Brief Report: Whole Blood Serotonin Levels and Gastrointestinal Symptoms in Autism Spectrum Disorder
Open accessAbstract
Elevated whole blood serotonin levels are observed in more than 25% of children with autism spectrum disorder (ASD). Co-occurring gastrointestinal (GI) symptoms are also common in ASD but have not previously been examined in relationship with hyperserotonemia, despite the synthesis of serotonin in the gut. In 82 children and adolescents with ASD, we observed a correlation between a quantitative measure of lower GI symptoms and whole blood serotonin levels. No significant association was seen between functional constipation diagnosis and serotonin levels in the hyperserotonemia range, suggesting that this correlation is not driven by a single subgroup. More specific assessment of gut function, including the microbiome, will be necessary to evaluate the contribution of gut physiology to serotonin levels in ASD.
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Written from the paper’s full text.
TL;DR
In 82 children and adolescents with ASD, whole blood serotonin levels correlated with a quantitative measure of lower GI symptoms but not with functional constipation diagnosis or hyperserotonemia subgroup membership. No significant behavioral or IL-6 associations were found, and the authors call for larger longitudinal studies including non-ASD participants.
Key findings
- 23% of participants had whole blood 5-HT levels two standard deviations above the mean for their race and pubertal status; functional constipation was the most common Rome III diagnosis, occurring in 39% of the sample.
- Functional constipation was present in 10/19 (53%) of the hyperserotonemia subgroup versus 22/57 (39%) of remaining participants (Fisher’s exact p = 0.30), and normalized 5-HT levels did not differ significantly between FC and no GI diagnosis groups (Mean Z = 1.3 ± 1.9 vs. 0.7 ± 1.6, p = 0.14).
- In the Caucasian-only sample controlling for age and sex, log-transformed whole blood 5-HT correlated with QPGS lower GI score at trend level by Pearson’s correlation (r = 0.21, p = 0.066) and marginally by Spearman’s correlation (ρ = 0.23, p = 0.048); item-level Spearman correlations were found for pain around or below the belly button (ρ = 0.36, p = 0.001), resisting bowel movements/“holding in” stool (ρ = 0.30, p = 0.011), and large bowel movements that clogged the toilet (ρ = 0.25, p = 0.030).
- No behavioral measure differed significantly by hyperserotonemia status, though RBS-R compulsive behavior showed a trend-level higher score in the hyperserotonemia subgroup (6.4 ± 6.5 vs. 4.1 ± 4.3, p = 0.07); IL-6 did not differ significantly (1.6 ± 1.5 vs. 1.5 ± 0.9 pg/mL, p = 0.783) and did not correlate with whole blood 5-HT.
Methods
- 120 six- to eighteen-year-olds were recruited through the Autism Speaks Autism Treatment Network and affiliated clinics; 38 were excluded for medications affecting 5-HT, leaving 82 children and adolescents with ASD diagnosed by DSM-IV criteria and verified with the ADOS.
- GI symptoms were assessed with the parent-report Questionnaire on Pediatric Gastrointestinal Symptoms–Rome III (QPGS), with self-report for four higher-functioning individuals >16 years; fasting whole blood 5-HT was measured by HPLC, hyperserotonemia was defined against published control levels corrected for race, age, and sex, and IL-6 was measured by ELISA.
- Analyses used Fisher’s exact tests, one-way ANOVA, log-transformed 5-HT due to skewness, and Pearson’s and Spearman’s correlations in the Caucasian-only population with correction for age and sex.
Limitations
- The paper states that GI diagnoses were based on parent report using the QPGS, which underestimates gastroenterologist-diagnosed constipation; direct stool assessment and microbiota examination would be more valid, and behavioral symptoms were also parent-reported rather than directly observed.
- The paper states that the sample size is too small to detect moderate effect sizes in the hyperserotonemia subgroup, and the cross-sectional design without a treatment component prevents causal inferences about the weak correlation.
- Evident from the text: only six non-verbal children were included, limiting the non-verbal status analysis; the continuous correlation analysis was restricted to Caucasian participants; and the item-level correlations are described as exploratory and needing confirmation in a larger, independent sample.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Cites
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Claims the paper makes
0 of 8 cited sources checked · 0 supported · 0 flagged
- Findingown data
Functional constipation (FC) was the most common Rome III diagnosis, occurring in 39% of the sample.
“Functional constipation (FC) was the most common Rome III diagnosis, occurring in 39 % of the sample.”
Quote in the paperNot a substantial claim - Findingown data
The QPGS lower GI score differentiated the FC and no GI disorder groups.
“As a quantitative measure, the QPGS lower GI score differentiated the FC (27.3 ± 10.0) and no GI disorder groups (8.3 ± 4.9, p < 0.001), but it did not differ in the hyperserotonemia subgroup in comparison to the rest of the participants.”
