959503

research-article2020
AUT0010.1177/1362361320959503AutismChakraborty et al.

Original Article

Autism

Gastrointestinal problems are associated 1­–11

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DOI: 10.1177/1362361320959503
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social communication difficulties in young journals.sagepub.com/home/aut

children with autism spectrum disorders

Payal Chakraborty1 , Kimberly L H Carpenter1,

Samantha Major1 , Megan Deaver2, Saritha Vermeer1,
Brianna Herold1, Lauren Franz1, Jill Howard1
and Geraldine Dawson1

Abstract
Individuals with autism spectrum disorder are more likely than typically developing individuals to experience a range
of gastrointestinal abnormalities, including chronic diarrhea, constipation, food sensitivities, and abdominal pain. These
gastrointestinal symptoms have been associated with higher levels of irritability and aggressive behavior, but less is known
about their relationship with core autism spectrum disorder symptoms. We investigated the relationship between autism
spectrum disorder and gastrointestinal symptom severity while accounting for three associated behavioral symptom
domains (Irritability, Aggressiveness, and Specific Fears), in a sample of 176 children (140 males and 36 females) ages 2–
7 years old with autism spectrum disorder. Most participants had at least one reported gastrointestinal symptom (93.2%)
and had more than one gastrointestinal symptom (88.1%). After accounting for each associated behavioral symptom
domain, repetitive behaviors and stereotypies were positively associated with gastrointestinal symptom severity. Social
and communication difficulties were not significantly associated with gastrointestinal symptom severity after accounting
for associated behavioral symptoms. Our findings replicate a previously described association between irritability and
aggression and gastrointestinal symptoms. Furthermore, gastrointestinal symptom severity is associated with repetitive
behaviors, a subset of core autism spectrum disorder symptoms. This suggests that gastrointestinal symptoms may
exacerbate repetitive behaviors, or vice versa, independent from other associated behavioral symptoms.

Lay Abstract
Individuals with autism spectrum disorder are more likely than typically developing individuals to experience a range
of gastrointestinal abnormalities, including chronic diarrhea, constipation, food sensitivities, and abdominal pain. These
gastrointestinal symptoms have been associated with higher levels of irritability and aggressive behavior, but less is known
about their relationship with core autism spectrum disorder symptoms. We investigated the relationship between
autism spectrum disorder symptom severity and gastrointestinal symptoms while accounting for three associated
behavioral symptom domains (Irritability, Aggressiveness, and Specific Fears), in a sample of 176 children (140 males
and 36 females) ages 2–7 years old with autism spectrum disorder. A large majority (93.2%) of the sample had at least
one reported gastrointestinal symptom, and most (88.1%) participants had more than one gastrointestinal symptom.
Various types of gastrointestinal symptoms were reported; the most common symptoms reported were constipation,
food limits, gas/bloating, and stomach pain. After accounting for each associated behavioral symptom domain, repetitive
behaviors and stereotypies were significantly associated with gastrointestinal symptom severity. Increased severity
of autism spectrum disorder symptoms was correlated with increased gastrointestinal symptom severity. Social and
communication difficulties were not significantly associated with gastrointestinal symptom severity after accounting

