The intestinal permeability syndrome, celiac disease, gluten sensitivity, autistic spectrum, mycotoxins and immunological tolerance

Abstract

The onset of several human diseases takes place in an inefficient intestine. We probably should re-evaluate the relationship between food and health. Three million Italians and twenty million Americans suffer from the gluten sensitivity syndrome, similar yet different from celiac disease. Different pathological status arise as a consequence of sensitivity to gluten, depending on the genetic polymorphism of the subjects and the environment in which they live. If we gain more knowledge on interactions between food, eating habits, genomics and the environment, this could mean better prevention and/or treatment. The era of epigenetics has begun, while the dogma of genetic determinism seems to be fading.

Full text

REVIEW
The intestinal permeability syndrome, celiac disease, gluten
sensitivity, autistic spectrum, mycotoxins and immunological
tolerance
M. Proietti •A. Del Buono •G. Pagliaro •
R. Del Buono •C. Di Rienzo
Received: 12 July 2012 / Accepted: 6 March 2013
ÓSpringer-Verlag Italia 2013
Abstract The onset of several human diseases takes
place in an inefficient intestine. We probably should re-
evaluate the relationship between food and health. Three
million Italians and twenty million Americans suffer from
the gluten sensitivity syndrome, similar yet different from
celiac disease. Different pathological status arise as a
consequence of sensitivity to gluten, depending on the
genetic polymorphism of the subjects and the environment
in which they live. If we gain more knowledge on inter-
actions between food, eating habits, genomics and the
environment, this could mean better prevention and/or
treatment. The era of epigenetics has begun, while the
dogma of genetic determinism seems to be fading.
Keywords Mycotoxins Immunological tolerance 
Intestinal permeability syndrome Celiac disease 
Gluten sensitivity Autistic spectrum
Intestinal permeability
Several investigations indicate that the gastric-intestinal
barrier is highly dependant on the genome of intestinal
bacteria [1–3]. An intestine with questionable bacterial
flora compromises the production of digestive enzymes
affecting normal biochemical conditions, (pH levels, vita-
mins, peptides and bacteria) and generates secondary
minimal submucosal inflammation [4–6]; it can also alter
some enzymatic patterns present on cell membranes, in
particular on the microvillus (one notable case is that of
lactase) [1,7].
Under normal conditions, the microvillus sustain phys-
iological digestion and absorption of micronutrients, while
in abnormal conditions they could determine the passage of
macromolecules beyond the gastric-intestinal barrier (GIB)
[8], which, due to their size, could be identified as non-self
and, resulting immunogen, could trigger an immunological
response [9,10].
The gastric-intestinal epithelium is normally a selec-
tively permeable barrier and its function is determined by
the formation of protein–protein complexes, desmosome
junctions, hemidesmosome junctions, gap-junctions,
adherens junctions and tight junctions. The latter,
mechanically connect adjacent cells sealing intracellular
space. Over the last decade, more attention is being paid to
the tight junctions, because their alteration could cause a
break-down in the barrier function which helps to promote
immunological reactions (autoimmune and inflammatory
diseases) [11,12].
Experimental evidence [13,14] suggests that dysfunc-
tion of tight junctions is a contributing cause, and perhaps
the main cause for the onset of systemic immunological
inflammatory diseases, inflammatory bowel disease (IBD),
food allergies and celiac disease [15]. It seems these may
M. Proietti C. Di Rienzo
Italian Association of Toxic Elements Studys, Rome, Italy
e-mail: maurizioproietti57@alice.it
A. Del Buono
Academy of Micronutrition ‘‘L. Pauling’’, Caserta, Italy
G. Pagliaro (&)
Department of Biochemistry, Biology and Genetics,
School of Medicine, Universita
`Politecnica delle Marche,
Ancona, Italy
e-mail: giacomo.pagliaro@uniurb.it
R. Del Buono
Universita
`Campus Bio-Medico, Rome, Italy
123
Mediterr J Nutr Metab
DOI 10.1007/s12349-013-0125-3