Quote in the paperNot a substantial claim - Findingown data
Whole blood 5-HT levels correlated with resisting bowel movements/"holding in" stool.
“Exploratory, item-level Spearman’s correlations were identified between whole blood 5-HT levels and pain around or below the belly button (ρ = 0.36, p = 0.001), resisting bowel movements/“holding in” stool (ρ = 0.30, p = 0.011), and large bowel movements that clogged the toilet (ρ = 0.25, p = 0.030).”
Quote in the paperNot a substantial claim - Findingown data
Lower GI symptoms were not significantly higher in the non-verbal subgroup compared to the verbal subgroup.
“Lower GI symptoms were not significantly higher in the non-verbal subgroup (20.3 ± 15.6, n = 6) in comparison to the verbal subgroup (15.7 ± 11.2, p = 0.341).”
Quote in the paperNot a substantial claim - Findingown data
Whole blood 5-HT levels correlated with pain around or below the belly button.
“Exploratory, item-level Spearman’s correlations were identified between whole blood 5-HT levels and pain around or below the belly button (ρ = 0.36, p = 0.001), resisting bowel movements/“holding in” stool (ρ = 0.30, p = 0.011), and large bowel movements that clogged the toilet (ρ = 0.25, p = 0.030).”
Quote in the paperNot a substantial claim
- Findingown data
In 82 children and adolescents with ASD, there is a correlation between a quantitative measure of lower GI symptoms and whole blood serotonin levels.
“In 82 children and adolescents with ASD, we observed a correlation between a quantitative measure of lower GI symptoms and whole blood serotonin levels.”
- Also stated in: § Results · hedged
“When considered as a continuous variable in the Caucasian- only sample, controlling for age and sex, a trend-level Pearson’s correlation (r = 0.21, p = 0.066) and a marginally significant Spearman’s correlation (ρ = 0.23, p = 0.048) were observed between log-transformed whole blood 5-HT levels and the QPGS lower GI score (Fig. 2).”
- Also stated in: § Discussion · plain
“we did identify a correlation between whole blood 5-HT levels and lower GI symptoms.”
Quote in the paperSubstantial claim - Also stated in: § Results · hedged
- Findingown data
Whole blood 5-HT levels did not correlate with behavioral measures.
“The hyperserotonemia group did not differ significantly on any behavioral measure, nor did whole blood 5-HT levels correlate with these measures.”
Quote in the paperSubstantial claim - Findingown data
The QPGS lower GI score did not differ in the hyperserotonemia subgroup in comparison to the rest of the participants.
“As a quantitative measure, the QPGS lower GI score differentiated the FC (27.3 ± 10.0) and no GI disorder groups (8.3 ± 4.9, p < 0.001), but it did not differ in the hyperserotonemia subgroup in comparison to the rest of the participants.”
Quote in the paperNot a substantial claim - Findingreasoning
We did not observe the expected association between FC and minimally verbal status in this population.
“Finally, we did not observe the expected association between FC and minimally verbal status in this population, likely because our population only included six non-verbal children.”
Quote in the paperNot a substantial claim - Findingown data
Normalized whole blood 5-HT levels were not significantly higher in the FC group in comparison to those with no GI diagnosis.
“Approaching the analysis from the opposite perspective, normalized whole blood 5-HT levels were not significantly higher in the FC group (Mean Z = 1.3 ± 1.9) in comparison to those with no GI diagnosis (Mean Z = 0.7 ± 1.6, p = 0.14).”
Quote in the paperNot a substantial claim - Findingown data
The hyperserotonemia group did not differ significantly on any behavioral measure.
“The hyperserotonemia group did not differ significantly on any behavioral measure, nor did whole blood 5-HT levels correlate with these measures.”
Quote in the paperSubstantial claim - Findingown data
Whole blood 5-HT levels correlated with large bowel movements that clogged the toilet.
“Exploratory, item-level Spearman’s correlations were identified between whole blood 5-HT levels and pain around or below the belly button (ρ = 0.36, p = 0.001), resisting bowel movements/“holding in” stool (ρ = 0.30, p = 0.011), and large bowel movements that clogged the toilet (ρ = 0.25, p = 0.030).”
Quote in the paperNot a substantial claim - Findingown data
A trend-level association was seen with RBS-R compulsive behavior, with higher scores in the hyperserotonemia subgroup.
“A trend-level association was seen with RBS-R compulsive behavior, with higher scores in the hyperserotonemia subgroup (6.4 ± 6.5 vs. 4.1 ± 4.3, p = 0.07), without correction for multiple comparisons.”
Quote in the paperNot a substantial claim - Findingcitation
23% of participants had 5-HT levels two standard deviations above the mean for their race and pubertal status.
“Comparing to published norms (McBride et al. 1998), 23 % of the participants had 5-HT levels two standard deviations above the mean for their race and pubertal status.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites McBride et al. 1998 source
Not checked in the free run.
