowicz4,PawełKrukow1, Lasik Zofia2
1
Department of Clinical Neuropsychiatry Medical University, Lublin, Poland,
2
Institute for Microecology,
Poznań, Poland,
3
Department of Dietetics Higher School of Social Sciences, Lublin, Poland,
4
Department of Psychology University of Pedagogy, Bialystok, Poland
Depressive episodes are associated not only with changes in neurotransmission in the central nervous
system, but also may lead to structural changes in the brain through neuroendocrine, inflammatory, and
immunological mechanisms. The aim of this article is to present a new hypothesis connecting the
inflammatory theory of depression with IgG food hypersensitivity and leaky gut syndrome. This new
potential pathway that may mediate the pathogenesis of depression implies the existence of subsequent
developmental stages. Overproduction of zonulin triggered, for example, by gliadin through activation of
the epidermal growth factor receptor and protease-activated receptor causes loosening of the tight
junction barrier and an increase in permeability of the gut wall (‘leaky gut’). This results in a process
allowing larger molecules that would normally stay in the gut to cross into the bloodstream and in the
induction of IgG-dependent food sensitivity. This condition causes an increased immune response and
consequently induces the release of proinflammatory cytokines, which in turn may lead to the
development of depressive symptoms. It seems advisable to assess the intestinal permeability using as a
marker, for example, zonulin and specific IgG concentrations against selected nutritional components in
patients with depression. In the case of increased IgG concentrations, the implementation of an
elimination–rotation diet may prove to be an effective method of reducing inflammation. This new
paradigm in the pathogenesis of depressive disorders linking leaky gut, IgG-dependent food sensitivity,
inflammation, and depression is promising, but still needs further studies to confirm this theory.
Keywords: Depression, Leaky gut, IgG hypersensitivity, Zonulin, Inflammatory theory of depression, Gluten sensitivity
Introduction
Depression is a heterogeneous psychiatric disorder
with multifactorial aetiology and therefore needs
improved integration models, based on behavioural
studies, sociology, and neuroscience to better reflect
both the complexity and variety of mood disorders.
1
Among the factors deserving special attention are bio-
logical ones, including psychoneuroendocrinology and
psychoimmunology, posing a bridge between strictly
biological and psychological approaches.
2
More and
more evidence indicates that depressive episodes are
associated not only with changes in neurotransmission
in the central nervous system (CNS), but also may
lead to structural changes in the brain through
neuroendocrine, inflammatory, and immunological
mechanisms.
3–5
Different factors potentially con-
nected with systemic inflammation in depression are
taken into consideration; these include psychosocial
stressors, poor diet, physical inactivity, obesity,
smoking, altered gut permeability, atopy, dental
caries, sleep, and Vitamin D deficiency.
6
The aim of this article is to present a new hypothesis
connecting the inflammatory theory of depression
with IgG food hypersensitivity and leaky gut
syndrome (LGS).
Inflammatory theory of depression
Among many theories of depression, the cytokine
(macrophage) theory of depression, first demonstrated
in 1991 by Robert Smith,
7
has aroused much interest
among researchers. It is assumed that changes in
behaviour, typical of depression, are the result of the
Correspondence to: Hanna Karakuła-Jachnowicz, Department of Clinical
Neuropsychiatry, Medical University of Lublin, ul. Głuska 1, 20-439
Lublin, Poland. Email: karakula.hanna@gmail.com, hanna.karakula@
umlub.pl
©W.S.Maney&SonLtd2014
MORE OpenChoice articles are open access and distributed under the terms of the Creative Commons Attribution Non-Commercial License 3.0
DOI 10.1179/1476830514Y.0000000158 Nutritional Neuroscience 2014 VOL. 0NO. 01

interaction of proinflammatory cytokines produced in
the peripheral and/or CNS with the neuroendocrine
system. This leads to activation of the hypothalamic-
pituitary-adrenal (HPA) axis and elimination of
tryptophan, a serotonin precursor (as a result of
activation of indole 2,3-dioxygenase, an enzyme that
converts tryptophan into kynurenine).
8
Cytokines are a large group of more than 100 regu-
latory proteins, proinflammatory and anti-inflamma-
tory mediators, which can be considered immune
regulating hormones that regulate growth, prolifer-
ation, and cell activity.