1
The Duke University, USA Corresponding author:
2
Eastern Virginia Medical School, USA Payal Chakraborty, Division of Epidemiology, College of Public Health,
The Ohio State University, Columbus, OH 43210-1132, USA.
Email: chakraborty.82@osu.edu
2 Autism 00(0)
for associated behavioral symptoms. Our findings replicate a previously described association between irritability
and aggression and gastrointestinal symptoms. Furthermore, we found that repetitive behaviors, but not social or
communication symptoms, are associated with gastrointestinal symptom severity, even after accounting for associated
behavioral symptoms. This suggests that gastrointestinal symptoms may exacerbate repetitive behaviors, or vice versa,
independent from other associated behavioral symptoms.
Keywords
autism spectrum disorders, gastrointestinal, repetitive behaviors and interests, social cognition and social behavior
Introduction
Autism spectrum disorder (ASD) is a neurodevelopmental
disorder characterized by impairments in social communi-
cation and the presence of repetitive behaviors and
restricted interests. Gastrointestinal (GI) abnormalities,
such as chronic diarrhea (Chaidez et al., 2014; Horvath
et al., 1999; Nikolov et al., 2009; Sanctuary et al., 2018),
constipation (Chaidez et al., 2014; Nikolov et al., 2009;
Sanctuary et al., 2018), food sensitivities (Ashwood et al.,
2006; McElhanon et al., 2014; Rudzki & Szulc, 2018;
Sanctuary et al., 2018), and abdominal pain (Chaidez
et al., 2014; Horvath et al., 1999; Sanctuary et al., 2018),
are more common in children with ASD than in the typical
population.
In addition to the high prevalence of GI symptoms,
individuals with ASD also have higher rates of comorbid
psychiatric and behavioral challenges. For example, chil-
dren with ASD have higher rates of internalizing and
externalizing behaviors, such as anxiety, depression, and
self-injurious behaviors, compared to their counterparts
without ASD (Hansen et al., 2018; Matson & Williams,
2014).
GI symptoms experienced by individuals with ASD
have been found to be related to these comorbid behavioral
problems. For example, in populations of individuals with
and without ASD, anxiety has been linked to GI symptoms
(Cryan & Dinan, 2012; Mazurek et al., 2013; Waters et al.,
2013). In individuals with ASD, irritability and aggres-
siveness are also strongly associated with GI symptoms
(Chaidez et al., 2014; Mazefsky et al., 2014), and develop-
ment of behavioral symptoms, including aggression and
irritability, in children has been linked to underlying GI
abnormalities (Buie et al., 2010). The relationship between
these psychiatric comorbidities and GI symptoms among
individuals with ASD is expected because this is also
observed in typical development; individuals with GI
symptoms are more likely to experience internalizing
behaviors, such as depression and anxiety, and deficits in
social and adaptive behavior skills (Ballenger et al., 2001;
Hommel et al., 2010).
Studies that have specifically explored the relationship
between GI symptoms and severity of core ASD symp-
toms in children with ASD have shown mixed results.
Some studies have reported associations with affect and
mood-related problems only and found no relationship
with ASD symptom severity (Mazefsky et al., 2014;
Nikolov et al., 2009). Other studies using clinical and par-
ent measures reported associations between GI symptoms
and core ASD symptoms (Adams et al., 2011; Chaidez
et al., 2014; Gorrindo et al., 2012; Kang et al., 2017), such
as social withdrawal (Chaidez et al., 2014; Nikolov et al.,
2009), stereotypy (Chaidez et al., 2014), and expressive
language deficits (Gorrindo et al., 2012). In addition, treat-
ment of GI symptoms was associated with reduced sever-
ity of ASD symptoms and other co-occurring behaviors
(Kang et al., 2017). These mixed findings from studies that
use clinical data and parent report may be due to variabil-
ity in the method used to measure ASD symptoms.
Furthermore, some of these studies employed small sam-
ple sizes, as low as 18 participants. However, the largest
sample size utilized was from a study conducted among
2756 children and adolescents with ASD did demonstrate
a relationship between core ASD symptoms and GI symp-
toms, suggesting that these two sets of symptoms may in
fact be related (Neuhaus et al., 2018).
Despite evidence of the association between core ASD
symptoms and GI symptoms, it is unclear whether core
ASD symptoms are independently related to GI symptoms,
or if this relationship is mediated by the occurrence of
comorbid behavioral problems. Thus, we sought to explore
the independent relationships between increased GI symp-
toms and associated behavioral problems—specifically,
irritability, aggressiveness, and anxiety/fears—and core
ASD symptoms. Elucidating these relationships in young
children is especially of interest because behavioral issues
exacerbated by GI discomfort can affect development and
increase morbidity later in life (Ballenger et al., 2001). Due
to the large burden imposed by lifelong GI pain (i.e. diffi-
culty potty training, increased family burden, missing
school, enhanced sensory discomfort, reduced quality of
life, increased healthcare utilization, dietary modifications,
etc.) (Dufton et al., 2009; Hommel et al., 2010; Hyams
et al., 1996), it is important to understand whether GI prob-
lems in ASD are related to the disorder itself or if they are
the downstream result of co-occurring mood disturbances.
Understanding this relationship will clarify treatment tar-
gets, helping to understand whether treatment for GI prob-
lems should be focused on anxiety/depression symptoms or
Chakraborty et al. 3
ASD-specific behaviors (social and language deficits and
repetitive behaviors).
In the present study, we explored the relationship
between ASD and GI symptom severity, while account-
ing for three associated behavioral and internalizing
symptoms, irritability, aggressiveness and specific fears,
in a sample of children with ASD, using a variety of gold
standard clinical and parent report measures for autism
severity. We hypothesized that GI symptom severity
would be associated with behavioral and internalizing
symptoms, as previously described. We also hypothe-
sized that GI symptom severity would remain associated
with core ASD symptoms after controlling for associated
behavioral symptoms. Specifically, we sought to exam-
ine the relationship between GI symptoms and ASD
symptom severity independent of co-occurring associ-
ated behavioral challenges in young children with ASD.
Understanding this relationship is important because GI
symptoms not only directly impact quality of life of chil-
dren with ASD, but these symptoms are also linked to
various behavioral problems, which further affect child
and family outcomes.
Methods
Study sample
We performed a secondary analysis of data from the base-
line visit (prior to treatment) of a Phase II randomized-con-
trolled trial conducted at Duke University Medical Center
in Durham, NC, (ClinicalTrials.gov ID: NCT02176317)
studying the efficacy of intravenous umbilical cord blood
transfusion to improve the core symptoms of ASD in young
children (DukeACT).
The study population consisted of 180 children with
confirmed ASD diagnoses based on the Diagnostic and
Statistical Manual of Mental Disorders, Fifth Edition
(DSM-5) (American Psychiatric Association, 2013), and
informed by the Autism Diagnostic Observation Schedule,
Second Edition (ADOS-2) (Lord et al., 2012) and the
Autism Diagnostic Interview, Revised (ADI-R) (Le
Couteur et al., 2003) by expert clinicians. Participants
were included in the study if they were 2 years and 0 months
to 7 years and 11 months old (M = 64.9 months, SD = 19.5).
Mean Full Scale IQ (FSIQ) of study participants was 69.0
