Blood–brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders
Open accessAbstract
Autism spectrum disorders (ASD) are complex conditions whose pathogenesis may be attributed to gene–environment interactions. There are no definitive mechanisms explaining how environmental triggers can lead to ASD although the involvement of inflammation and immunity has been suggested. Inappropriate antigen trafficking through an impaired intestinal barrier, followed by passage of these antigens or immune-activated complexes through a permissive blood–brain barrier (BBB), can be part of the chain of events leading to these disorders. Our goal was to investigate whether an altered BBB and gut permeability is part of the pathophysiology of ASD. Postmortem cerebral cortex and cerebellum tissues from ASD, schizophrenia (SCZ), and healthy subjects (HC) and duodenal biopsies from ASD and HC were analyzed for gene and protein expression profiles. Tight junctions and other key molecules associated with the neurovascular unit integrity and function and neuroinflammation were investigated. Claudin (CLDN)-5 and -12 were increased in the ASD cortex and cerebellum. CLDN-3, tricellulin, and MMP-9 were higher in the ASD cortex. IL-8, tPA, and IBA-1 were downregulated in SCZ cortex; IL-1b was increased in the SCZ cerebellum. Differences between SCZ and ASD were observed for most of the genes analyzed in both brain areas. CLDN-5 protein was increased in ASD cortex and cerebellum, while CLDN-12 appeared reduced in both ASD and SCZ cortexes. In the intestine, 75% of the ASD samples analyzed had reduced expression of barrier-forming TJ components (CLDN-1, OCLN, TRIC), whereas 66% had increased pore-forming CLDNs (CLDN-2, -10, -15) compared to controls. In the ASD brain, there is an altered expression of genes associated with BBB integrity coupled with increased neuroinflammation and possibly impaired gut barrier integrity. While these findings seem to be specific for ASD, the possibility of more distinct SCZ subgroups should be explored with additional studies.
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In impaired BBB, LPS or SCFAs may cause brain inflammation and facilitate access to the brain for harmful substances like heavy metals.
“In the case of impaired BBB, which can be observed in certain (but not all) autistic subjects [37,254], LPS or SCFAs may cause brain inflammation and thus, further facilitate access to the brain for harmful substances, like heavy metals, that can accumulate there [228,246,255].”
From The Role of Microbiota-Gut-Brain Axis in Neuropsychiatric and Neurological Disorders (2021) · cites this paper as [37]
Evidence for increased intestinal permeability has been reported in postmortem analysis of ASD individuals.
“Evidence for increased intestinal permeability has been reported in postmortem analysis of ASD individuals [111].”
From Role of diet and its effects on the gut microbiome in the pathophysiology of mental disorders (2022) · cites this paper as [111]
ASD has been associated with impaired intestinal barrier function.
“Along with altered bowel habits, ASD has been associated with impaired intestinal barrier function (D'Eufemia et al., 1996; de Magistris et al., 2010; Fiorentino et al., 2016).”
From Microbiota-related Changes in Bile Acid & Tryptophan Metabolism are Associated with Gastrointestinal Dysfunction in a Mouse Model of Autism (2017) · cites this paper as Fiorentino et al., 2016
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The Role of Microbiota-Gut-Brain Axis in Neuropsychiatric and Neurological Disorders
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The Gut Microbiota and Autism Spectrum Disorders
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Intestinal Microbiota Influences Non-intestinal Related Autoimmune Diseases
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Immune Dysregulation in Autism Spectrum Disorder: What Do We Know about It?
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- Authors
- Fiorentino, M., Sapone, A., Senger, S., Camhi, S. S., Kadzielski, S. M., Buie, T. M., Kelly, D. L., Cascella, N., & Fasano, A.
- Affiliations
- Harvard University (US)
- Beth Israel Deaconess Medical Center (US)
- Massachusetts General Hospital (US)
- University of Maryland, Baltimore (US)
- Sheppard Pratt Health System (US)
- Corresponding author
- Fiorentino, Maria
- ORCID
- Venue
- Molecular Autism
- Published
- 2016-11-29
- Volume
- 7
- Issue
- 1
- Pages
- 49-49
- ISSN
- 2040-2392 (ISSN-L)
- PMC
- PMC5129651
- OpenAlex
- W2559475643
- Cited by
- 494
- References
- 124
- Citations by year
- 2026: 40 · 2025: 52 · 2024: 63 · 2023: 66 · 2022: 64 · 2021: 71 · 2020: 56 · 2019: 33 · 2018: 34 · 2017: 15
- FWCI
- 14.97
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Molecular Autism (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Health Sciences › Medicine › Psychiatry and Mental health › Child Nutrition and Feeding Issues
- Keywords
- autism spectrum disorder, blood-brain barrier, intestinal epithelial barrier, intestinal permeability, tight junctions, claudins, neuroinflammation, schizophrenia, gene-environment interaction, antigen trafficking, postmortem brain, duodenal biopsy, tricellulin, MMP-9, interleukin-8, IL-1β, Iba1, neurovascular unit
- MeSH terms
- Autism Spectrum Disorder, Adolescent, Adult, Biopsy, Blood-Brain Barrier, Calcium-Binding Proteins, Cerebellum, Cerebral Cortex, Child, Child, Preschool, DNA-Binding Proteins, Duodenum, Female, Humans, Male, Microfilament Proteins, Middle Aged, Permeability, Schizophrenia, Gene Expression, Case-Control Studies, Interleukin-8, Tight Junctions, Matrix Metalloproteinase 9, Interleukin-1beta, Claudins, Claudin-3, Claudin-5, MARVEL Domain Containing 2 Protein
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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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