9
A wide range of biological
activities of cytokines known so far includes pyrogenic
activity, hyperalgesic activity, the effect on energy
balance in the body by changing the appetite level
and metabolism, modulation of the autonomic
nervous system activity, the effect on the functioning
and structure of the cardiovascular system, mood low-
ering effects, increased drowsiness, and the regulation
of hormones, and other cytokines.
10
Cytokines are
also signalling molecules involved in a diverse set of
physiological roles with extensive cross-talk.
11,12
The increase in the proinflammatory cytokine con-
centration and their effects on the CNS contribute to
the development of neuropsychological and somatic
depressive symptoms.
13
Many studies conducted so far have shown elevated
levels of proinflammatory cytokines in the serum of
patients with a major depressive episode. In these
studies, multiple cytokines such as tumour necrosis
factor (TNF-α), interferon-γ, interleukin IL-1β, IL-2,
IL-4, IL-6, IL-8, and IL-10 were taken into account.
Two recent meta-analyses confirmed the importance
of higher interleukin-1, -6, and TNF-αlevels in the
serum of patients with depression.
14,15
Elevated levels
of these cytokines in the cerebrospinal fluid of depress-
ive patients were also shown in numerous studies.
16,17
The importance of elevated C-reactive protein is high-
lighted
18,19
in the absence of clearly consistent findings
with regard to other cytokines.
15
An interesting
phenomenon, confirming the link between the inflam-
matory process and depression symptoms, is the
co-occurrence of depression with inflammatory diseases
such as asthma, chronic obstructive pulmonary disease,
diabetes, allergy, and rheumatoid arthritis.
20
Immunostimulatory treatment using interferon-
alpha (IFN-alpha) in hepatitis C or cancer (mela-
noma, leukaemia) shows that this treatment is
associated with much higher rates of depression as
compared to those of the general population.
21
Among patients receiving IFN-alpha, the percentage
of depressed individuals is nearly 45%.
22
Further
evidence on the important role of proinflammatory
cytokines in the pathogenesis of depression is provided
by a study demonstrating that the concentration of
inflammatory cytokines correlates positively with the
severity of depressive symptoms,
23
while antidepress-
ive treatment and clinical improvement leads to
reduction of proinflammatory cytokine concentration
in patients with depression.
10
A meta-analysis of 22
studies evaluating the relationship between the efficacy
of antidepressant medication in the treatment of
depression and levels of inflammatory markers
showed that the use of antidepressive drugs (especially
serotonin-specific reuptake inhibitors) was associated
with decreased levels of IL-1βand IL-6.
24
It has been established that Proinflammatory cyto-
kines may contribute to the development and pro-
gression of depression through the following pathways:
1. Pathological activation of the immune response,
including the acute-phase reaction as well as changes
occurring early in response to tissue damage: this reac-
tion is manifested, among other things, with a sharp
increase in the production of many proteins, including
acute phase proteins: the C-reactive protein, alpha-1
acid glycoprotein, and α-chymotrypsin, together with
changes in their structure.
25,26
2. Changes in neurotransmitter systems: inflammatory
cytokines can cross the blood–brain barrier, using
both the space with increased permeability and the
active transport principle. The migration of cytokines
to the CNS can trigger various psychopathological
changes,
27
i.a., due to the influence of changes in the
synthesis, reuptake, and metabolism of neurotransmit-
ters involved in the regulation of mood such as dopa-
mine, serotonin, or glutamate.
28–30
It turns out that
cytokines can cause a decrease in the availability of
serotonin, with an increase in concentrations of neuro-
toxic tryptophan metabolites via 2,3-dioxygenase
indoleamine activation. Substances produced during
the catabolism of tryptophan (called TRYCATs)
may adversely affect the behaviour processes. For
example, kynurenine elicits anxiety and depressive
behaviour.
31,32
Toxic metabolites of tryptophan are also produced
under the influence of tryptophan 2,3-dioxygenase,
activated by cortisol,
33
whose concentration is often
increased in depression.
34
Dopamine is also a neuro-
transmitter whose concentration and availability is
reduced under the influence of cytokines in selective
areas of the brain.