be contributing factors to the development of Autism
[16–22].
Overall, the results of these studies show or at least seem
to suggest that diseases associated with the leaky gut
syndrome may disappear and/or stop if the patient’s
intestinal barrier function is restored. The evidence in
support of this is still incomplete, but solid enough to
encourage researchers to continue on this path [2].
The tight junctions are the primary target of external
agents, which act as chemical and/or biological pollutants
[13,23]. They can interact with the protein matrix of the
joints, altering the conformation and thus increase perme-
ability for external agents [24].
Our observations have been identified via the unaware
ingestion of biological contaminants (mycotoxins) and
subsequent sporulation dysbiosis of Candida [25], factors
that could determine leaky gut syndrome. This could
establish a new balance of the microbiota [26–29] which can
often result in relevant clinical signs or symptoms [15,28].
In any case, the timing of the onset of typical symptoms
of the syndrome should be checked, also in relation to age.
It may be necessary to understand the reason why in some
subjects there is no outbreak and if it is a temporary or
permanent situation. A study of this kind may reveal other
mechanisms, probably of the immune system, which are
still unknown.
Immunological tolerance: celiac disease, gluten
sensitivity
The most particular feature of celiac disease is undoubtedly
the environmental factor that causes it: gliadin [30–37]. It
is an immunogenic peptide, resistant to pancreatic and
gastric enzymatic digestion which only because of modi-
fications to the tight junctions, are able to reach the lamina
propria (part of the intestinal mucosa), where the immune
response takes place [38]. In other words, unless the door is
opened, you cannot pass.
However, it is precisely here, at the level of the lamina
propria where transglutaminase tissue type II (tTG) cata-
lyzes covalent bonds between glutamine and lysine [39].
The deamminated peptides thus create epitopes (part of the
antigen that binds with the specific antibody) with an
increased immunostimulatory potential [40].
With this modification there is an increased affinity of
the antigens, presented by the APC (antigen-presenting
cell) to the macrophages, to the B-lymphocytes and to the
T CD4?(lymphocytes helper), with the HLA system II
(human leukocyte antigen II) and then with the two
genes or protein molecules DQ2 and DQ8 produced by
them [41–43]. Lesions of the intestinal mucosa (villous
atrophy and crypt hyperplasia) detectable with biopsy, are
the result of the dynamics of this immunological process
and adaptable over time [44]. Although we are aware of the
genetic component in celiac disease with increased risk of
disease in first degree relatives [45], (the concordance in
monozygotic twins is over 75 % and concordance in
dizygotic twins is of 13 %), there should always be a
‘‘primum movens’’, which may well be the opening of tight
junctions. Gluten sensitivity, on the other hand, is not a
mild form of celiac disease (CD), but a disease itself [46].
While it is different from the molecular and immune point
of view, the cause may be the same: the opening of the
tight junctions. The fact that 1 % of people worldwide are
suffering from gluten sensitivity [47] could explain the
interest in this morbid condition and its possible evolution
to the typical form. Gluten sensitivity (GS) does not present
alterations of the intestinal permeability; [48] it probably
only manifests the submucosal inflammation which, as we
know, is significantly greater in celiac disease [49]. ‘‘In
celiac disease an autoimmune mechanism is activated,
conditioned by an adaptive response of the immune system,
but in GS, there is a genetic mechanism that involves the
innate immune system, without involvement of the intes-
tinal barrier function, where there are signs of infection but
not damage, as occurs in celiac disease’’ [23].
To date, there are no laboratory or histological tests able
to confirm this type of ‘‘reactivity’’; as a result, it is a
diagnosis which is reached by exclusion. The diagnosis
will be followed by nutritional changes with elimination of
gluten and an open challenge (a controlled re-introduction
of food containing gluten) to assess if there is a real
improvement of symptoms based on reduction or elimi-
nation of gluten from the diet and if this protein food is
reintroduced, the disorders reappear.
We can establish that the precipitating factor in both CD
and GS is gluten, but another external or environmental
factor should be considered: mycotoxins. Therefore, it
could be said that food becomes the common denominator
of the damage, not only for its content of macronutrients,
quality and quantity, but also because of the different
mycotoxins that may synergistically contribute to the leaky
gut syndrome [21,50]. Among the major mycotoxins
probably involved that favour the syndrome (aflatoxins,
ochratoxins, etc.), our attention has focused on deoxyni-
valenol (DON). Due to ease of contamination of most
common foods such as pasta and bread, mycotoxins
including DON, the most studied, are particularly fond of
tight junctions [8]. This could be related to an innumerable
quantity of clinical manifestations that occur for no
apparent reason. Future research should be intensified on a
larger number of mycotoxins and their mutual interactions.
Over the last hundred years man has tried to favour
genetic rearrangements, producing interspecific hybrids in
the genus Triticum (wheat) and intergeneric between
Mediterr J Nutr Metab
123

