Edited by: Manuel Fernando Casanova, University of South Carolina, United States
Reviewed by: Owen Murray Rennert, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), United States; David Cochran, University of Massachusetts Medical School, United States
This article was submitted to Child and Adolescent Psychiatry, a section of the journal Frontiers in Psychiatry
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Individuals with autism spectrum disorder (ASD) are at heightened risk of psychiatric comorbidities across the lifespan, including elevated rates of internalizing, externalizing, and self-injurious behaviors. Identification of medical comorbidities that contribute to these concerns may elucidate mechanisms through which psychiatric concerns arise, as well as offer additional avenues for intervention. Gastrointestinal (GI) conditions are of particular interest, as they are prevalent among those with ASD, may share genetic or neurobiological etiologies with the core features of ASD, and are linked with psychiatric difficulties in the general population. In this paper, we draw on data from nearly 2,800 children and adolescents with ASD within the Simons Simplex Collection to characterize the unique contributions of (1) autism symptoms, (2) psychosocial factors (child's age, sex, verbal and nonverbal IQ, adaptive behavior, race, and household income), and (3) GI concerns with respect to multiple psychiatric outcomes. Multiple regression models revealed unique contributions of ASD symptoms and multiple psychosocial factors such as verbal IQ, adaptive behavior, and family income to internalizing, externalizing, and self-injurious behavior. In general, higher levels of psychiatric symptoms were associated with more ASD symptoms, higher verbal IQ, lower adaptive behavior skills, and lower family income. Furthermore, levels of GI symptoms accounted for unique variance in psychiatric outcomes over and above these other factors, linking increased GI problems with increased psychiatric symptoms in children with ASD. Taken together, results indicate that the presence and quantity of GI symptoms should be considered when evaluating psychiatric and behavioral concerns among children with ASD, and that treatment of GI conditions may be an important component in alleviating a broad array of mental health concerns in this group.
Despite their absence from diagnostic criteria, internalizing and externalizing symptoms are frequent and pervasive among individuals with autism spectrum disorder (ASD). As early as toddlerhood, children later diagnosed with ASD evidence diminished positive affect and heightened negative affect relative to children without ASD (
Along with significant psychiatric symptoms, ASD is often characterized by a number of medical comorbidities, including seizure disorders (
Among medical comorbidities, gastrointestinal symptoms are particularly prominent among individuals with ASD, occurring nearly four times as frequently as comparison groups without ASD (
The cause(s) of such pervasive GI concerns in ASD are not fully understood, but several pathways are plausible. First, it may be that shared genetic substrates underlie both ASD and GI dysfunction, at least for some individuals with ASD. Increasingly understood to stem from complex genetic bases, ASD has thus far been associated with familial and
The cumulative data to date support the co-occurring relationship between psychiatric and GI concerns in children with ASD. As early as preschool age, children with ASD with significant GI symptoms demonstrate higher levels of internalizing, aggressive, and repetitive behavior, with positive correlations between GI and behavioral symptoms (
To some extent, these findings echo relations observed in the general population, as children without ASD also tend to display increased GI concerns in the context of both externalizing disorders such as ADHD (
Our overarching goal in this paper was to explore the role of gastrointestinal concerns as they relate to psychiatric symptoms among children and adolescents with ASD. Within this goal, we pursued two aims. First, we sought to document the prevalence and variety of GI concerns within a large, well-characterized sample of children and adolescents with ASD. Second, we sought to understand relationships between ASD symptoms and GI concerns over and above the effects of psychosocial factors. Given the prevalence and pervasiveness of psychiatric and gastrointestinal comorbidities in ASD, better understanding of the relations between these components may offer additional avenues for intervention for children and adults with ASD, as well as inform our understanding of the multisystemic nature and mechanisms of ASD.
Data for the current analyses were obtained as part of the Simons Simplex Collection [SSC; (
The resulting sample included 2,756 children (13.6% female, 86.4% male) with the following parent-reported racial/ethnic backgrounds: African American (4.0%), Asian (4.0%), Native American or Hawaiian (0.3%), more than one race (7.8%), other than listed (4.5%), and white (78.6%). Table
Demographic and clinical characteristics for participants.
