Differential immune responses and microbiota profiles in children with autism spectrum disorders and co-morbid gastrointestinal symptoms

Destanie R. Rose, Houa Yang, Gloria Serena, Craig Sturgeon, Bing Ma, Milo Careaga, Heather K. Hughes, Kathleen Angkustsiri, Melissa Rose, Irva Hertz-Picciotto, Judith A Van de Water, Robin L Hansen, Jacques Ravel, Alessio Fasano, Paul Ashwood

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

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 (ASDGI), children with ASD but without current or previous GI symptoms (ASDNoGI), typically developing children with GI symptoms (TDGI) and typically developing children without current or previous GI symptoms (TDNoGI). 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 ASDGI group produced increased levels of mucosa-relevant cytokines including IL-5, IL-15 and IL-17 compared to ASDNoGI. The production of the regulatory cytokine TGFβ1 was decreased in the ASDGI group compared with both the ASDNoGI and TDNoGI 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 ASDGI 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.

Original languageEnglish (US)
JournalBrain, Behavior, and Immunity
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Microbiota
Cytokines
Permeability
Autism Spectrum Disorder
Metagenome
Metagenomics
Interleukin-15
Toll-Like Receptor 4
Interleukin-17
Interleukin-5
Habits
Blood Cells
Mucous Membrane

Keywords

  • ASD
  • Autism
  • Cytokines
  • Gastrointestinal
  • Immune
  • Microbiota
  • Mucosal Immunity
  • Zonulin

ASJC Scopus subject areas

  • Immunology
  • Endocrine and Autonomic Systems
  • Behavioral Neuroscience

Cite this

Differential immune responses and microbiota profiles in children with autism spectrum disorders and co-morbid gastrointestinal symptoms. / Rose, Destanie R.; Yang, Houa; Serena, Gloria; Sturgeon, Craig; Ma, Bing; Careaga, Milo; Hughes, Heather K.; Angkustsiri, Kathleen; Rose, Melissa; Hertz-Picciotto, Irva; Van de Water, Judith A; Hansen, Robin L; Ravel, Jacques; Fasano, Alessio; Ashwood, Paul.

In: Brain, Behavior, and Immunity, 01.01.2018.

Research output: Contribution to journalArticle

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abstract = "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 (ASDGI), children with ASD but without current or previous GI symptoms (ASDNoGI), typically developing children with GI symptoms (TDGI) and typically developing children without current or previous GI symptoms (TDNoGI). 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 ASDGI group produced increased levels of mucosa-relevant cytokines including IL-5, IL-15 and IL-17 compared to ASDNoGI. The production of the regulatory cytokine TGFβ1 was decreased in the ASDGI group compared with both the ASDNoGI and TDNoGI 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 ASDGI 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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AU - Rose, Destanie R.

AU - Yang, Houa

AU - Serena, Gloria

AU - Sturgeon, Craig

AU - Ma, Bing

AU - Careaga, Milo

AU - Hughes, Heather K.

AU - Angkustsiri, Kathleen

AU - Rose, Melissa

AU - Hertz-Picciotto, Irva

AU - Van de Water, Judith A

AU - Hansen, Robin L

AU - Ravel, Jacques

AU - Fasano, Alessio

AU - Ashwood, Paul

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AB - 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 (ASDGI), children with ASD but without current or previous GI symptoms (ASDNoGI), typically developing children with GI symptoms (TDGI) and typically developing children without current or previous GI symptoms (TDNoGI). 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 ASDGI group produced increased levels of mucosa-relevant cytokines including IL-5, IL-15 and IL-17 compared to ASDNoGI. The production of the regulatory cytokine TGFβ1 was decreased in the ASDGI group compared with both the ASDNoGI and TDNoGI 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 ASDGI 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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