(SD = 20.9).
Participants were also included if (1) they were stable
on current medications for at least 2 months prior to the
infusion, (2) participants and parents/guardians were
English speaking, and (3) an autologous umbilical cord
blood unit or ⩾4/6 human leukocyte antigen (HLA)-
matched allogeneic unrelated umbilical cord blood unit
from the Carolinas Cord Blood Bank was available.
Participants were excluded if they had (1) a history of prior
cell therapy, (2) use of intravenous immunoglobulin
(IVIG) or other anti-inflammatory medications (with the
exception of non-steroidal anti-inflammatory drugs
(NSAIDs)), (3) known genetic syndrome (e.g. Fragile X),
presence of dysmorphic features, pathogenic mutation or
copy number variation associated with ASD, and/or other
significant medical and/or psychiatric comorbidity, (4)
obvious physical dysmorphology, (5) an uncontrolled sei-
zure disorder, (6) significantly impaired renal or liver
function, (7) known active CNS infection, evidence of
uncontrolled infection, and/or HIV positivity, (8) family
unwilling or unable to commit to study-related assess-
ments, and/or (9) clinically significant abnormalities in
complete blood count.
Of the 180 participants who participated in the study, 37
were female and 143 were male. Forty-one (23%) partici-
pants identified as non-White, and 139 (77%) identified as
White. Thirty-two (18%) identified as Hispanic, and 148
(82%) identified as non-Hispanic. The present analysis
consisted of 176 children (140 males and 36 females); four
participants were excluded because they were pilot sub-
jects (N = 2), had bipolar disorder (N = 1), or did not speak
English as a first language (N = 1). Community members
were not involved in the design of this study.
Measures
The measures used for the present study are a subset of the
measures collected in the baseline visit of the clinical trial,
and include a combination of clinician-administered
assessments and parent report interviews and question-
naires (Table 1).
Cognitive functioning. FSIQ was assessed using Mullen
Sales of Early Learning (MSEL) for children under 4 years
of age and Differential Ability Scales, Second Edition
(DAS-II) for children 4 years of age and older.
Core ASD symptoms.  Core ASD symptoms were measured
using multiple assessments: ADOS-2 (Lord et al., 2012),
Pervasive Developmental Disorder-Behavior Inventory
(PDDBI) (Cohen et al., 2003), Vineland Adaptive Behav-
ior Scales, Third Edition (VABS-3), and overall Clinical
Global Impression Scale-Severity (CGI-S). The CGI-S is
based on a seven-point scale rated by a clinician assessing
the severity of the participant’s autism symptoms at the
time of the visit, and the impact of these symptoms on their
daily functioning. Specific dependent variables that
reflected core autism symptoms were as follows: Autism
Composite Score (PDDBI), Repetitive, Ritualistic, and
Pragmatic Problems Composite (PDDBI), Receptive/
Expressive Social Communication Composite (PDDBI),
Stereotypy Standard Score (Aberrant Behavior Checklist-
Community (ABC-C)), Inappropriate Speech Standard
Score (ABC-C), VABS-3 Communication Standard Score,
VABS-3 Socialization Standard Score, ADOS-2 Compari-
son Score, and overall CGI-S score.
4 Autism 00(0)
Table 1.  Summary of study measures.
Cognitive Autism severity
functioning
Full Scale IQ ADOS-2 Comparison Score
(FSIQ) Overall CGI-Severity Score
Autism Composite Score (PDDBI)
Repetitive, Ritualistic, and Pragmatic Problems Composite (PDDBI)
Receptive/Expressive Social Communication Composite (PDDBI)
Stereotypy (ABC-C)
Inappropriate Speech (ABC-C)
VABS-3 Communication Domain
VABS-3 Socialization Domain
ADOS-2: Autism Diagnostic Observation Schedule, Second Edition; CGI: Clinical Global Impression; PDDBI: Pervasive Developmental Disorder-
Behavior Inventory; ABC-C: Aberrant Behavior Checklist-Community; VABS-3: Vineland Adaptive Behavior Scales, Third Edition; PedsQL-GI:
Pediatric Quality of Life Inventory-Gastrointestinal Symptoms Scales.
Associated symptoms.  Three aspects of associated behavio-
ral symptoms were investigated: Irritability, Aggressive-
ness, and Specific Fears. Irritability was measured from the
ABC-C (Aman et al., 1985). Aggressiveness and Specific
Fears were also measured from the PDDBI. Irritability and
aggressiveness were chosen because these symptoms are
related to GI problems (Buie et al., 2010; Chaidez et al.,
2014; Mazefsky et al., 2014). Specific Fears was of interest
because of the relatively high prevalence of anxiety symp-
toms among children with ASD and their documented asso-
ciation with GI symptoms.
GI symptoms. Severity of GI symptoms was measured
using Pediatric Quality of Life Inventory-Gastrointestinal
Symptoms Scales (PedsQL-GI) (Varni et al., 2014). This
measure has been used in previous autism research (Arnold
et al., 2019). The PedsQL-GI is a parent measure that asks
questions about several GI symptoms (stomach pain,
stomach discomfort, food limits, trouble swallowing,
heartburn, nausea/vomiting, gas/bloating, constipation,
bloody stool, and diarrhea) over the past month. The scale
is scored from 0 to 100, with a higher score indicating
lower symptom severity. The Composite Score from this
scale was used as the primary outcome of interest.
Statistical analysis
Descriptive statistics in Table 1 were reported with means
and standard deviations for continuous variables, and fre-
quencies and percentages for categorical variables.
Unadjusted linear regression models were conducted to
examine correlations between GI symptoms and age, sex,
FSIQ, ASD symptoms, and three associated behavioral
symptom domains (Irritability, Aggressiveness, and
Specific Fears). Next, three separate multivariable regres-
sion models were conducted for each ASD core symptom
domain, while accounting for each associated symptom
domain individually. FSIQ was included as a covariate for
Associated behavioral Gastrointestinal
symptoms symptoms
Irritability (ABC-C) PedsQL-GI Symptoms
Aggressiveness (PDDBI) Inventory Composite
Specific Fears (PDDBI) Score
all multivariable models. Statistical significance was tested
at an alpha level of 0.05. Finally, a cluster plot was created
based on Pearson correlations using all symptom domains
assessed in the analysis. All analyses were conducted in R
(R Foundation, Vienna).
Ethical statement
This study was approved by the Duke University School of
Medicine Institutional Review Board (Pro00070514).
Results
A total of 176 children (140 males and 36 females) ages
2–7 years old with ASD were included in the study. The
average age of the participants in the sample was
64.9 months (SD = 19.5) (Table 2).
Ninety-three percent of the sample had at least one
reported GI symptom, and 88.1% of children had more
than one reported GI symptom (Figure 1). A range of GI
symptoms was experienced in the sample; constipation,
food limits, gas/bloating, and stomach pain were the most
commonly reported (Figure 2).
In the unadjusted analysis, irritability, aggressiveness,
and specific fears were correlated with GI symptoms
(Table 3). In addition, repetitive behaviors measured by
the PDDBI and ABC-C were associated with GI symp-
toms, but social and communication difficulties measured
by PDDBI and VABS-3 were not associated with GI symp-
toms. ADOS-2 Severity Score was not also associated with
GI symptoms.
In the multivariable linear regression models, Irritability,
Aggressiveness, and Specific Fears remained associated
with GI symptom severity (Tables 4 to 6). Of the core ASD
symptom measures, only repetitive behaviors and stereotyp-
ies were significantly associated with GI symptom severity.
Specifically, higher levels of GI symptom severity were
associated with increased scores on both the Repetitive,
Chakraborty et al. 5