35
Another process, also disrupted in depression, is
associated with the capacity of cytokines to increase
glutamate release, which consequently leads to an
increase in glutamate transmission, and finally results
in enhanced generation of free radicals.
An important consequence of the increased glutama-
tergic transduction is also reduced production of the
nerve growth factor (brain derived neurotrophic
factor (BDNF)). Increased glutamate neurotrans-
mission and BDNF reduced levels lead to changes in
neuronal plasticity.
36
3. The effect on the HPA axis and release of cortico-
tropin-releasing hormone (CRH) and adrenocortico-
tropic hormone (ACTH): proinflammatory cytokines
Karakuła-Juchnowicz et al. The role of IgG hypersensitivity in the pathogenesis and therapy of depressive disorders
Nutritional Neuroscience 2014 VOL. 0NO. 02

intensify noradrenergic neurotransmission and
activate the HPA axis.
37
HPA hyperactivity has been
proposed as the neurobiological basis of major
depression.
38
It is well documented that patients with
major depressive disorder have elevated plasma corti-
sol levels as well as decreased sensitivity to external
dexamethasone and CRH.
39
4. The processes described above, expressed in immuno-
logical and glandular malfunctions and neurotrans-
mitters dysregulation, can lead to brain cell loss and
reduction in neurogenesis. According to the latest
views on the pathogenesis of depression, stress
factors can cause atrophy of hippocampal cells (as a
result of hypercortisolism caused by HPA axis hyper-
activity) and impairment of neurogenesis in predis-
posed subjects.
40
Although there is a growing body of evidence sup-
porting the importance of inflammation and
immune activation in at least part of the population
of depressive patients,
3,15,18,41
the role of inflam-
mation and inflammatory processes similar to those
described in cases of schizophrenia
42
requires further
investigation in depression as do potential issues
governing the integrity of the intestinal barrier via
sulphonation,
43
tight-junction (TJ) modulators,
44
the
contributing role of pathogenic agents,
42
and IgG
food hypersensitivity.
45
Leaky gut and IgG hypersensitivity
There is an increasing number of reports on the role
of the gastrointestinal tract in the pathogenesis of
depression.
46
One of the factors leading to a systemic
inflammatory response is increased intestinal per-
meability, also called leaky gut syndrome (LGS).
LGS is a dysfunction of the intestinal barrier,
resulting from damaged connections between entero-
cytes.
47
These connections –intercellular tight junc-
tions (TJs) –are protein complexes, with junctions
between enterocytes that are the structural basis for
the epithelium barrier.
48
They play two fundamental
roles, serving as: (1) a gate that regulates the passage
of ions, water, and other molecules through the para-
cellular route; and (2) a fence that blocks the lateral
diffusion within the plane of the membrane of lipids
and proteins, thereby maintaining the polarized distri-
bution of lipids and proteins between the apical and
basolateral plasma membrane domains.
49
TJs also
control the balance between the body’s immune toler-
ance and response to antigens. Proteins that make up
TJs –zonulin, occludin, and claudins, modulate the
permeability of the described connections.
50,51
We
already know much about the structure of TJs, but
relatively little is known about their physiological
and pathophysiological modulation.
Zonulin is a precursor of acute phase protein-hapto-
globin 2. This protein controls paracellular
permeability through the epidermal growth factor
receptor
52
and protease-activated receptor (PAR)-
2.
44,53
The main role of zonulin is to regulate the flow
of molecules from the intestinal lumen by loosening
TJs.
44,54
It has been shown that overproduction of zonulin
can be triggered by exposure to bacteria,
53,55,56
drugs,
53
stress,
57
or foods.
53
For example, the dietary
protein gliadin, which is a class of proteins present in
wheat and several other cereals within the grass
genus Triticum, binds to the CXCR3 receptor,
leading to MyD88-dependent zonulin release and
increased intestinal permeability.
53,56,58
This, in turn,
may result in higher serum concentrations of the proin-
flammatory cytokines, free radicals, and others.
59
The
bowel dysfunction could, through a TJ opening,
induce immune activation which could contribute to
mitochondrial dysfunction and finally result in oxi-
dative stress.
