Blood–brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders

Abstract

BackgroundAutism 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.Methods 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.ResultsClaudin (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.ConclusionsIn 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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“…These two alterations are often described in literature to be co-occurring with ASD [82][83][84]. However, abnormally high concentrations of opioid peptides in either plasma or the nervous system of patients with ASD have not consistently been found [81].…”

“…Under physiological conditions, opioid peptides, including β-CM7, are produced in the gut by the lytic activity of peptidases and part of these opioid peptides can cross, after which they enter the bloodstream [81,82]. Tight junctions in the BBB stop the majority of opioid peptides to enter the CNS [83,84]. The opioid excess theory hypothesizes that in ASD patients there are multiple alterations that interfere with the formation of opioid peptides and their passing through membranes.…”

“…In addition, the peptidase enzyme activity can either be decreased due to a defective functioning or a shortage of peptidases. In both cases less opioid peptides are broken down, resulting in elevated levels in the gut, blood and brain [82][83][84].…”

“…In addition, the peptidase enzyme activity can either be decreased due to a defective functioning or a shortage of peptidases. In both cases less opioid peptides are broken down, resulting in elevated levels in the gut, blood and brain [82][83][84].Excessive amounts of opioid peptides passing the BBB might influence brain development and functioning by directly binding to opioid receptors. Additionally, these large amounts of opioid peptides saturate peptidase enzymes and not all peptides will be hydrolyzed, pass the BBB, and bind to opioid receptors in the brain [80].…”

The Gut Microbiota - The Environmental Causative Factor and the Potential Therapeutic Targets of Autism Spectrum Disorder

“…The gut microbiota can also act through SCFAs to promote the enteric 5-HT production and homeostasis [20]. In addition, recent publication reported specific finding in ASD that altered blood-brain barrier integrity could be couple with increased neuroinflammation which possibly impaired gut barrier integrity [21]. More research will be performed to elucidate the specific mechanisms of how gut microbiota imbalances lead to ASD and to provide potential therapeutic targets to ASD.…”