Table 2.  Characteristics of the study sample (N = 176).

Variable Descriptive
statistics
Age (months), M (SD) 64.9 (19.5)
Male, N (%)
 Male 140 (79.5%)
 Female 36 (20.5%)
Full Scale IQ, M (SD) 69.0 (20.9)
Overall CGI-Severity Score, M (SD) 4.7 (1.0)
ADOS-2 Comparison Score, M (SD) 8.0 (1.6)
Number of Children with Reported GI 164 (93.2%)
symptoms, N (%)
Peds-QL GI Symptoms Inventory 84.7 (12.4)
Composite Scorea, M (SD) Figure 2.  Frequency distribution of types of GI symptoms
  Stomach Pain Composite, M (SD) 83.3 (19.8) experienced, N = 176.
  Stomach Discomfort Composite, M (SD) 89.0 (16.5)
  Food Limits Composite, M (SD) 74.4 (26.0)
Problems composite score did not persist when adjusting for
  Trouble Swallowing Composite, M (SD) 95.5 (12.4)
specific fears (β = −0.187, 95% CI = −0.378, 0.004). Social
  Heart Burn Composite, M (SD) 93.8 (12.3)
and communication–related problems were still not signifi-
  Nausea/Vomiting Composite, M (SD) 93.8 (13.0)
cantly associated with GI symptoms.
  Gas/Bloating Composite, M (SD) 81.5 (20.3)
  Constipation Composite, M (SD) 78.5 (23.0)
In each regression model, we also tested interaction
  Bloody Stool Composite, M (SD) 95.7 (12.6) terms between each associated behavioral symptom and
  Diarrhea Composite, M (SD) 89.1 (16.9) each ASD symptom scale. None of the interaction terms
was statistically significant, and thus, the interaction terms
M: mean; SD: standard deviation; N: number; %: percent; CGI: Clinical were not retained in the models.
Global Impression; ADOS-2: Autism Diagnostic Observation Schedule,
Similar to the regression analyses, the correlation anal-
Second Edition; GI: gastrointestinal; Peds-QL: Pediatric Quality of Life
Inventory. ysis depicted by the cluster plot also demonstrated that GI
a
A higher score indicates lower symptom severity. symptoms were more closely related to irritability, aggres-
siveness, specific fears, repetitive behaviors, and stereo-
typies (Figure 3). Specifically, food limits, stomach pain,
and diarrhea were more related to repetitive behaviors and
associated symptoms compared to other GI symptoms,
such as bloody stool, heartburn, and constipation.

Figure 1.  Frequency distribution of numbers of concurrent GI
symptoms experienced, N = 176.
Ritualistic, and Pragmatic Problems Composite (irritability:
β = −0.197, 95% confidence interval (CI) = −0.372, −0.023;
aggressiveness: β = −0.188, 95% CI = −0.374, −0.002) and
Stereotypy Standard Score (irritability: β = −0.452, 95%
CI = −0.880, −0.024; aggressiveness: β = −0.509, 95%
CI = −0.911, −0.106; specific fears: β = −0.509, 95%
CI = −0.918, −0.099). The relationship between GI symp-
tom severity and the Repetitive, Ritualistic, and Pragmatic
Discussion
The present study had two primary findings. First, we
found that behavioral symptoms (irritability, aggressive-
ness, and specific fears) were associated with GI symp-
tom severity. Second, we found that repetitive and
stereotypic behaviors, a subset of core ASD symptoms,
were associated with GI symptom severity, but social and
communication problems were not. Importantly, the asso-
ciation between GI symptom severity and repetitive/ste-
reotypic behaviors remained even after controlling for
behavioral symptoms, with the exception of specific fears.
Our findings support a growing body of research demon-
strating that GI symptoms are related to several behavio-
ral problems in ASD, including core ASD symptoms, and
suggest that treatment of GI abnormalities may influence
both core ASD symptoms and associated behavioral
symptoms.
Among this sample of children ages 2–7 years old with
ASD, we observed a high prevalence of parent-reported GI
6 Autism 00(0)

Table 3.  Unadjusted associations with Peds-QL GI Symptoms Inventory Composite Score and demographic characteristics, ASD
symptom measures, and overall functioning, N = 176.

Variable Beta 95% CI P-value

Age 0.063 (−0.031, 0.157) 0.189
Sex −0.903 (−5.457, 3.650) 0.698
IQ 0.084 (−0.003, 0.171) 0.061
Overall CGI-Severity Score −0.033 (−1.857, 1.792) 0.972
ADOS-2 Comparison Score −0.101 (−1.229, 1.027) 0.861
Irritability (ABC-C) −0.516 (−0.734, −0.298) <0.001
Aggressiveness (PDDBI) −0.345 (−0.495, −0.196) <0.001
Specific Fears (PDDBI) −0.377 (−0.546, −0.208) <0.001
Repetitive, Ritualistic, and Pragmatic Problems Composite (PDDBI) −0.334 (−0.478, −0.190) <0.001
Receptive/Expressive Social Communication Composite (PDDBI) 0.174 (−0.033, 0.381) 0.102
Autism Composite (PDDBI) −0.328 (−0.473, −0.184) <0.001
Stereotypy (ABC-C) −0.791 (−1.161, −0.422) <0.001
Inappropriate Speech (ABC-C) −0.558 (−1.12, 0.004) 0.053
VABS-3 Communication Domain 0.088 (−0.013, 0.190) 0.090
VABS-3 Socialization Domain 0.042 (−0.089, 0.174) 0.528

Peds-QL: Pediatric Quality of Life Inventory; GI: gastrointestinal; ASD: autism spectrum disorder; CI: confidence interval; CGI: Clinical Global
Impression; ADOS-2: Autism Diagnostic Observation Schedule, Second Edition; ABC-C: Aberrant Behavior Checklist-Community; PDDBI: Pervasive
Developmental Disorder-Behavior Inventory; VABS-3: Vineland Adaptive Behavior Scales, Third Edition.