It remains unclear whether gliadin-induced zonulin
activation is a specific reaction, that is whether
gliadin-dependent activation of the zonulin system
requires interaction of gliadin with a specific entero-
cyte receptor(s), or is a consequence of an unspecific
response.
60
A possible gliadin mechanism of action
may lead to a zonulin-mediated increase in actin poly-
merisation and intestinal permeability. Enterocytes
exposed to gliadin physiologically react by secreting
zonulin into the intestinal lumen. While in normal
intestinal tissues this secretion is self-limited in time,
the zonulin system in gut tissues of subjects with
coeliac disease (CD) is chronically upregulated,
leading to a sustained increase in intestinal
permeability to macromolecules, including gliadin,
from the lumen to the lamina propria, and ultimately
to intestinal permeability, immune, and autoimmune
disorders.
60
Increasing evidence points to possible con-
nections between autoimmune diseases, such as
coeliac disease or type 1 diabetes, and an earlier
increase in intestinal permeability, where, apart from
a genetic predisposition and environmental factors,
impairment of the intestinal barrier function must
occur.
61,62
The hypothesis about the dysregulation of
the zonulin release system, which triggers the disease
mechanism, immunological impairment of the gut
wall with increased intestinal permeability combined
with exposure to non-specific antigens, e.g. dietary or
bacterial factors may result in chronic inflammation
or autoimmune disease in genetically predisposed
subjects.
53,61–63
Zonulin impact on intestinal permeability depends
on time of administration and dosage. These results
were confirmed independently in vivo in intestinal per-
meability assay, wherein zonulin induced a significant,
reversible increase in the gastric mucosal permeability
of the duodenum and small intestine.
44
Zonulin can
Karakuła-Juchnowicz et al. The role of IgG hypersensitivity in the pathogenesis and therapy of depressive disorders
Nutritional Neuroscience 2014 VOL. 0NO. 03

be used as a biomarker of impaired gut barrier func-
tion for several autoimmune, neurodegenerative, and
tumour diseases and can be a potential therapeutic
target for the treatment of these devastating
conditions.
44
However, it should be stressed that other factors, for
instance commensal bacteria
64
or glycated and lipoxi-
dated proteins and peptides,
65
may also disturb the gut
immune homeostasis, leading to LGS, chronic
immunological overactivation, and low-grade inflam-
mation. Advanced glycation end products constitute
a group of heterogeneous compounds, whose high
concentrations in the body may be linked to activation
of a specific receptor called RAGE and substantially
exaggerate and prolong an inflammatory condition.
65
Production of similar compounds is facilitated by
foods undergoing high-temperature processing and
may adversely affect bowel receptors or exert an
impact on systemic inflammation.
65,66
The other proteins that play an important role
in regulating the intestinal barrier by modulating the
permeabilityof tight junctions are tight junction-associ-
ated MARVEL proteins (with occludin being the best
studied member of this protein family), junctional
adhesion molecules, and more than 20 members of
the claudin family.
67,68
It is likely that claudins interact
with many proteins.
69,70
Better understanding of these
interactions may provide insight into the entire cycle
of TJ regulation.
71
For example, the results of some
studies
72,73
demonstrate increased intestinal claudin
expression in response to milk protein components.
Occludin in turn was first identified as an integral mem-
brane protein connected with TJs in chickens
74
and in
mammals.
75
These proteins interact with the actin
cytoskeleton via TJ adaptor proteins like zonula occlu-
dens, which are membrane-associated guanylate kinase
inverted, and cingulin.
67
The factors aggravating TJs functioning are, i.a.,
psychological stress (increasing levels of CRH), proin-
flammatory cytokines, bacterial dysbiosis, nuclear
transcription factor NFKB (involved in the cellular
response to stimuli–stress, cytokines, free radicals,
antigens), oxidative stress, and others.
45,59
In their
study on mice, Riba et al.
76
found that stress from
maternal separation induces irritable bowel-like syn-
drome connected with increased paracellular intestinal
permeability and visceral hypersensitivity in adult
offspring, but also causes a specific IgG response to
soluble food antigens.
Selective permeability due to loss of intestinal
barrier is observed, i.a., in coeliac disease, inflamma-
tory bowel disease, obesity, atopic dermatitis, food
hypersensitivity, diabetes, sarcoidosis, neoplastic dis-
eases, cystic fibrosis, and also in autism.