Age (years) | 9.03 (3.6) | 4–18 |
ADI-R Current Behavior total score | 27.47 (10.1) | 1–60 |
ADOS Calibrated Severity Score | 7.44 (1.7) | 4–10 |
Verbal IQ standard score | 78.04 (31.3) | 5–167 |
Nonverbal IQ standard score | 84.52 (26.2) | 9–161 |
Vineland-2 Composite standard score | 73.13 (12.1) | 27–115 |
CBCL Anxious/Depressed T-Score | 58.36 (8.9) | 50–98 |
CBCL Externalizing T-Score | 56.58 (10.6) | 32–97 |
RBS-R Self Injurious | 2.09 (2.9) | 0–21 |
The presence and degree of symptoms associated with ASD were assessed using the total score from the age-appropriate ADI-R Current Behavior algorithm, consistent with the procedure described in Neuhaus et al. (
Parents completed extensive interviews regarding the child's medical history, including the presence/absence of 7 distinct GI symptoms. Symptoms were considered to be present if they were recurrent, not attributed to known acute illnesses (e.g., food poisoning), and caused “significant bother” for the family. We computed a summary variable tallying the number of symptoms reported for each child with ASD: constipation, diarrhea, severe abdominal pain, gastro-esophageal reflux, vomiting, excessive gas, and bloating. We included data of reported symptoms that were present beyond the age of 36 months, in order to exclude symptoms (e.g., physiologic reflux) that may be benign during infancy and very early childhood, with expected resolution over time.
We identified three psychiatric symptom clusters of interest. Parent-reported internalizing and externalizing symptoms were measured via the age-appropriate versions of the Child Behavior Checklist [CBCL; (
A number of child and family characteristics relevant to the emergence of psychiatric symptoms were extracted from the background and clinical information available in the SSC dataset. These included child age, biological sex, verbal and nonverbal IQ scores as assessed with age-appropriate standardized measures (
In order to understand relations between child/family factors and psychiatric outcomes, we assessed direct contributions of these factors to each of our three psychiatric symptom areas (internalizing, externalizing, self-injurious behavior). Within the two age groups corresponding to ADI-R scoring algorithms (4 through 9 years of age; 10+ years of age), we used SPSS version 19 to create separate three-level multiple regression models predicting each psychiatric measure. Within each model, missing data were handled with pairwise deletion.
At Level 1 of the models, we entered ASD symptoms to quantify the variance in psychiatric outcomes attributable to core features of ASD.
At Level 2, we entered psychosocial factors hypothesized to account for additional variance in psychiatric concerns. These consisted of child's age, child's biological sex, child's verbal and nonverbal IQ scores, child's adaptive behavior, family's annual income, and child's race (African American, Asian, or white).
At Level 3, we entered GI concerns present after the age of 36 months to assess contribution of these concerns over and above ASD symptoms and psychosocial factors.
Consistent with previous literature, families in the SSC frequently reported that their child with ASD had significant GI symptoms. Over one third of the sample (37.7%) experienced at least one symptom, with a mean of 0.61 (
Prevalence of parent-reported GI concerns.
Bloating | 4.6% |
Constipation | 24.1% |
Diarrhea | 10.6% |
Excessive Gas | 6.9% |
Reflux | 5.5% |
Severe Abdominal Pain | 5.1% |
Vomiting | 4.2% |
The sample as a whole had a mean Anxious/Depressed T-score of 58.36 (
Unique contributions of child and family factors to internalizing symptoms.
ASD symptoms | 0.11 | 4.24 |
0.13 | 3.68 |
Age | 0.24 | 10.71 |
−0.01 | −0.18 |
Child sex | −0.04 | −1.57 | 0.04 | 1.38 |
Verbal IQ | 0.43 | 10.06 |
0.41 | 6.64 |
Nonverbal IQ | −0.06 | −1.55 | −0.01 | −0.21 |
Adaptive behavior | −0.09 | −2.57 |
−0.03 | −0.68 |
Household income | −0.09 | −4.07 |
−0.07 | −2.26 |
African American | −0.03 | −1.04 | −0.04 | −1.26 |
Asian | −0.02 | −0.77 | −0.05 | −1.47 |
White | −0.04 | −1.61 | 0.05 | 1.26 |
GI symptoms | 0.10 | 4.24 |
0.10 | 3.83 |
Among the older children and adolescents (ages 10:0 and older), ASD symptoms entered alone did not account for significant variance [
A similar set of findings emerged with respect to externalizing outcomes. The sample as a whole had a mean Externalizing T-score of 56.6 (
Unique contributions of child and family factors to externalizing symptoms.
