Autoimmune and gastrointestinal dysfunctions: does a subset of children with autism reveal a broader connection?
ABSTRACT A large number of autoimmune disorders have a gastrointestinal (GI) dysfunction component that may interplay with genetic, hormonal, environmental and/or stress factors. This narrarive review investigates possible links between autism, immune system abnormalities and GI symptoms in a subgroup of children with autism. A literature search on Medline (1950 to September 2010) was conducted to identify relevant articles by using the keywords 'autism and gastrointestinal' (71 publications) and 'autism and immune' (237 publications), cross-referencing and general searching to evaluate the available literature on the immunological and GI aspects of autism. Sufficient evidence exists to support that a subgroup of children with autism may suffer from concomitant immune-related GI symptoms.
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ABSTRACT: Gastrointestinal symptoms are a common feature in children with autism, drawing attention to a potential association with celiac disease or gluten sensitivity. However, studies to date regarding the immune response to gluten in autism and its association with celiac disease have been inconsistent. The aim of this study was to assess immune reactivity to gluten in pediatric patients diagnosed with autism according to strict criteria and to evaluate the potential link between autism and celiac disease. Study participants included children (with or without gastrointestinal symptoms) diagnosed with autism according to both the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview, Revised (ADI-R) (n = 37), their unaffected siblings (n = 27), and age-matched healthy controls (n = 76). Serum specimens were tested for antibodies to native gliadin, deamidated gliadin, and transglutaminase 2 (TG2). Affected children were genotyped for celiac disease associated HLA-DQ2 and -DQ8 alleles. Children with autism had significantly higher levels of IgG antibody to gliadin compared with unrelated healthy controls (p<0.01). The IgG levels were also higher compared to the unaffected siblings, but did not reach statistical significance. The IgG anti-gliadin antibody response was significantly greater in the autistic children with gastrointestinal symptoms in comparison to those without them (p<0.01). There was no difference in IgA response to gliadin across groups. The levels of celiac disease-specific serologic markers, i.e., antibodies to deamidated gliadin and TG2, did not differ between patients and controls. An association between increased anti-gliadin antibody and presence of HLA-DQ2 and/or -DQ8 was not observed. A subset of children with autism displays increased immune reactivity to gluten, the mechanism of which appears to be distinct from that in celiac disease. The increased anti-gliadin antibody response and its association with GI symptoms points to a potential mechanism involving immunologic and/or intestinal permeability abnormalities in affected children.PLoS ONE 06/2013; 8(6):e66155. · 3.53 Impact Factor
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ABSTRACT: Epidemiological studies have associated infection during pregnancy with increased risk of neurodevelopmental disorders in children, which is modeled in rodents by stimulating the immune system of pregnant dams with microorganisms or their mimics, such as poly(I:C) or LPS. In two prenatal mouse models, we show that in utero exposure of the fetus to cytokines/inflammatory mediators elicited by maternal immune stimulation with poly(I:C) yields offspring that exhibit a proinflammatory phenotype due to alterations in developmental programming of their immune system. Changes in the innate and adaptive immune elements of these pro-inflammatory offspring result in more robust responses following exposure to immune stimuli than those observed in control offspring from PBS-injected pregnant dams. In the first model, offspring from poly(I:C)-injected immunologically naïve dams showed heightened cellular and cytokine responses 4 hrs after injection of zymosan, a TLR2 agonist. In the second model, using dams with immunological memory, poly(I:C) injection during pregnancy produced offspring that showed preferential differentiation toward Th17 cell development, and earlier onset of clinical symptoms of EAE following immunization with MOG35- 55. Such "fetal programming" in offspring from poly(I:C)-injected dams not only persists into neonatal and adult life, but also can have profound consequences on health and disease.Brain Behavior and Immunity 05/2013; · 5.61 Impact Factor
© 2010 Expert Reviews Ltd
Possible gastrointestinal symptoms in a
subset of children with autism
Expert Rev. Gastroenterol. Hepatol. 4(2), 125–127 (2010)
“The fact that certain gastrointestional problems already exist in
some children with developmental delay disorders indicates that
children with autism might also be susceptible.”