- Findingown data
No significant association was seen between functional constipation diagnosis and serotonin levels in the hyperserotonemia range.
“No significant association was seen between functional constipation diagnosis and serotonin levels in the hyperserotonemia range, suggesting that this correlation is not driven by a single subgroup.”
- Also stated in: § Results · plain
“FC diagnosis was present in 10/19 (53 %) of the hyperserotonemia subgroup and 22/57 (39 %) of the remaining participants, excluding those with other GI diagnoses (Fisher’s exact p = 0.30).”
Quote in the paperSubstantial claim - Also stated in: § Results · plain
- Findingown data
IL-6 levels did not differ significantly in the hyperserotonemia subgroup.
“IL-6 levels did not differ significantly in the hyperserotonemia subgroup (1.6 ± 1.5 vs. 1.5 ± 0.9 pg/mL, p = 0.783), and no significant correlation was observed between IL-6 and whole blood 5-HT levels.”
Quote in the paperNot a substantial claim - Findingown data
No significant correlation was observed between IL-6 and whole blood 5-HT levels.
“IL-6 levels did not differ significantly in the hyperserotonemia subgroup (1.6 ± 1.5 vs. 1.5 ± 0.9 pg/mL, p = 0.783), and no significant correlation was observed between IL-6 and whole blood 5-HT levels.”
Quote in the paperNot a substantial claim - Study design and conductnone given
Our sample size is too small to detect moderate effect sizes in the subgroup of children with hyperserotonemia.
“As an additional concern, our sample size, while larger than most studies of this robust biomarker, is too small to detect moderate effect sizes in the subgroup of children with hyperserotonemia.”
Quote in the paperSubstantial claim - Interpretationown data
We failed to replicate the recent report of a correlation between whole blood 5-HT levels and IL-6 levels.
“We also failed to replicate the recent report of a correlation between whole blood 5-HT levels and IL-6 levels (Yang et al. 2015), with IL-6 similar to other reports (Ashwood et al. 2011; Masi et al. 2015).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Yang et al. 2015 source
Not checked in the free run.
- Interpretationown data
The lack of significant association between hyperserotonemia and FC suggests that there is not a unifying subgroup of children with ASD defined by elevated blood 5-HT levels and constipation.
“The lack of significant association between hyperserotonemia and FC suggests that there is not a unifying subgroup of children with ASD defined by elevated blood 5-HT levels and constipation.”
Quote in the paperSubstantial claim - Interpretationown data
The correlation between lower GI symptoms and whole blood serotonin is not driven by a single subgroup.
“suggesting that this correlation is not driven by a single subgroup.”
Quote in the paperSubstantial claim
- May combine two claims. 11
- Classified as probably not a substantial claim. 2
May combine two claims.
Findingown dataParticipants with FC did not differ from those with no GI diagnosis on demographic characteristics, ASD severity, or IQ.
“Participants with FC did not differ from those with no GI diagnosis on demographic characteristics, ASD severity, or IQ (Table 2).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataParticipants with hyperserotonemia did not differ significantly from the rest of the participants on demographic characteristics, ADOS severity, or IQ.
“Participants with hyperserotonemia did not differ significantly from the rest of the participants on demographic characteristics, ADOS severity, or IQ (Table 1).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe distribution of whole blood 5-HT levels showed significant skewness, with an extended tail toward elevated levels.
“The distribution of whole blood 5-HT levels showed significant skewness, with an extended tail toward elevated levels (Fig. 1).”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationBlood 5-HT is synthesized in the gut, where it plays a critical role in regulating motility and inflammation.
“Blood 5-HT is synthesized in the gut, where it plays a critical role in regulating motility and inflammation (Gershon 2013).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Gershon 2013 source
Not checked in the free run.
May combine two claims.
PremisecitationGastrointestinal (GI) symptoms are more prevalent in children with ASD than in controls, with constipation most commonly reported.
“Gastrointestinal (GI) symptoms are more prevalent in children with ASD than in controls, with constipation most commonly reported (Aldinger et al. 2015; Chaidez et al. 2014; Chandler et al. 2013; Gorrindo et al. 2012; Ibrahim et al. 2009; McElhanon et al. 2014).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationElevated whole blood serotonin (hyperserotonemia) occurs in approximately 30% of children with autism spectrum disorder (ASD), or more than 25%.
“Elevated whole blood serotonin levels are observed in more than 25 % of children with autism spectrum disorder (ASD).”
- Also stated in: § Introduction · plain
“Elevated whole blood serotonin (5-hydroxytryptamine, 5-HT), termed hyperserotonemia, occurs in approximately 30 % of children with autism spectrum disorder (ASD) (Gabriele et al. 2014).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Gabriele et al. 2014 source
Not checked in the free run.