ASD symptoms | 0.12 | 4.55 |
0.20 | 5.54 |
Age | 0.02 | −0.98 | −0.17 | −5.37 |
Child sex | 0.00 | 0.14 | 0.06 | 1.95 |
Verbal IQ | 0.32 | 7.19 |
0.45 | 7.30 |
Nonverbal IQ | −0.07 | −1.55 | −0.22 | −3.59 |
Adaptive behavior | −0.28 | −7.46 |
−0.18 | −3.56 |
Household income | −0.11 | −4.65 |
−0.11 | −3.51 |
African American | −0.01 | −0.56 | −0.03 | −0.70 |
Asian | −0.04 | −1.37 | 0.02 | 0.50 |
White | −0.03 | −0.92 | 0.10 | 2.62 |
GI symptoms | 0.09 | 4.05 |
0.12 | 3.83 |
For older children and adolescents, there were again significant contributions from each level of the model [ASD symptoms: 5.3% of variance,
Among the younger children in the sample, the regression model predicting self-injurious behaviors revealed significant unique variance associated with each level of the model, including ASD symptoms alone [4.6%,
Unique contributions of child and family factors to self-injurious symptoms.
ASD symptoms | 0.13 | 4.59 |
0.17 | 4.65 |
Age | 0.04 | 1.52 | −0.04 | −1.20 |
Child sex | 0.00 | 0.00 | 0.06 | 1.82 |
Verbal IQ | 0.03 | 0.66 | 0.09 | 1.42 |
Nonverbal IQ | 0.00 | 0.08 | −0.16 | −2.54 |
Adaptive behavior | −0.18 | −4.75 |
−0.09 | −1.66 |
Household income | −0.12 | −5.20 |
−0.07 | −2.18 |
African American | −0.01 | −0.30 | −0.08 | −2.15 |
Asian | −0.04 | −1.69 | −0.03 | −0.80 |
White | −0.02 | −0.84 | −0.03 | −0.71 |
GI symptoms | 0.11 | 4.62 |
0.04 | 1.39 |
Finally, for the older children and adolescents, the regression model predicting self-injurious behavior revealed a more distinctive set of findings. As before, ASD symptoms and psychosocial factors each accounted for unique variance [ASD: 6.3%,
Our findings underscore the intertwined roles of psychiatric and gastrointestinal symptoms among children and adolescents with ASD. Although individuals with ASD are at elevated risk for both psychiatric and medical comorbidities across the lifespan (
Beyond GI concerns, our analyses also identified a number of other child and family factors that corresponded to increased psychiatric symptoms in this sample. For both internalizing and externalizing symptoms, we found increased psychiatric difficulties when children had more ASD symptoms, higher verbal IQ scores, lower adaptive behavior skills, and lower household income. These findings fit with previous literature linking increased internalizing concerns with stronger cognitive skills (
With regard to the prevalence of GI symptoms among individuals with ASD, our findings suggest marked GI symptoms among approximately one third of children and adolescents in this sample. As discussed earlier, estimates of prevalence span a wide range among published studies on GI function in ASD, likely due to methodological differences between them (
Taken together, our findings have implications for assessment and intervention across disciplines. With regard to mental health providers, our findings indicate a need to assess for GI symptoms even when those are not the presenting complaint, as they may serve to contribute to the behavioral concerns for which a family is seeking services. Although GI symptoms accounted for relatively small proportions of variance in psychiatric symptoms in our analyses, they were nonetheless significantly associated with mental/behavioral health. Moreover, effects of GI symptoms were not limited to a single psychiatric symptom area but rather applied across three different measures. As such, despite the limited variance in some models, appropriate treatment of GI symptoms may be an important part of reducing a broad array of mental health symptomatology in this population, and may be critical in improving quality of life and overall functioning. Such recommendations are bolstered by observations that the presence of significant GI conditions among children with ASD may moderate response to psychopharmacological treatment for behavior problems (
Conversely, with respect to medical providers, our findings suggest that families seeking treatment for GI symptoms may benefit from a comprehensive assessment of possible “downstream” behavioral or psychological effects. Use of brief, standardized, broad-based questionnaire measures such as those included in the analyses presented here [e.g., Child Behavior Checklist; (
As always, conclusions from the current findings should be considered within the context of the sample and measures with which they were observed. By design, the Simons Simplex Collection comprises children and adolescents with ASD with minimal familial, perinatal, or historical risk factors for autism, with the goal of enriching possible