Table 4.  Associations between ASD symptoms scales and Peds-QL GI Symptoms Inventory Composite Score adjusting for
Irritability, N = 176.a

Symptom scales ASD symptom scale Irritability

Beta 95% CI P-value Beta 95% CI P-value

Autism Composite Score (PDDBI) −0.175 (–0.354, 0.004) 0.057 −0.373 (−0.636, −0.11) 0.006
  Repetitive, Ritualistic, and Pragmatic Problems −0.197 (–0.372, –0.023) 0.028 −0.335 (−0.605, −0.065) 0.016
Composite
  Receptive/Expressive Social Communication Composite 0.051 (–0.209, 0.311) 0.701 −0.492 (−0.713, −0.271) <0.001
Stereotypy (ABC-C) −0.452 (–0.880, –0.024) 0.040 −0.378 (−0.622, −0.133) 0.003
Inappropriate Speech (ABC-C) −0.011 (–0.627, 0.604) 0.971 −0.492 (−0.745, −0.239) <0.001
VABS-3 Communication Domain 0.031 (–0.121, 0.184) 0.688 −0.494 (−0.715, −0.273) <0.001
VABS-3 Socialization Domain −0.057 (–0.209, 0.095) 0.462 −0.498 (–0.718, −0.277) <0.001
ADOS-2 Comparison Score 0.028 (–1.074, 1.131) 0.960 −0.494 (−0.715, −0.273) <0.001
Overall CGI Severity 2.258 (–0.125, 4.642) 0.065 −0.493 (−0.711, −0.274) <0.001

ASD: autism spectrum disorder; Peds-QL: Pediatric Quality of Life Inventory; GI: gastrointestinal; CI: confidence interval; PDDBI: Pervasive
Developmental Disorder-Behavior Inventory; ABC-C: Aberrant Behavior Checklist-Community; VABS-3: Vineland Adaptive Behavior Scales, Third
Edition; ADOS-2: Autism Diagnostic Observation Schedule, Second Edition; CGI: Clinical Global Impression.
a
Each row in this table represents a separate linear regression model, with each symptom scale as the primary association of interest, while adjusting
for only (not shown) and Irritability.

symptoms; 93.2% of the children in our sample had at least
one GI symptom. The prevalence of GI symptoms in our
sample was relatively high compared to published preva-
lence estimates (range: 4.2%–96.8%, median: 46.8%)
reported in other studies using ASD populations from a
2018 review (Holingue et al., 2018).
Results of the present study indicated that GI symptom
severity was associated with the three associated behavioral
symptoms (irritability, aggressiveness, and specific fears),
which is consistent with findings from other studies involv-
ing ASD populations (Chaidez et al., 2014; Mazefsky et al.,
2014; Mazurek et al., 2013). These results are also
consistent with findings demonstrating a relationship
between other internalizing and mood-related problems and
GI abnormalities in the general population. Interestingly, we
did not find associations between GI symptoms and the
severity of social and communication symptoms. Mazefsky
et al. (2014) reported an association between the number of
GI symptoms and social problems, but no difference in the
mean Social Responsiveness Score (SRS) between those
with and without GI symptoms. Chaidez et al. (2014)
reported an association between GI symptoms and social
withdrawal. Our results did indicate that there is an associa-
tion between GI symptoms and repetitive behaviors and
Chakraborty et al. 7

Table 5.  Associations between ASD symptoms scales and Peds-QL GI Symptoms Inventory Composite Score adjusting for
Aggressiveness, N = 176.a

Symptom scales ASD symptom scale Aggressiveness

Beta 95% CI P-value Beta 95% CI P-value

Autism Composite Score (PDDBI) −0.162 (−0.350, 0.026) 0.093 –0.250 (−0.436, −0.064) 0.009
  Repetitive, Ritualistic, and Pragmatic Problems −0.188 (−0.374, −0.002) 0.049 –0.220 (−0.413, −0.026) 0.028
Composite
  Receptive/Expressive Social Communication 0.013 (−0.248, 0.274) 0.925 –0.341 (−0.491, −0.191) <0.001
Composite
Stereotypy (ABC-C) −0.509 (−0.911, −0.106) 0.014 –0.275 (−0.431, −0.12) 0.001
Inappropriate Speech (ABC-C) −0.260 (−0.819, 0.299) 0.363 –0.321 (−0.476, −0.166) <0.001
VABS-3 Communication Domain −0.021 (−0.175, 0.134) 0.794 –0.345 (–0.496, −0.194) <0.001
VABS-3 Socialization Domain −0.081 (−0.232, 0.071) 0.299 –0.350 (−0.500, −0.201) <0.001
ADOS-2 Comparison Score 0.125 (−0.973, 1.223) 0.824 –0.342 (−0.491, −0.193) <0.001
Overall CGI Severity 1.761 (−0.638, 4.159) 0.152 –0.331 (−0.480, −0.182) <0.001

ASD: autism spectrum disorder; Peds-QL: Pediatric Quality of Life Inventory; GI: gastrointestinal; CI: confidence interval; PDDBI: Pervasive
Developmental Disorder-Behavior Inventory; ABC-C: Aberrant Behavior Checklist-Community; VABS-3: Vineland Adaptive Behavior Scales, Third
Edition; ADOS-2: Autism Diagnostic Observation Schedule, Second Edition; CGI: Clinical Global Impression.
a
Each row in this table represents a separate linear regression model, with each symptom scale as the primary association of interest, while adjusting
for IQ (not shown) and Aggressiveness.

Table 6.  Associations between ASD Symptoms Scales and Peds-QL GI Symptoms Inventory Composite Score adjusting for
Specific Fears, N = 176.a

Symptom scales ASD symptom scale Specific Fears

Beta 95% CI P-value Beta 95% CI P-value

Autism Composite Score (PDDBI) −0.165 (−0.352, 0.023) 0.087 −0.282 (−0.493, −0.070) 0.010
  Repetitive, Ritualistic, and Pragmatic Problems −0.187 (−0.378, 0.004) 0.056 −0.244 (−0.472, −0.017) 0.037
Composite
  Receptive/Expressive Social Communication Composite 0.069 (−0.191, 0.330) 0.603 −0.368 (−0.536, −0.199) <0.001
Stereotypy (ABC-C) −0.509 (−0.918, −0.099) 0.016 −0.287 (−0.465, −0.109) 0.002
Inappropriate Speech (ABC-C) −0.301 (−0.859, 0.256) 0.291 −0.343 (−0.518, −0.168) <0.001
VABS-3 Communication Domain 0.022 (−0.131, 0.175) 0.778 −0.368 (−0.536, −0.199) <0.001
VABS-3 Socialization Domain −0.041 (−0.193, 0.111) 0.598 −0.368 (−0.537, −0.199) <0.001
ADOS-2 Comparison Score 0.315 (−0.789, 1.419) 0.577 −0.371 (−0.540, −0.202) <0.001
Overall CGI Severity 1.940 (−0.461, 4.342) 0.115 −0.359 (−0.527, −0.191) <0.001