5,77,78
There is a growing interest in the role of microbiota
in the maintenance of proper TJ functioning, the
brain–gut axis, and in the development of psychiatric
disorders.
79
The effect that intestinal bacteria has on
CNS and, consequently, psychiatric disorders are mul-
tidirectional, and is based primarily not only on cyto-
kine levels modulation, tryptophan metabolism, but
also on intestinal permeability.
45,80
Autochthonic bac-
teria are an important component in reducing levels of
proinflammatory cytokines and in maintaining intesti-
nal barrier continuity. This is the reason why bacterial
dysbiosis can lead to TJ unsealing. Increased intestinal
permeability allows bacterial lipopolysaccharides to
penetrate into the blood. In depression, significantly
elevated levels of IgM and IgA antibodies against
gram-negative enterobacteria lipopolysaccharides
were found.
5
This observation is very important
because metabolites of certain bacteria not only
adversely affect the functioning of the CNS but also
penetrate into the blood. A perfect example is the
study of Naseribafrouei et al.
81
They showed that the
Oscillibacter type strain, found in depression patients,
has a homolog of neurotransmitter GABA –valeric
acid as its main metabolic end product.
81
This mech-
anism may contribute to the psychopathology of
depression.
The type of diet can also contribute to LGS develop-
ment, either by mechanical TJ damage or by having a
negative effect on microbiota balance. A study by
Drago et al.
56
shows that gliadin containing foods
may lead to increased gut permeability. Gliadin acti-
vates zonulin signalling irrespective of the genetic
expression of autoimmunity, which leads to increased
intestinal permeability to macromolecules.
56
Taken together, many factors contribute to LGS,
which is the reason why intestinal bacteria (autochtho-
nous microflora; microbiota) and incompletely
digested nutrients move from the intestinal lumen
into the blood. This condition leads to the activation
of the immune system,
82
which may initiate
production of specific IgG antibodies against nutri-
ents, and consequently, the development of food
hypersensitivity, which is delayed and IgG-depen-
dent.
83
Inflammation, emerging as a consequence of
this process, is chronically sustained by repeated con-
sumption of allergenic foods.
46,84–86
The role of
specific IgG antibodies has been confirmed in coeliac
patients where IgG-dependent delayed reaction to
gluten occurs.
87,88
The delayed nature of the reaction is a considerable
diagnostic obstacle that makes it impossible for the
patient to identify the factor causing the allergy. This
results from the characteristics of IgG-dependent
responses. While IgE antibodies are responsible
for acute, immediately appearing allergic reactions,
IgG-dependent reactions take much longer to
develop.
89,90
These antibodies play a significant role
in shaping the body’s normal immune response.
Karakuła-Juchnowicz et al. The role of IgG hypersensitivity in the pathogenesis and therapy of depressive disorders
Nutritional Neuroscience 2014 VOL. 0NO. 04

Specific IgG-food-antigen complexes activate the
complementary system and phagocytic migration,
degrading the immune complex.
91
The immune
system can be activated where the immune complex
is formed at the binding site of the receptor, e.g. in
the choroid plexus CNS, renal glomerular basement
membrane, blood vessel walls, etc. Production of
proinflammatory cytokines (IL-1, IL-6, and TNF-α),
proteolytic enzymes, and free radicals –damaging
the surrounding tissue –is observed. Sustained inflam-
mation can be an initiating factor in the development
of chronic diseases.
91–93
As mentioned above, intesti-
nal barrier discontinuity resulting in elevated levels
of proinflammatory cytokines has been reported in
patients with depression.
It is worth mentioning that type II hypersensitivity
reaction (cytostatic–cytotoxic reaction) does not lead
to the development of a chronic inflammation state
and, consequently, is not involved in depression devel-
opment and/or its maintenance. In this reaction,
IgM/IgG antibodies bind to the antigens and join
complement fractions. As a result, cytolysis of the
effector cell is observed.
Gluten sensitivity and depression
Only recently has coeliac disease been separated from
gluten sensitivity (non-coeliac gluten sensitivity,
NCGS) and gluten allergic reactions (IgE-mediated).
