Gastrointestinal problems are associated with increased repetitive behaviors but not social communication difficulties in young children with autism spectrum disorders

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 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 communication 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, children 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 aggressiveness are also strongly associated with GI symptoms (Chaidez et al., 2014; Mazefsky et al., 2014), and development 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 symptoms 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 parent 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, treatment of GI symptoms was associated with reduced severity 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 variability in the method used to measure ASD symptoms. Furthermore, some of these studies employed small sample 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 symptoms, 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 symptoms 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. difficulty 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 problems 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 targets, helping to understand whether treatment for GI problems should be focused on anxiety/depression symptoms or 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 accounting 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 hypothesized that GI symptom severity would remain associated with core ASD symptoms after controlling for associated behavioral symptoms. Specifically, we sought to examine the relationship between GI symptoms and ASD symptom severity independent of co-occurring associated behavioral challenges in young children with ASD. Understanding this relationship is important because GI symptoms not only directly impact quality of life of children 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 baseline visit (prior to treatment) of a Phase II randomized-controlled 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 seizure 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 assessments, 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%) participants 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 subjects (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 questionnaires (Table 1).

Table 1.

Summary of study measures.

Cognitive functioning	Autism severity	Associated behavioral symptoms	Gastrointestinal symptoms
Full Scale IQ (FSIQ)	ADOS-2 Comparison Score 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	Irritability (ABC-C) Aggressiveness (PDDBI) Specific Fears (PDDBI)	PedsQL-GI Symptoms Inventory Composite Score

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.

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 Behavior 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 Comparison Score, and overall CGI-S score.

Associated symptoms

Three aspects of associated behavioral symptoms were investigated: Irritability, Aggressiveness, 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 symptoms among children with ASD and their documented association 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 frequencies 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 regression models were conducted for each ASD core symptom domain, while accounting for each associated symptom domain individually. FSIQ was included as a covariate for 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).

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 symptoms, N (%)	164 (93.2%)
Peds-QL GI Symptoms Inventory Composite Score^a, M (SD)	84.7 (12.4)
Stomach Pain Composite, M (SD)	83.3 (19.8)
Stomach Discomfort Composite, M (SD)	89.0 (16.5)
Food Limits Composite, M (SD)	74.4 (26.0)
Trouble Swallowing Composite, M (SD)	95.5 (12.4)
Heart Burn Composite, M (SD)	93.8 (12.3)
Nausea/Vomiting Composite, M (SD)	93.8 (13.0)
Gas/Bloating Composite, M (SD)	81.5 (20.3)
Constipation Composite, M (SD)	78.5 (23.0)
Bloody Stool Composite, M (SD)	95.7 (12.6)
Diarrhea Composite, M (SD)	89.1 (16.9)

M: mean; SD: standard deviation; N: number; %: percent; CGI: Clinical Global Impression; ADOS-2: Autism Diagnostic Observation Schedule, Second Edition; GI: gastrointestinal; Peds-QL: Pediatric Quality of Life Inventory.

A higher score indicates lower symptom severity.

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).

Figure 1.

Frequency distribution of numbers of concurrent GI symptoms experienced, N = 176.

Figure 2.

Frequency distribution of types of GI symptoms experienced, N = 176.

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 symptoms, but social and communication difficulties measured by PDDBI and VABS-3 were not associated with GI symptoms. ADOS-2 Severity Score was not also associated with GI symptoms.

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.

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 stereotypies were significantly associated with GI symptom severity. Specifically, higher levels of GI symptom severity were associated with increased scores on both the Repetitive, 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 symptom severity and the Repetitive, Ritualistic, and Pragmatic Problems composite score did not persist when adjusting for specific fears (β = −0.187, 95% CI = −0.378, 0.004). Social and communication–related problems were still not significantly associated with GI symptoms.

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
Symptom scales	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 Composite	−0.197	(–0.372, –0.023)	0.028	−0.335	(−0.605, −0.065)	0.016
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.

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.

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
Symptom scales	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 Composite	−0.188	(−0.374, −0.002)	0.049	–0.220	(−0.413, −0.026)	0.028
Receptive/Expressive Social Communication Composite	0.013	(−0.248, 0.274)	0.925	–0.341	(−0.491, −0.191)	<0.001
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

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
Symptom scales	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 Composite	−0.187	(−0.378, 0.004)	0.056	−0.244	(−0.472, −0.017)	0.037
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

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.

In each regression model, we also tested interaction terms between each associated behavioral symptom and each ASD symptom scale. None of the interaction terms was statistically significant, and thus, the interaction terms were not retained in the models.