ASD: autism spectrum disorder; Peds-QL: Pediatric Quality of Life Inventory; GI: gastrointestinal; CI: confidence interval; PDDBI: Pervasive
Developmental Disorder-Behavior Inventory; ABC-C: Aberrant Behavior Checklist-Community; VABS-3: Vineland Adaptive Behavior Scales, Third
Edition; ADOS-2: Autism Diagnostic Observation Schedule, Second Edition; CGI: Clinical Global Impression.
a
Each row in this table represents a separate linear regression model, with each symptom scale as the primary association of interest, while adjusting
for IQ (not shown) and Specific Fears.

stereotypies, a subset of core ASD symptoms. A few studies
also reported associations with repetitive behaviors and GI
symptoms, specifically constipation (Marler et al., 2017;
Peters et al., 2014) and diarrhea (Peters et al., 2014). These
results suggest that the relationship between core ASD
symptoms (both social problems and repetitive behaviors)
and GI symptoms warrants further study.
The mechanism of the relationship between GI abnor-
malities and repetitive behaviors is not well understood.
Some researchers have posited that the serotonin system
may mediate this relationship (Peters et al., 2014), as pre-
vious research has linked the serotonin system to both
ASD and GI symptoms. From a behavioral perspective, it
is also possible that if children are resistant to toilet train-
ing or refuse to eat certain foods that lead to unhealthy
diets, they may experience more GI symptoms. Food
selectivity, in particular, has been shown to be related to
sensory sensitivity (Cermak et al., 2010; Chistol et al.,
2018), and sensory sensitivity is related to repetitive
behaviors (Schulz & Stevenson, 2019). Although we did
not evaluate sensory sensitivities by themselves, they were
included in the composite measures. In addition, circum-
scribed interests may be a means to cope with discomfort
from GI symptoms. More research is needed to understand
the mechanism and temporal causal relationship between
behavioral and GI symptoms in ASD.
8 Autism 00(0)

Figure 3.  Correlations between symptom measures, N = 176. This is a cluster plot of Pearson correlations between ASD
symptom, associated symptom, and GI symptom domains. Thicker and darker lines represent higher correlation coefficients.