94
According to the consensus document developed in
2012, a spectrum of gluten-related disorders includes
three main forms of gluten reactions: allergic (e.g.
food allergy), autoimmune (e.g. coeliac disease, der-
matitis herpetiformis, and gluten ataxia), and possibly
immune-mediated (e.g. NCGS).
95,96
CD is a chronic immune-mediated enteropathy trig-
gered by gluten ingestion in subjects who have genetic
compatibility of the HLA DQ2 or DQ8 haplotype.
97
This disorder affects one percent of the general
population and is characterized by villous atrophy,
crypt hyperplasia, and increased intraepithelial
lymphocytes.
94,98
Classic CD manifestations (but only in 50 per cent
of patients) are severe diarrhoea and consequent
weight loss with failure to thrive due to severe intesti-
nal malabsorption. All the other cases are clinically
atypical, associated, for example, with anaemia, osteo-
porosis, musculoskeletal and neurological disorders,
endocrinopathies, or skin diseases.
99
NCGS is a relatively new term for conditions in
which symptoms are triggered by gluten ingestion, in
the absence of coeliac-specific antibodies and of classi-
cal coeliac villous atrophy, with a variable presence of
first generation anti-gliadin antibodies.
100
The Human Leukocyte Antigen (HLA) classifi-
cation is not particularly useful in the NCGS diagnosis
process (only 50% of positive DQ2/DQ8 outcomes)
and, moreover, anti-gliadin antibodies in the first gen-
eration of the IgG class tend to be positive in subjects
with gluten sensitivity.
96,101,102
Unfortunately, despite the fact that NCGS occurs
six times more frequently than CD, the majority of
research has not separated these two disorders.
103
Although there is some evidence connecting CD
with neurologic and psychiatric symptoms,
94
there
have been very few studies so far examining connec-
tions between NCGS and mental disorders. In the
mainstream of this trend, there is Fasano’s group
research, focused on possible links between NCGS
and schizophrenia, identifying a biomarker and a sub-
sequent diagnostic tool for the condition of gluten sen-
sitivity and the role of the timing of gluten
introduction in CD pathogenesis in infants.
44
Biesiekierski
104
confirmed the existence of NCGS in
patients with irritable bowel syndrome in a random-
ized, double blind, placebo-controlled trial. The role
of intestinal barrier dysfunction was confirmed in
patients suffering from autism.
105
There is still a lack of studies on the importance of
leaky gut and IgG food allergy in the pathogenesis
of depression. Gluten sensitivity or intolerance has
been mentioned only in a few reports so far. For
example, Carta et al.
106
found that major depressive
disorder, dysthymic disorder, and adjustment dis-
orders were more common in a group of coeliac
patients as compared to the controls. Ludvigsson
et al.
107
achieved similar results with regard to
depression, but prevalence of CD in patients diag-
nosed with bipolar disorder was similar to the con-
trols. Ruuskanen et al.
108
in their research found that
the elderly population with gluten sensitivity was
more than twice as likely to have depression as com-
pared to the elderly sample without gluten sensitivity.
Carr,
95
in turn, described a case of an 11-year-old
girl who had been on a gluten-free diet since early
childhood due to health issues associated with wheat
consumption. At the age of 10 she had to consume a
wheat-containing diet for a week. After this short
period, her mood dropped suddenly, and she also
claimed that she had wanted to kill herself. Her
parents immediately changed her diet back to a strictly
gluten-free diet and after several days her mental state
improved significantly. In the pilot study, Peters
et al.
109
evidenced that even short-term gluten
exposure in patients with NCGS can cause symptoms
similar to depression.
The role of IgG-based elimination diet in the
therapy of depression
There is some evidence confirming the fact that the
quality of diet has an influence on leaky gut syndrome,
immune functioning and systemic inflammation in
depressive patients.
6
For example, whole grain foods
Karakuła-Juchnowicz et al. The role of IgG hypersensitivity in the pathogenesis and therapy of depressive disorders
Nutritional Neuroscience 2014 VOL. 0NO. 05

include fibre and beta glucans that can probably
modulate immune functioning.
110
Other dietary immunomodulating factors of con-
siderable current interest to mental health researchers
include prebiotics and probiotics.