Similar to the regression analyses, the correlation analysis depicted by the cluster plot also demonstrated that GI symptoms were more closely related to irritability, aggressiveness, specific fears, repetitive behaviors, and stereotypies (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 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.

Discussion

The present study had two primary findings. First, we found that behavioral symptoms (irritability, aggressiveness, and specific fears) were associated with GI symptom 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 association between GI symptom severity and repetitive/stereotypic behaviors remained even after controlling for behavioral symptoms, with the exception of specific fears. Our findings support a growing body of research demonstrating that GI symptoms are related to several behavioral 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 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 prevalence 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 involving 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 association between GI symptoms and repetitive behaviors and 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 abnormalities and repetitive behaviors is not well understood. Some researchers have posited that the serotonin system may mediate this relationship (Peters et al., 2014), as previous 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 training 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, circumscribed 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.

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 behaviors. 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 better explore the relationship between GI symptoms and repetitive behaviors, and the potential impact on GI treatments 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 inclusion and exclusion criteria, which were not required for the present analysis. For example, we excluded participants with a known genetic syndrome. Also, our study population, 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 findings 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 symptoms 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.

Footnotes

Acknowledgements

The authors gratefully acknowledge the participation of the children and their families.

Author’s note

The author Payal Chakraborty is now affiliated to The Ohio State University, USA.

Declaration of conflict of interests

The author(s) declared the following potential conflicts of interest 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

Samantha Major

References

Adams

J. B.

Johansen

L. J.

Powell

L. D.

Quig

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 statistical manual of mental disorders (5th ed.). American Psychiatric Publishing.

Anagnostou

Jones

Huerta

Halladay

A. K.

Wang

Scahill

Horrigan

J. P.

Kasari

Lord

Choi

Sullivan

Dawson

(2015). Measuring social communication behaviors as a treatment endpoint in individuals with autism spectrum disorder. Autism, 19(5), 622–636. https://doi.org/10.1177/1362361314542955

Arnold

L. E.

Luna

R. A.

Williams

Chan

Parker

R. A.

Hollway

J. A.

Jeffs

Coury

D. L.

Hayes

Savidge

(2019). Probiotics for gastrointestinal 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

Wills

Van de Water

(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

Nutt

Lydiard

R. B.

Mayer

E. A.

, & International Consensus Group on Depression and Anxiety. (2001). Consensus statement on depression, anxiety, and functional gastrointestinal disorders. The Journal of Clinical Psychiatry, 62(Suppl. 8), 48–51.

Buie

Campbell

D. B.

Fuchs

G. J.

III. Furuta

G. T.

Levy

Vandewater

Whitaker

A. H.

Atkins

Bauman

M. L.

Beaudet

A. L.

Carr

E. G.

Gershon

M. D.

Hyman

S. L.

Jirapinyo

Jyonouchi

Kooros

Kushak

Levitt

Levy

S. E.

. . . Winter

(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

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

10.

Chaidez

Hansen

R. L.

Hertz-Picciotto

(2014). Gastrointestinal problems in children with autism, developmental delays or typical development. Journal of Autism and Developmental Disorders, 44(5), 1117–1127. https://doi.org/10.1007/s10803-013-1973-x

11.

Chistol

L. T.

Bandini

L. G.

Must

Phillips

Cermak

S. A.

Curtin

(2018). Sensory sensitivity and food selectivity 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

12.

Cohen

I. L.

Schmidt-Lackner

Romanczyk

Sudhalter

(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.

13.

Cryan

J. F.

Dinan

T. G.

(2012). Mind-altering microorganisms: The impact of the gut microbiota on brain and behaviour. Nature Reviews Neuroscience, 13(10), 701–712. https://doi.org/10.1038/nrn3346

14.

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

15.

Gorrindo

Williams

K. C.

Lee

E. B.

Walker

L. S.

McGrew

S. G.

Levitt

(2012.). Gastrointestinal dysfunction in autism: Parental report, clinical evaluation, and associated factors. Autism Research, 5(2), 101–108. https://doi.org/10.1002/aur.237

16.

Hansen

B. H.

Oerbeck

Skirbekk

Petrovski

B. É.

Kristensen

(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

17.

Holingue

Newill

Lee

L.-C.

Pasricha

P. J.

Daniele Fallin

(2018). Gastrointestinal symptoms in autism spectrum disorder: A review of the literature on ascertainment and prevalence. Autism Research : Official Journal of the International Society for Autism Research, 11(1), 24–36. https://doi.org/10.1002/aur.1854

18.