Triticum and Secale (Triticale), to improve yields per
hectare [51]. To our knowledge, and based on a strictly
scientific basis, nobody has ever tested to see if these
genetic changes have favoured an immunological response,
and therefore increased or not the conditions that lead to
celiac disease, GS, autism and possibly other diseases in
the last 30 years. The Toulouse INRA [8] has studied the
molecular mechanisms and the immune response to grain,
flour and pasta free of mycotoxins with particular reference
to DON. Perhaps, there is already an answer in the results
of these studies, but deeper investigations are necessary or
further testing before coming to a definitive solution on this
issue—namely whether the genetic changes induced by
artificial mutations and crosses have some relationship to
celiac disease and autism [16,17,52,53]. It is also nec-
essary to consider another factor which could be relevant:
lectins. The genetic difference between types of wheat is
also due to proteins called lectins, which are not only in
saprophytes and pathogens, but also in food and on the
membrane of blood elements, in particular red blood cells
[54]. When we consume food containing lectins incom-
patible to our recognition code, we activate a minimal
immune response (minimal Flogosis), so even lectins could
trigger damage to the walls of the digestive system. If the
same food also contains mycotoxins (in meaningful bio-
logical quantities), such as DON, they may support the
hypothesis of a response with clinically relevant symptoms.
In other words, lectins would be giving the green light to
mycotoxins (macromolecules). Could lectins be opening
the door? For these reasons and to evaluate the actual
dependence on gluten of the clinical abnormalities high-
lighted in patients with gluten sensitivity (GS), a group of
researchers who are part of the ‘‘CAMPO Consortium’’ and
the ‘‘Dino Leone Foundation’’ from Bari, have started a
research to study the relationship between nature, food
composition, mycotoxins and the immune system.
Deoxynivalenol (DON or vomitoxin)
The deoxynivalenol (DON) is a mycotoxin, one of the
metabolites of some fungi (molds) belonging to the genus
Fusarium (F. graminearum and F. culmorum, etc.). These
can be considered ‘‘natural and involuntary toxic factors’’,
carcinogenic, teratogenic and mutagenic [55]. More toxins
may originate from the same fungi, as in the case of
Candida (Candida albicans) and there may be synergies
between different toxins, as in the case of ochratoxin A
(OTA) and citrinin.
On a global scale, the DON mycotoxin is by far the most
frequent and the most feared and therefore the most stud-
ied. It could particularly contaminate cereals and their
derivatives (flour, bread, etc.). Considering its extreme
stability (heat stable) during the different technological
treatments, and the almost total absence of decontamina-
tion processes, it could easily be found in the finished food.
It may be necessary to characterize the toxic effects of
DON, in particular on the entire intestine, including the
stomach, the first organ to be in contact with food. This
mycotoxin could reduce the barrier function of the intestine
(reduction of the electrical resistance of the epithelium,
increased cellular permeability to molecules, and increased
passage of bacteria) [56]. The alteration of the barrier
function GIB could be associated with a reduction of
protein function (claudins) [57] in a particular region of the
intestinal tissue, the so-called tight junctions. These act as a
‘‘hinge’’ between the intestinal cells. This was observed
both in cell culture and in the intestines of piglets that had
ingested contaminated food.
DON could reduce the function of the intestinal barrier,
probably causing an increase of bacteria passage through
the intestine. The intestinal permeability would thus be
altered. This could have important consequences in terms
of susceptibility to infections (Salmonella,Escherichia,
etc.) [58]. The transit of pollutants such as heavy metals
and pesticides may then increase the harmful effects and
local and systemic immunological responses may occur.
This may affect the prognosis of diseases such as gluten
sensibility and autism. The induced damage could also
offer indirect assessments of great interest, since the
mucosal disorders could slightly change the cellular bio-
chemistry function. There may be a lack of Vit B 12 for the
reasons set out above, and then a decrease of desaturase,
and this would explain the alteration of the membrane, low
in polyunsaturated and rich in saturated (phosphoglycer-
ides). At the gastric level, the absorption of vitamin B12
may be penalized, which needs to be synthesized through
the intestinal intrinsic factor (IF) (or gastric or castle).
A B12 deficiency could prevent the physiological conver-
sion of homocysteine to methionine. According to an
individual’s predisposition to this, clinical signs may then
appear. DON can easily be found in school cafeterias,
kindergartens and primary schools, especially in bread and
to a limited extent in pasta [7]. The industry of these
products should be obliged to work with the wheat paying
more attention to contamination in the field and implement
specific fermentation processes reducing the amount of
mycotoxins.
Autism: an emergency?
After Reichelt’s work [59], the number of authors who
highlight the presence of high levels of peptides ‘‘opioids’’
(casomorphine and glutomorphine) in the urine of children
with autism has increased [60]. This evidence may suggest
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123