There is a continuing debate as to whether
or not gastrointestional (GI) problems may
exist in a subset of children with autism. If
GI disorders are common in some children
with developmental disorders, why could
they not also exist in children with autism?
It is known that constipation and fecal
impaction are common in children with
mental retardation , Rett syndrome ,
Prader–Willi syndrome, Hunter disease
and autism [3,4]. It is also an established
fact that a certain percentage of children
with autism have varying degrees of men-
tal retardation, thus is it not possible that
these children may experience the increased
risk of GI symptoms associated with mental
retardation? A recent review by Buie et al. in
Pediatrics reported that the prevalence of GI
symptoms (constipation, diarrhea, bloating,
belching, abdominal pain, reflux, vomiting
and flatulence) in children with autism
spectrum disorders (ASD) range widely
from nine to 91% based on 11 studies that
average 44% . It is interesting to note that
D’Eufemia et al. observed that 43% (nine
out of 21) of children with ASD had altered
intestinal permeability (leaky gut) compared
with 0% of controls (zero out of 40) .
Other GI problems common in genetic-
ally related mental disorders include: possi-
ble functional megacolon in Rett syndrome,
where 76% of these patients experience
GI symptoms ; gallbladder dysfunction
(gallstones and cholecystectomy) in Rett
syndrome ; and gastroparesis in Prader–
Willi syndrome . Levy even stated that
“Down syndrome is recognized as one of
the most common predisposing condi-
tions for a group of serious GI anomalies
– tracheo–esophageal fistula, duodenal
obstruction with or without pyloric stenosis,
annular pancreas, imperforate anus and
Hirschsprung’s disease” . He added that
“intestinal anomalies can be found in many
other genetic disorders, with recent evidence
suggesting the presence of GI develop mental
regulatory genes on chromosome 13q.”
In terms of celiac disease, The North
American Society for Pediatric Gastro-
enterology, Hepatology and Nutrition rec-
ognizes in their clinical guidelines that at
least three developmentally delayed condi-
tions have higher risk rates than the normal
population . They reported that strong
evidence exists for an association between
Down syndrome and celiac disease, with a
prevalence rate of 5–12%. Approximately
one third of Down syndrome patients with
celiac disease exhibit no GI symptoms.
Hilhorst et al. reported a 43-times higher
celiac rate in patients with Down syn-
drome . According to the 1999 Health
Care Guidelines of the Down Syndrome
Medical Interest Group, an initial screen-
ing for celiac disease is recommended at the
age of 2 years . Approximately 4–8% of
children with Turner syndrome have celiac
disease [14–18], and one study revealed an
8% rate in children with Williams syn-
drome . The North American Society
for Pediatric Gastroenterology, Hepatology
and Nutrition also recognized increased
rates of celiac disease in children with
Type 1 diabetes mellitus. The 2009
American Diabetes Association Standards
of Medical Care in Diabetes listed the
increased rates of celiac disease to be 1–16%
versus 0.3–1% in the general population,
and recommended celiac disease screening
in these patients . Children with cere-
bral palsy are also at risk as 43% have high
serological celiac markers .