Hommel

K. A.

McGraw

K. L.

Ammerman

R. T.

Heubi

J. E.

Hansen

Dunlap

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

19.

Horvath

Papadimitriou

J. C.

Rabsztyn

Drachenberg

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

20.

Hyams

J. S.

Burke

Davis

P. M.

Rzepski

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

21.

Kang

D.-W.

Adams

J. B.

Gregory

A. C.

Borody

Chittick

Fasano

Khoruts

Geis

Maldonado

McDonough-Means

Pollard

E. L.

Roux

Sadowsky

M. J.

Lipson

K. S.

Sullivan

M. B.

Caporaso

J. G.

Krajmalnik-Brown

(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

22.

Le Couteur

Lord

Rutter

. (2003). The autism diagnostic interview-revised (ADI-R). Western Psychological Services.

23.

Lord

Rutter

DiLavore

Risi

Gotham

Bishop

Luyster

Guthrie

(2012). Autism diagnostic observation schedule: ADOS-2. Western Psychological Services.

24.

Marler

Ferguson

B. J.

Lee

E. B.

Peters

Williams

K. C.

McDonnell

Macklin

E. A.

Levitt

Margolis

K. G.

Beversdorf

D. Q.

Veenstra-VanderWeele

(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

25.

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

26.

Mazefsky

C. A.

Schreiber

D. R.

Olino

T. M.

Minshew

N. J.

(2014). The association between emotional and behavioral problems and gastrointestinal symptoms among children with high-functioning autism. Autism, 18(5), 493–501. https://doi.org/10.1177/1362361313485164

27.

Mazurek

M. O.

Vasa

R. A.

Kalb

L. G.

Kanne

S. M.

Rosenberg

Keefer

Murray

D. S.

Freedman

Lowery

L. A.

(2013). Anxiety, sensory over-responsivity, and gastrointestinal problems in children with autism spectrum disorders. Journal of Abnormal Child Psychology, 41(1), 165–176. https://doi.org/10.1007/s10802-012-9668-x

28.

McElhanon

B. O.

McCracken

Karpen

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

29.

Neuhaus

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

30.

Nikolov

R. N.

Bearss

K. E.

Lettinga

Erickson

Rodowski

Aman

M. G.

McCracken

J. T.

McDougle

C. J.

Tierney

Vitiello

Arnold

L. E.

Shah

Posey

D. J.

Ritz

Scahill

(2009). Gastrointestinal symptoms in a sample of children with pervasive developmental disorders. Journal of Autism and Developmental Disorders, 39(3), 405–413. https://doi.org/10.1007/s10803-008-0637-8

31.

Peters

Williams

K. C.

Gorrindo

Rosenberg

Lee

E. B.

Levitt

Veenstra-VanderWeele

(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

32.

Rudzki

Szulc

(2018). “Immune gate” of psychopathology-the role of gut derived immune activation in major psychiatric disorders. Frontiers in Psychiatry, 9, Article 205. https://doi.org/10.3389/fpsyt.2018.00205

33.

Sanctuary

M. R.

Kain

J. N.

Angkustsiri

German

J. B.

(2018). Dietary considerations in autism spectrum disorders: The potential role of protein digestion and microbial putrefaction in the gut-brain axis. Frontiers in Nutrition, 5, Article 40.

34.

Schulz

S. E.

Stevenson

R. A.

(2019). Sensory hypersensitivity predicts repetitive behaviours in autistic and typically-developing children. Autism, 23(4), 1028–1041. https://doi.org/10.1177/1362361318774559

35.

Varni

J. W.

Bendo

C. B.

Denham

Shulman

R. J.

Self

M. M.

Neigut

D. A.

Nurko

Patel

A. S.

Franciosi

J. P.

Saps

Verga

Smith

Yeckes

Heinz

Langseder

Saeed

Zacur

G. M.

Pohl

J. F.

(2014). PedsQL gastrointestinal symptoms module: Feasibility, reliability, and validity. Journal of Pediatric Gastroenterology and Nutrition, 59(3), 347–355. https://doi.org/10.1097/MPG.0000000000000414

36.

Waters

A. M.

Schilpzand

Bell

Walker

L. S.

Baber

(2013). Functional gastrointestinal symptoms in children with anxiety disorders. Journal of Abnormal Child Psychology, 41(1), 151–163. https://doi.org/10.1007/s10802-012-9657-0