that children with autism, during the digestive process, due
to an altered digestion of these proteins caused by mech-
anisms which are not yet clear (but still imply the
involvement of tight junctions), absorb abnormal peptides
that influence the mechanism of neurotransimssion [59], as
they manage to overtake the blood–brain barrier. These
molecules, due to their affinity to the lreceptors, may
contribute to the cause of the behaviour of these patients
[19]. For this reason, often they are put on a diet free of
such foods [60]. A period of abstinence from gluten and
casein, which varies depending on the case, could lower the
levels of opioid peptides [61]. Results seem very encour-
aging, especially when applied before pre-school age, in
the early years of life when potential development and
neural plasticity are still very active. These considerations
could become mandatory in all pregnant women with a
family risk factor, especially if we take into consideration
some studies that indicate high levels of mycotoxins in the
umbilical cord, higher than in plasma. Dysbiosis follows
the alteration of tight junctions [3,25]. It is known that
after restoration of balance (eubiosis [25]) intestinal per-
meability decreases, simultaneously improving the general
health of children [12].
The positive side of the natural diet without gluten and
casein is expressed by the significant improvement
achieved by the children who follow this diet: increased
attention, improved interactive capabilities, regression of
hyperactivity, lower violent behaviour, increased resistance
to infection and better quality sleep [19].
Conclusions
The results of extensive research may encourage further
study on the effects of food contaminated by mycotoxins,
both in human and animal diets, thus avoiding pollution of
the entire food chain. This would be the road to reducing
the problem of intestinal permeability, breeding ground for
different pathologies. Currently, one of the goals of
researchers is to understand the delicate immunological
balance probably related to the consumption of foods rich
in ‘‘heavy’’ gluten, and evaluate consumption in relation to
the rapid spread of diseases related to gluten. The grains of
industrial agriculture, which for the most part are hyper-
fertilized, often grown in environments which favour
contamination by fungi with consequent development of
mycotoxins. These grains contain a higher proportion of
gluten, up to 12 % more compared to non-hyper fertilized
ones and seem to make life difficult not only for border-line
patients of celiac disease, but for all subjects with corre-
lated immunological manifestations including the ‘‘meta-
bolic syndrome’’. It therefore seems that increasing
sensitivity to different diseases is determined by the
increased use of modern grains, with more gluten at the
expense of older grains with less gluten, and with which
man has evolved. For some this is still a hypothesis, for
others a certainty. The task of the research, carried out by
multidisciplinary working groups, should be to eliminate
every shadow of doubt as far as possible.
Conflict of interest None.
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