title: Blood-brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders.
abstract: 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.
  
  
  
  Postmortemcerebral 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, andMMP-9were higher in the ASD cortex.IL-8,tPA, andIBA-1were downregulated in SCZ cortex;IL-1bwas 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.
authors.affiliation: Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children, Boston, MA USA ; Department of Pediatrics, Harvard Medical School, Boston, MA USA.
authors.forename: Maria
authors.identifier: 0000-0001-5318-7313
authors.initials: M
authors.lastname: Fiorentino
authors.affiliation: Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children, Boston, MA USA ; Department of Medicine, Celiac Center, Division of Gastroenterology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Sapone
authors.affiliation: Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children, Boston, MA USA ; Department of Pediatrics, Harvard Medical School, Boston, MA USA.
authors.forename: Stefania
authors.initials: S
authors.lastname: Senger
authors.affiliation: Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children, Boston, MA USA ; Center for Celiac Research and Division of Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital for Children, Boston, MA USA.
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Camhi
authors.affiliation: Department of Pediatrics, Harvard Medical School, Boston, MA USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Kadzielski
authors.affiliation: Department of Pediatrics, Harvard Medical School, Boston, MA USA.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Buie
authors.affiliation: Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD USA.
authors.forename: Deanna L
authors.initials: DL
authors.lastname: Kelly
authors.affiliation: Neuropsychiatry Program, Sheppard Pratt Health System, Baltimore, MD USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Cascella
authors.affiliation: Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children, Boston, MA USA ; Center for Celiac Research and Division of Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital for Children, Boston, MA USA ; Department of Pediatrics, Harvard Medical School, Boston, MA USA.
authors.forename: Alessio
authors.initials: A
authors.lastname: Fasano
mesh_terms: D000293:Adolescent; D000328:Adult; D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001706:Biopsy; D001812:Blood-Brain Barrier / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002135:Calcium-Binding Proteins; D016022:Case-Control Studies; D002531:Cerebellum / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002540:Cerebral Cortex / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D062465:Claudin-3 / Q000235:genetics / Q000276:immunology; D062507:Claudin-5 / Q000235:genetics / Q000276:immunology; D057167:Claudins / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D004386:Duodenum / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology; D062794:MARVEL Domain Containing 2 Protein / Q000235:genetics / Q000276:immunology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000276:immunology; D008840:Microfilament Proteins; D008875:Middle Aged; D010539:Permeability; D012559:Schizophrenia / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019108:Tight Junctions / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: C112986:AIF1 protein, human; C522352:CLDN12 protein, human; C568122:CLDN3 protein, human; C107466:CLDN5 protein, human; D002135:Calcium-Binding Proteins; D062465:Claudin-3; D062507:Claudin-5; D057167:Claudins; D004268:DNA-Binding Proteins; C508585:IL1B protein, human; D053583:Interleukin-1beta; D016209:Interleukin-8; D062794:MARVEL Domain Containing 2 Protein; C516798:MARVELD2 protein, human; D008840:Microfilament Proteins; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: Autism spectrum disorders; Blood–brain barrier; Duodenal biopsies; Gut permeability; Gut–brain axis; Neuroinflammation; Postmortem brain; Schizophrenia