Similarly, given the nature and goals of the SSC sample and procedures, we cannot speak to the generalizability of our findings to a broader population of individuals without ASD, such as those with other neurodevelopmental or psychiatric diagnoses. For instance, individuals with intellectual disabilities may also experience heightened prevalence of psychiatric comorbidities and gastrointestinal concerns when compared to the general population (
With regard to measurement, the measures used in the current study carry both advantages and limitations. Our measures of GI (parent-reported symptoms present after the age of 36 months) and psychiatric symptoms (standardized parent-report questionnaires) rely upon parent report. A medical evaluation based on standard diagnostic criteria (ROME IV; DSM 5) and comprehensive testing (e.g., imaging, GI studies, direct assessment) may determine the etiology of symptoms, and extend our understanding of potential mechanisms underlying the gastroenterology-psychiatry relationship. Our approach also cannot clarify whether the GI concerns assessed are reported by caregivers with equal reliability, as some may be more apparent to parents (e.g., vomiting) while others (e.g., nausea, pain) may yield fewer observable signs and rely more on children's ability to understand and communicate their internal state. In addition, the nature of our GI variable does not include evaluation of the severity and impact on quality of life. Severity, rather than quantity, of GI symptoms may have greater impact on psychiatric well-being, and symptom severity may show stronger associations between measures of GI and psychiatric health. For example, a child with severe abdominal pain may experience greater negative impact, with reduced participation in physical activities and increased school absenteeism, compared to a child with multiple but less severe GI symptoms who may continue in their normative roles. The summary variable in the current study cannot capture the severity of GI concerns, and such questions will be important aspects for future work. Finally, as GI symptoms are aggregated into a composite score, we cannot identify whether and how specific GI concerns have more fine-grained or unique associations with particular psychiatric symptoms.
Despite these considerations, this approach likely mirrors typical clinical situations encountered by medical and mental health providers, in which families present for medical or psychiatric issues and clinicians must rely upon parent report or questionnaire methods to gain information, with limited access to prior diagnostic evaluations and/or referrals to specialty evaluation. It is also promising to note that parents' reports of children's GI symptoms tend to be relatively strong indicators of true GI conditions (
Moving forward, conclusions from our analyses and others [e.g., (
Future research should also explore how comorbidities between ASD, behavioral, and medical (including GI) concerns relate to the biological mechanisms and genetic substrates of ASD. A number of candidate genes in which
Together, findings presented here reinforce the need for conceptualizing ASD as a diagnosis affecting multiple neurobiological systems. With this perspective comes the potential of (1) identifying comprehensive research questions to clarify ASD etiology and mechanism, (2) exploring meaningful subgroups within the larger ASD diagnosis to guide that research, and (3) offering multiple points of intervention through which to support affected individuals and their families. In light of the current findings, ties between psychiatric and gastrointestinal comorbidities may be particularly well-suited for these purposes and will continue to be an important avenue for investigation.
This study was carried out in accordance with the recommendations of the University of Washington Human Subjects Committee with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the University of Washington Human Subjects Committee.
The authors made substantial contributions to the data collection (RB), conception and design (EN, SW, and ST), and analysis (EN). All authors participated in interpretation of the data and manuscript drafting, revising, and approval.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We thank all of the families at the participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, RB, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, E. Hanson, D. Grice, A. Klin, R. Kochel, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, and E. Wijsman). We appreciate obtaining access to phenotypic data on SFARI Base. Approved researchers can obtain the SSC population dataset described in this study (SSC distribution 15, obtained from SFARI Base) by applying at