Amy Brown, PhD
Author for correspondence
John A. Burns School of
Medicine, 651 Ilalo Street,
MEB 223, University of
HI 96813, USA
Tel.: +1 808 692 0907
Fax: +1 808 692 1246
Dominic Chow, MD
Associate Professor, Departments of Pediatrics
and Medicine, University of Hawaii, Honolulu,
HI 96813, USA
Satona Murakami, MD
Department of Orthopedic Surgery, Graduate
School of Medical Sciences, Nagoya City
University, Nagoya, Japan
William Goh, MD
Fellow, Maternal–Fetal Medicine, Department
of Obstetrics and Gynecology, University of
Hawaii, Honolulu, HI 96813, USA
Aimee Perreira, MD
Research Fellow, Queens Medical Center,
Honolulu, HI 96813, USA
Sandi Kwee, MD
Assistant Professor, Department of Medicine,
University of Hawaii, Honolulu, HI 96813, USA
Payel Sil, MS
Graduate Student, Department of
Complementary and Alternative Medicine,
University of Hawaii, Honolulu, HI 96813, USA
Graduate Student, Department of Molecular
Biosciences and Bioengineering, University of
Hawaii, Honolulu, HI 96816, USA
For reprint orders, please contact email@example.com
Expert Rev. Gastroenterol. Hepatol. 4(2), (2010)
Hans Asperger himself suggested a possible link between celiac
disease and autism more than half a century ago . Why would
the very real possibility of GI problems, including gluten problems,
existing in a subset of children with autism even be debated by
some researchers? The fact that certain GI problems already exist
in some children with developmental delay disorders indicates that
children with autism might also be susceptible. This is particularly
true since approximately 30% of children with autism exhibit some
degree of mental retardation, and that celiac disease is observed in
approximately 10% of children with Down syndrome, Turner syn-
drome and Williams syndrome. Finally, GI symptoms in children
with ASD range from 9 to 91%, averaging 44% . In light of these
findings, does it make logical sense to eliminate the possibility of
GI problems and/or celiac disease existing in a subset of children
with autism without thorough scientific investigation? Where is
the scientific objectivity when weak research results  are nation-
ally promoted as “putting to rest the nagging suggestion that there
exists a link between autism and gastrointestinal disease” . This
comment in Pediatrics was based on a study by Ibrahim et al. who
reported no significant differences in prevalence of GI symptoms in
children with autism (77.2%) compared with controls (72.2%) .
Their retrospective study of Mayo Clinic medical records (121 chil-
dren with autism between 1976 and 1997) attempted to determine
whether autistic children had more visits to the hospital for GI
symptoms than nonautistic children. The conclusion that there
is no link between GI symptoms and autism was used to suggest
that parents do not need to place their children on restrictive diets.
Serious limitations of Ibrahim’s study include, but are not
• It was a retrospective study relying entirely upon medical
records that tend to be incomplete;
• This was not a clinical study testing the efficacy of diet in
• It is not clear whether these were children under the broader ASD
or the more specific autistic disorder. Specifically, it was not clear
if Asperger syndrome and pervasive developmental disorder, not
otherwise classified, were included in the autism diagnosis;
• Subjects were not all formally diagnosed with autism by clinicians,
but most frequently as developmental delay (33%), delayed speech
and language (42%), attention-deficit/hyperactivity disorder
(18%) and mental retardation (16%) ;
• Categorization of GI problems ranged from very mild to severe,
but were grouped together anyway. For instance, gastroesophageal
reflux disease is known to be higher in autistic children, but in
this study gastroesophageal reflux disease and vomiting were
grouped together, possibly diluting any significant difference;
• Much variability exists among physicians regarding inquiries
of GI symptoms in children with or without autism;
• It was not possible to include time-to-event data that are
important for dietary reactions;
• They failed to assess or compare the duration, severity and
recurrence of the GI symptoms between the autistic subjects
and the normal controls;
• Researchers did not document diets (especially gluten-/casein-
free diets), dietary supplement use or medications with possible
GI side effects;
• The misclassification of symptoms and clinical diagnoses may
have reduced the overall power of the study;
• They concluded that the significantly greater prevalence of con-
stipation and food intolerance among children with autism
could be behaviorally induced.
“...43% (nine out of 21) of children with autism
spectrum disorders had altered intestinal
permeability (leaky gut) compared with 0% of
controls (zero out of 40).”
Propagating medical conclusions based on a single, retro-
spective study with the above limitations, in light of the fact that
GI problems do exist in subsets of children with developmental
delayed disorders (including autism), is not only curious, but may
jeopardize the health of a subset of children with autism who may
have GI symptoms that need to be treated. Recent recommenda-
tions for the evaluation and treatment of common GI problems
in children with ASD have been published in Pediatrics . The
researchers state that children with ASD can benefit from the
evaluation of abdominal pain, chronic constipation and other
Financial & competing interests disclosure
Amy C Brown is CEO of Natural Remedy Labs, LLC, a Cengage textbook
author and current grant recipient of the Broad Medical Research Program
of the Broad Foundation. The authors have no other relevant affiliations or
financial involvement with any organization or entity with a financial
interest in or financial conflict with the subject matter or materials discussed
in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Papers of special note have been highlighted as:
• of interest
•• of considerable interest
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Possible gastrointestinal symptoms in a subset of children with autism