The role that associated behavioral symptoms, such as
irritability, may play in the relationship between repetitive
behaviors and GI symptoms has also not been explored.
In the present study, we modeled interactions between
associated symptom measures and repetitive behaviors
and found that the interactions were not significant. This
suggests that children who experience both repetitive
behaviors and associated behavior symptoms did not
experience greater GI symptom severity. However, it is
possible that due to our small sample size, we did not have
the power to detect an interaction. Nevertheless, given the
high variability of symptoms experienced in ASD, larger
longitudinal studies are needed to explore more nuanced
relationships between GI symptoms and the various
behavioral problems common in ASD.
Because our study was cross-sectional by design, we
were not able to measure a temporal relationship in the
onset of GI symptoms and increases in repetitive behav-
iors. Moreover, the causal pathway between GI and
behavioral problems is not well understood; it is possible
that treatment of GI symptoms could lead to reduced
repetitive behaviors. In some studies, treatment of GI
symptoms, for example, with microbiota gut therapy, has
been shown to reduce ASD core symptoms, although it is
unclear how much repetitive behaviors, specifically
improved (Kang et al., 2017). Future research is needed to
Chakraborty et al. 9
better explore the relationship between GI symptoms and
repetitive behaviors, and the potential impact on GI treat-
ments and behavior in ASD populations.
One strength of this study is the use of multimodal
measures of ASD symptoms that provide a more nuanced
understanding of the impact on core symptoms. The social
and communication measures used in the present study are
also recommended for use in clinical trials (Anagnostou
et al., 2015). One limitation to the present study is that we
assessed our main outcome, GI symptom severity, using a
parent report measure, rather than assessing GI symptoms
clinically. However, we used a validated parent report
measure (Varni et al., 2014), and parent report has been
shown to be highly correlated with clinical diagnoses of GI
symptoms. Furthermore, even though the measure of
Specific Fears captures some anxiety, it does not capture
more generalized forms of anxiety. Despite this limitation,
Specific Fears emerged as an important correlate of GI
symptoms in our analysis. In addition, our data came from
a clinical trial which necessitated several specific inclu-
sion and exclusion criteria, which were not required for the
present analysis. For example, we excluded participants
with a known genetic syndrome. Also, our study popula-
tion, especially those with autologous cord blood, likely
represent higher socio-economic status groups compared
to the general population. Thus, our sample may differ
from the general population of young children with ASD.
In summary, we found significant associations between
GI symptom severity and irritability, aggressiveness, and
specific fears. We also found significant associations
between GI symptoms and repetitive/stereotypic behaviors,
but not social communication difficulties. Our study find-
ings support other research that has suggested that GI
symptoms have an independent association with some
types of ASD symptoms. These findings also highlight the
importance of understanding treatments to reduce GI symp-
toms among children with ASD, as GI abnormalities not
only impact comfort and quality of life, but they may also
impact associated and core ASD behavioral symptoms.
Author’s note
The author Payal Chakraborty is now affiliated to The Ohio State
University, USA.
Acknowledgements
The authors gratefully acknowledge the participation of the chil-
dren and their families.
Declaration of conflict of interests
The author(s) declared the following potential conflicts of inter-
est with respect to the research, authorship, and/or publication of
this article: Dr Dawson is on the Scientific Advisory Boards of
Janssen Research and Development; Akili, Inc; LabCorp, Inc;
Roche Pharmaceutical Company; and Tris Pharma; and is a
consultant to Apple; Gerson Lehrman Group; Guidepoint, Inc;
Axial Ventures; Teva Pharmaceutical; and is CEO of DASIO,
LLC. Dr Dawson has received book royalties from Guilford
Press, Oxford University Press, and Springer Nature Press. In
addition, Dr Dawson has the following patent applications:
1802952, 1802942, 15141391, and 16493754. Drs Dawson and
Carpenter have developed technology that has been licensed and
Dawson and Duke University have benefited financially. Dr
Howard reports personal fees from Roche.
Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article:
The authors gratefully acknowledge funding from The Marcus
Foundation.
ORCID iDs
Payal Chakraborty https://orcid.org/0000-0003-4939-3637
Samantha Major https://orcid.org/0000-0001-5969-1721
References
Adams, J. B., Johansen, L. J., Powell, L. D., Quig, D., & Rubin, R.
A. (2011). Gastrointestinal flora and gastrointestinal status
in children with autism: Comparisons to typical children and
correlation with autism severity. BMC Gastroenterology,
11, Article 22. https://doi.org/10.1186/1471-230X-11-22
Aman, M. G., Singh, N. N., Stewart, A. W., & Field, C. J. (1985).
The aberrant behavior checklist: A behavior rating scale for
the assessment of treatment effects. American Journal of
Mental Deficiency, 89(5), 485–491.
American Psychiatric Association. (2013). Diagnostic and sta-
tistical manual of mental disorders (5th ed.). American
Psychiatric Publishing.
Anagnostou, E., Jones, N., Huerta, M., Halladay, A. K., Wang,
P., Scahill, L., Horrigan, J. P., Kasari, C., Lord, C., Choi, D.,
Sullivan, K., & Dawson, G. (2015). Measuring social com-
munication behaviors as a treatment endpoint in individu-
als with autism spectrum disorder. Autism, 19(5), 622–636.
https://doi.org/10.1177/1362361314542955
Arnold, L. E., Luna, R. A., Williams, K., Chan, J., Parker, R.
A., Wu, Q., Hollway, J. A., Jeffs, A., Lu, F., Coury, D. L.,
Hayes, C., & Savidge, T. (2019). Probiotics for gastroin-
testinal symptoms and quality of life in autism: A placebo-
controlled pilot trial. Journal of Child and Adolescent
Psychopharmacology, 29(9), 659–669. https://doi.org/10.
1089/cap.2018.0156
Ashwood, P., Wills, S., & Van de Water, J. (2006). The immune
response in autism: A new frontier for autism research.
Journal of Leukocyte Biology, 80(1), 1–15. https://doi.
org/10.1189/jlb.1205707
Ballenger, J. C., Davidson, J. R. T., Lecrubier, Y., Nutt, D.,
Lydiard, R. B., Mayer, E. A., & International Consensus
Group on Depression and Anxiety. (2001). Consensus state-
ment on depression, anxiety, and functional gastrointestinal
disorders. The Journal of Clinical Psychiatry, 62(Suppl. 8),
48–51.
Buie, T., Campbell, D. B., Fuchs, G. J., III., Furuta, G. T., Levy,
J., Vandewater, J., Whitaker, A. H., Atkins, D., Bauman,
10 Autism 00(0)
M. L., Beaudet, A. L., Carr, E. G., Gershon, M. D., Hyman,
S. L., Jirapinyo, P., Jyonouchi, H., Kooros, K., Kushak, R.,
Levitt, P., Levy, S. E., . . . Winter, H. (2010). Evaluation,
diagnosis, and treatment of gastrointestinal disorders in
individuals with ASDs: A consensus report. Pediatrics,
125(Suppl. 1), S1–S18. https://doi.org/10.1542/peds.2009-
1878C
Cermak, S. A., Curtin, C., & Bandini, L. G. (2010). Food
selectivity and sensory sensitivity in children with autism
spectrum disorders. Journal of the American Dietetic
Association, 110(2), 238–246. https://doi.org/10.1016/j.