- Also stated in: § Introduction · plain
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenA cross-sectional study without a treatment component does not allow us to make causal inferences regarding the observed, weak correlation.
“Finally, a cross-sectional study without a treatment component does not allow us to make causal inferences regarding the observed, weak correlation.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenBehavioral symptoms were measured using well-validated parent report measures that still fall short of direct observation.
“Behavioral symptoms were similarly measured using well-validated parent report measures that still fall short of direct observation.”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductcitationGI diagnoses were made based on parent report using the QPGS, which a previous study showed is predictive but underestimates constipation diagnosed by a gastroenterologist.
“First, GI diagnoses were made based on parent report using the QPGS, which a previous study showed is predictive but underestimates constipation diagnosed by a gastroenterologist (Gorrindo et al. 2012).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Gorrindo et al. 2012 source
Not checked in the free run.
May combine two claims.
InterpretationreasoningThese findings suggest that whole blood 5-HT levels may relate to GI symptoms, but they do not clarify whether this association is specific to ASD.
“These findings suggest that whole blood 5-HT levels may relate to GI symptoms, but they do not clarify whether this association is specific to ASD.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductown dataWe cannot rule out a weaker relationship between hyperserotonemia and FC since the observed ratio was 1.8, which would require a four-fold larger sample to test.
“We cannot rule out a weaker relationship since the observed ratio was 1.8, which would require a four-fold larger sample to test.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataThese results do not support the hypothesis that constipation leads to hyperserotonemia, or that mechanisms underlying hyperserotonemia cause predictable GI symptoms.
“Further, these results do not support the hypothesis that constipation somehow leads to hyperserotonemia, or, conversely, that the mechanisms underlying hyperserotonemia also cause predictable GI symptoms.”
Quote in the paperSubstantial claim
The paper relies on this without support.
No previous study examined the relationship between GI symptoms and 5-HT in ASD.
“To our knowledge, no previous study examined the relationship between GI symptoms and 5-HT in ASD.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Increased blood serotonin and GABA concentrations were detected in autistic children.
“Increased blood serotonin and GABA concentrations were detected in autistic children [262,263]”
From The Role of Microbiota-Gut-Brain Axis in Neuropsychiatric and Neurological Disorders (2021) · cites this paper as [263]
Administration of Bacteroides fragilis normalized plasma levels of 5-HT in an animal model of ASD.
“Interestingly, administration of Bacteroides fragilis normalized plasma levels of 5′-HT in an animal model of ASD [197,198].”
From Autism, Gastrointestinal Symptoms and Modulation of Gut Microbiota by Nutritional Interventions (2019) · cites this paper as [198]
Higher whole-blood 5-HT levels correlate with constipation in children with ASD.
“In fact, higher whole-blood 5-HT levels have been shown to correlate with constipation in children with ASD [39].”
From Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders (2018) · cites this paper as [39]
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- Authors
- Marler, S., Ferguson, B. J., Lee, E. B., Peters, B., Williams, K. C., McDonnell, E., Macklin, E. A., Levitt, P., Gillespie, C. H., Anderson, G. M., Margolis, K. G., Beversdorf, D. Q., & Veenstra-VanderWeele, J.
- Affiliations
- Vanderbilt University (US)
- University of Missouri (US)
- Nationwide Children's Hospital (US)
- Massachusetts General Hospital (US)
- University of Southern California (US)
- Yale University (US)
- Columbia University Irving Medical Center (US)
- NewYork–Presbyterian Hospital (US)
- Corresponding author
- Veenstra-VanderWeele, Jeremy
- ORCID
- Venue
- Journal of Autism and Developmental Disorders
- Published
- 2015-11-02
- Volume
- 46
- Issue
- 3
- Pages
- 1124-1130
- ISSN
- 0162-3257 (ISSN-L)
- 1573-3432
- PMC
- PMC4852703
- OpenAlex
- W1917634040
- Semantic Scholar
- 5a8adc6a55d749c29297a1f6e88485cc15241599
- Cited by
- 95
- References
- 24
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 7 · 2023: 10 · 2022: 11 · 2021: 12 · 2020: 9 · 2019: 13 · 2018: 6 · 2017: 6 · 2016: 4 · 2015: 1
- FWCI
- 3.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Autism and Developmental Disorders (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Health Resources and Services Administration (UA3MC11054)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Health Sciences › Medicine › Psychiatry and Mental health › Child Nutrition and Feeding Issues
- Keywords
- autism spectrum disorder, whole blood serotonin, hyperserotonemia, gastrointestinal symptoms, constipation, gut-brain axis, gut microbiota, children and adolescents
- MeSH terms
- Autism Spectrum Disorder, Adolescent, Child, Constipation, Female, Gastrointestinal Diseases, Humans, Male, Surveys and Questionnaires, Serotonin, Biomarkers
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