Differential immune responses and microbiota profiles in children with autism spectrum disorders and co-morbid gastrointestinal symptoms
Open accessAbstract
Objectives Many studies have reported the increased presence of gastrointestinal (GI) symptoms in children with autism spectrum disorders (ASD). Altered microbiome profiles, pro-inflammatory responses and impaired intestinal permeability have been observed in children with ASD and co-morbid GI symptoms, yet few studies have compared these findings to ASD children without GI issues or similarly aged typical developing children. The aim of this study was to determine whether there are biological signatures in terms of immune dysfunction and microbiota composition in children with ASD with GI symptoms.Methods Children were enrolled in one of four groups: ASD and GI symptoms of irregular bowel habits (ASD GI), children with ASD but without current or previous GI symptoms (ASD NoGI), typically developing children with GI symptoms (TD GI) and typically developing children without current or previous GI symptoms (TD NoGI). Peripheral blood mononuclear cells (PBMC) were isolated from the blood, stimulated and assessed for cytokine production, while stool samples were analyzed for microbial composition.Results Following Toll-Like receptor (TLR)-4 stimulation, the ASD GI group produced increased levels of mucosa-relevant cytokines including IL-5, IL-15 and IL-17 compared to ASD NoGI. The production of the regulatory cytokine TGFβ1 was decreased in the ASD GI group compared with both the ASD NoGI and TD NoGI groups. Analysis of the microbiome at the family level revealed differences in microbiome composition between ASD and TD children with GI symptoms; furthermore, a predictive metagenome functional content analysis revealed that pathways were differentially represented between ASD and TD subjects, independently of the presence of GI symptoms. The ASD GI also showed an over-representation of the gene encoding zonulin, a molecule regulating gut permeability, compared to the other groups.Conclusions Overall our findings suggest that children with ASD who experience GI symptoms have an imbalance in their immune response, possibly influenced by or influencing metagenomic changes, and may have a propensity to impaired gut barrier function which may contribute to their symptoms and clinical outcome.
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The balance of inflammatory cytokines was skewed in children with ASD and GI dysfunction when compared with regulatory cytokines such as TGF beta 1.
“Notably, the balance of inflammatory cytokines was skewed in children with ASD and GI dysfunction when compared with regulatory cytokines such as transforming growth factor (TGF) beta 1 [57].”
From The Gut Microbiota and Dysbiosis in Autism Spectrum Disorders (2018) · cites this paper as [57]
The gut microbiome likely alters brain functions through various mechanisms including environmental factors, host genetics, host immune response regulation, excretion of metabolites, regulation of neurotransmitters, or neuroactive compounds.
“the gut microbiome likely alters brain functions through various other mechanisms, including environmental factors (e.g. in utero exposure to infection, maternal conditions, and medications), host genetics, host immune response regulation [12, 57, 58], excretion of metabolites such as tyrosine analogues, p-cresol, 4-ethylphenylsulfate, indoles, lipopolysaccharides and free amino acids [59-62],”
From Gut microbiota changes in children with autism spectrum disorder: a systematic review (2020) · cites this paper as [12]
Alterations of host immune responses by gut microbiota are closely linked to ASD-related symptoms.
“Alterations of the host immune responses by gut microbiota are closely linked to ASD-related symptoms.”
From Gut microbiota changes in children with autism spectrum disorder: a systematic review (2020) · cites this paper as [12]
Implicated cytokine pathways include IL-5, IL-15, IL-17, IL-17a, IL-10, IL-1b, TNF-α, TGF-β1 and IFNγ.
“The implicated cytokine pathways include, and not limited to, IL-5, IL-15, IL-17, IL-17a, IL-10, IL-1b, TNF-α, TGF-β1 and IFNγ [12, 18, 65, 66].”
From Gut microbiota changes in children with autism spectrum disorder: a systematic review (2020) · cites this paper as [12]
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- Authors
- Rose, D. R., Yang, H., Serena, G., Sturgeon, C., Ma, B., Careaga, M., Hughes, H. K., Angkustsiri, K., Rose, M., Hertz-Picciotto, I., Van de Water, J., Hansen, R. L., Ravel, J., Fasano, A., & Ashwood, P.
- Affiliations
- University of California, Davis (US)
- University of Maryland, Baltimore (US)
- Massachusetts General Hospital (US)
- Corresponding author
- Ashwood, Paul
- ORCID
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2018-05
- Volume
- 70
- Pages
- 354-368
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC5953830
- OpenAlex
- W2793162366
- Cited by
- 227
- References
- 133
- Citations by year
- 2026: 21 · 2025: 31 · 2024: 20 · 2023: 21 · 2022: 40 · 2021: 26 · 2020: 31 · 2019: 26 · 2018: 11
- FWCI
- 8.36
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- University of California
- Autism Speaks
- NIH
- Johnson Foundation
- Emch Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- autism spectrum disorder, gastrointestinal symptoms, gut microbiota, immune dysfunction, cytokine production, TLR4, zonulin, intestinal permeability, intestinal barrier, TGF-β1, IL-17, children
- MeSH terms
- Autism Spectrum Disorder, Gastrointestinal Microbiome, Child, Child Development, Child, Preschool, Female, Gastrointestinal Diseases, Humans, Leukocytes, Mononuclear, Male, Monocytes, Comorbidity, Cytokines, Microbiota
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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