jada.2009.10.032
Chaidez, V., Hansen, R. L., & Hertz-Picciotto, I. (2014).
Gastrointestinal problems in children with autism, devel-
opmental delays or typical development. Journal of Autism
and Developmental Disorders, 44(5), 1117–1127. https://
doi.org/10.1007/s10803-013-1973-x
Chistol, L. T., Bandini, L. G., Must, A., Phillips, S., Cermak, S.
A., & Curtin, C. (2018). Sensory sensitivity and food selec-
tivity in children with autism spectrum disorder. Journal
of Autism and Developmental Disorders, 48(2), 583–591.
https://doi.org/10.1007/s10803-017-3340-9
Cohen, I. L., Schmidt-Lackner, S., Romanczyk, R., & Sudhalter,
V. (2003). The PDD Behavior Inventory: A rating scale
for assessing response to intervention in children with
pervasive developmental disorder. Journal of Autism and
Developmental Disorders, 33(1), 31–45.
Cryan, J. F., & Dinan, T. G. (2012). Mind-altering microor-
ganisms: The impact of the gut microbiota on brain and
behaviour. Nature Reviews Neuroscience, 13(10), 701–712.
https://doi.org/10.1038/nrn3346
Dufton, L. M., Dunn, M. J., & Compas, B. E. (2009). Anxiety and
somatic complaints in children with recurrent abdominal
pain and anxiety disorders. Journal of Pediatric Psychology,
34(2), 176–186. https://doi.org/10.1093/jpepsy/jsn064
Gorrindo, P., Williams, K. C., Lee, E. B., Walker, L. S., McGrew,
S. G., & Levitt, P. (2012.). Gastrointestinal dysfunction in
autism: Parental report, clinical evaluation, and associ-
ated factors. Autism Research, 5(2), 101–108. https://doi.
org/10.1002/aur.237
Hansen, B. H., Oerbeck, B., Skirbekk, B., Petrovski, B. É., &
Kristensen, H. (2018). Neurodevelopmental disorders:
Prevalence and comorbidity in children referred to mental
health services. Nordic Journal of Psychiatry, 72(4), 285–
291. https://doi.org/10.1080/08039488.2018.1444087
Holingue, C., Newill, C., Lee, L.-C., Pasricha, P. J., & Daniele
Fallin, M. (2018). Gastrointestinal symptoms in autism
spectrum disorder: A review of the literature on ascertain-
ment and prevalence. Autism Research : Official Journal of
the International Society for Autism Research, 11(1), 24–
36. https://doi.org/10.1002/aur.1854
Hommel, K. A., McGraw, K. L., Ammerman, R. T., Heubi,
J. E., Hansen, M., Dunlap, E., & Beidel, D. C. (2010).
Psychosocial functioning in children and adolescents
with gastrointestinal complaints and disorders. Journal of
Clinical Psychology in Medical Settings, 17(2), 159–166.
https://doi.org/10.1007/s10880-010-9193-4
Horvath, K., Papadimitriou, J. C., Rabsztyn, A., Drachenberg,
C., & Tildon, J. T. (1999). Gastrointestinal abnormalities in
children with autistic disorder. The Journal of Pediatrics,
135(5), 559–563. https://doi.org/10.1016/S0022-3476(99)
70052-1
Hyams, J. S., Burke, G., Davis, P. M., Rzepski, B., & Andrulonis,
P. A. (1996). Abdominal pain and irritable bowel syndrome
in adolescents: A community-based study. The Journal of
Pediatrics, 129(2), 220–226. https://doi.org/10.1016/s0022-
3476(96)70246-9
Kang, D.-W., Adams, J. B., Gregory, A. C., Borody, T., Chittick,
L., Fasano, A., Khoruts, A., Geis, E., Maldonado, J.,
McDonough-Means, S., Pollard, E. L., Roux, S., Sadowsky,
M. J., Lipson, K. S., Sullivan, M. B., Caporaso, J. G., &
Krajmalnik-Brown, R. (2017). Microbiota Transfer Therapy
alters gut ecosystem and improves gastrointestinal and
autism symptoms: An open-label study. Microbiome, 5, 10.
https://doi.org/10.1186/s40168-016-0225-7
Le Couteur, A., Lord, C., & Rutter, M. (2003). The autism diag-
nostic interview-revised (ADI-R). Western Psychological
Services.
Lord, C., Rutter, M., DiLavore, P., Risi, S., Gotham, K., Bishop,
S., Luyster, R., & Guthrie, W. (2012). Autism diagnostic
observation schedule: ADOS-2. Western Psychological
Services.
Marler, S., Ferguson, B. J., Lee, E. B., Peters, B., Williams, K.
C., McDonnell, E., Macklin, E. A., Levitt, P., Margolis, K.
G., Beversdorf, D. Q., & Veenstra-VanderWeele, J. (2017).
Association of rigid-compulsive behavior with functional
constipation in autism spectrum disorder. Journal of Autism
and Developmental Disorders, 47(6), 1673–1681. https://
doi.org/10.1007/s10803-017-3084-6
Matson, J. L., & Williams, L. W. (2014). Depression and mood
disorders among persons with Autism Spectrum Disorders.
Research in Developmental Disabilities, 35(9), 2003–2007.
https://doi.org/10.1016/j.ridd.2014.04.020
Mazefsky, C. A., Schreiber, D. R., Olino, T. M., & Minshew, N.
J. (2014). The association between emotional and behav-
ioral problems and gastrointestinal symptoms among chil-
dren with high-functioning autism. Autism, 18(5), 493–501.
https://doi.org/10.1177/1362361313485164
Mazurek, M. O., Vasa, R. A., Kalb, L. G., Kanne, S. M.,
Rosenberg, D., Keefer, A., Murray, D. S., Freedman, B., &
Lowery, L. A. (2013). Anxiety, sensory over-responsivity,
and gastrointestinal problems in children with autism spec-
trum disorders. Journal of Abnormal Child Psychology,
41(1), 165–176. https://doi.org/10.1007/s10802-012-9668-x
McElhanon, B. O., McCracken, C., Karpen, S., & Sharp, W.
G. (2014). Gastrointestinal symptoms in autism spectrum
disorder: A meta-analysis. Pediatrics, 133(5), 872–883.
https://doi.org/10.1542/peds.2013-3995
Neuhaus, E., Bernier, R. A., Tham, S. W., & Webb, S. J. (2018).
Gastrointestinal and psychiatric symptoms among children
and adolescents with autism spectrum disorder. Frontiers
in Psychiatry, 9, Article 515. https://doi.org/10.3389/
fpsyt.2018.00515
Nikolov, R. N., Bearss, K. E., Lettinga, J., Erickson, C.,
Rodowski, M., Aman, M. G., McCracken, J. T., McDougle,
C. J., Tierney, E., Vitiello, B., Arnold, L. E., Shah, B., Posey,
D. J., Ritz, L., & Scahill, L. (2009). Gastrointestinal symp-
toms in a sample of children with pervasive developmental
Chakraborty et al. 11
disorders. Journal of Autism and Developmental Disorders,
39(3), 405–413. https://doi.org/10.1007/s10803-008-0637-8
Peters, B., Williams, K. C., Gorrindo, P., Rosenberg, D., Lee, E.
B., Levitt, P., & Veenstra-VanderWeele, J. (2014). Rigid-
compulsive behaviors are associated with mixed bowel
symptoms in autism spectrum disorder. Journal of Autism
and Developmental Disorders, 44(6), 1425–1432. https://
doi.org/10.1007/s10803-013-2009-2
Rudzki, L., & Szulc, A. (2018). “Immune gate” of psychopathol-
ogy-the role of gut derived immune activation in major psy-
chiatric disorders. Frontiers in Psychiatry, 9, Article 205.
https://doi.org/10.3389/fpsyt.2018.00205
Sanctuary, M. R., Kain, J. N., Angkustsiri, K., & German, J. B.
(2018). Dietary considerations in autism spectrum disor-
ders: The potential role of protein digestion and microbial
putrefaction in the gut-brain axis. Frontiers in Nutrition, 5,
Article 40.
Schulz, S. E., & Stevenson, R. A. (2019). Sensory hypersensitiv-
ity predicts repetitive behaviours in autistic and typically-
developing children. Autism, 23(4), 1028–1041. https://doi.
org/10.1177/1362361318774559
Varni, J. W., Bendo, C. B., Denham, J., Shulman, R. J., Self,
M. M., Neigut, D. A., Nurko, S., Patel, A. S., Franciosi, J.
P., Saps, M., Verga, B., Smith, A., Yeckes, A., Heinz, N.,
Langseder, A., Saeed, S., Zacur, G. M., & Pohl, J. F. (2014).
PedsQL gastrointestinal symptoms module: Feasibility, reli-
ability, and validity. Journal of Pediatric Gastroenterology
and Nutrition, 59(3), 347–355. https://doi.org/10.1097/
MPG.0000000000000414
Waters, A. M., Schilpzand, E., Bell, C., Walker, L. S., & Baber,
K. (2013). Functional gastrointestinal symptoms in chil-
dren with anxiety disorders. Journal of Abnormal Child
Psychology, 41(1), 151–163. https://doi.org/10.1007/
s10802-012-9657-0