111
The effectiveness
of prebiotics in promoting the growth of strains of ben-
eficial bacteria, e.g. bifidobacteria in the gut, has been
demonstrated by some studies. Namely, it has been
argued that the use of prebiotics leads to a favourable
change in intestinal microbiology, reduces intestinal
inflammation, and alleviates symptoms, e.g. atopic
eczema, irritable bowel syndrome.
112,113
There are
more and more reports about the positive effect of
such strains of bacteria as Streptococcus thermophilus
or Lactobacillus acidophilus, and even probiotic
Escherichia coli Nissle 1917, which protect the intesti-
nal barrier against harmful factors by reducing the
symptoms of leaky gut.
114,115
Various potential immunomodulating factors
improving tightness of the intestinal barrier also
include amino acid L-glutamine, which has been con-
firmed by some studies demonstrating its positive
effect on intestinal enterocytes as well as its power to
reduce leaky gut.
115,116
Present in curry powder, curcumin is another com-
pound with a beneficial immunomodulating effect,
potentially reducing inflammatory condition and oxi-
dative stress related to the activityof tight junctions.
117
Tight junction damage between enterocytes leads
to increased intestinal permeability that causes
absorption of undigested proteins in small intestine
and higher levels of specific IgG antibodies as a
consequence.
86
The essential treatment in this case should be
implementation of an appropriate diet. An elimin-
ation-rotation diet may be a good choice in patients
with IgG food allergy in many diseases (e.g.
migraine
118,119
). This type of diet relies on elimination
of foods identified as causing allergic reactions and
rotation in taking a certain type of food (only for
one day and then a three-day interval). Such rotation
reduces the risk of occurrence hypersensitivity to
food products that have been well tolerated before.
120
Most publications connecting intestinal per-
meability with mental disorders refer to studies on
autism spectrum disorders. Demonstration of efficacy
of gluten and casein-free diets in patients suffering
from autism
105,121–124
has resulted in attempts to use
this type of therapeutic proceedings in other mental
disorders, including depression. So far, studies on the
connection of a gluten-free diet and depression have
involved depressive subjects only with coeliac disease
(CD). For example, Corvaglia et al.
125
reported
several cases of patients with CD who had been unsuc-
cessfully treated with antidepressants and whose
depressive symptoms improved with a gluten-free
diet. Pynnonen et al.
126
also achieved similar results
in adolescents with CD. It may be assumed that elim-
ination of a factor causing inflammation (gluten) con-
tributes to mental health improvement also in patients
experiencing NCGS and depression. So far there have
been no studies that take into consideration a gluten-
free diet in depressive patients with NCGS.
Conclusion
The presented new hypothesis assumes existence of a
new potential pathway that may mediate the patho-
genesis of depression, which implies the existence of
subsequent developmental stages. Overproduction of
zonulin triggered by, e.g. gliadin
60
through activation
of the epidermal growth factor receptor and pro-
tease-activated receptor (PAR)-2 causes loosening of
the TJ barrier and an increase in permeability of the
gut wall (‘leaky gut’). This results in a process allowing
larger molecules that would normally stay in the gut to
cross into the bloodstream and in induction of IgG-
dependent food sensitivity.
127,128
This condition
causes an increased immune response
93,129
and conse-
quently induces the release of proinflammatory cyto-
kines,
15
which in turn may lead to the development
of depressive symptoms.
130
In view of the foregoing considerations, it seems
advisable to assess the intestinal permeability using
as a marker, e.g. zonulin, occludin, and specific IgG
concentrations against selected nutritional com-
ponents in patients with depression. In the case of
increased IgG concentrations, the implementation of
an elimination–rotation diet may prove to be an effec-
tive method of reducing inflammation. It is necessary
to evaluate the concentration of all subclasses of
specific IgG (IgG 1–4) using validated research tools,
by a quantitative method.
This new paradigm in the pathogenesis of depressive
disorders linking leaky gut, IgG-dependent food sensi-
tivity, inflammation and depression is promising, but
still further studies are needed to confirm this theory.
Another field of interest, i.e. elimination diets in
depression treatment, requires well-designed clinical
trials to check their utility.
Disclaimer statements
Contributors All authors contributed equally.
Funding None.
Conflicts of interest None.
Ethics approval N/A
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