Sara Mcbride

Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders

Neurodevelopmental disorders, including autism spectrum disorder (ASD), are defined by core behavioral impairments; however, subsets of individuals display a spectrum of gastrointestinal (GI) abnormalities. We demonstrate GI barrier defects and microbiota alterations in the maternal immune activation (MIA) mouse model that is known to display features of ASD. Oral treatment of MIA offspring with the human commensal Bacteroides fragilis corrects gut permeability, alters microbial composition, and ameliorates defects in communicative, stereotypic, anxiety-like and sensorimotor behaviors. MIA offspring display an altered serum metabolomic profile, and B. fragilis modulates levels of several metabolites. Treating naive mice with a metabolite that is increased by MIA and restored by B. fragilis causes certain behavioral abnormalities, suggesting that gut bacterial effects on the host metabolome impact behavior. Taken together, these findings support a gut-microbiome-brain connection in a mouse model of ASD and identify a potential probiotic therapy for GI and particular behavioral symptoms in human neurodevelopmental disorders.

Modeling an autism risk factor in mice leads to permanent immune dysregulation

Increasing evidence highlights a role for the immune system in the pathogenesis of autism spectrum disorder (ASD), as immune dysregulation is observed in the brain, periphery, and gastrointestinal tract of ASD individuals. Furthermore, maternal infection (maternal immune activation, MIA) is a risk factor for ASD. Modeling this risk factor in mice yields offspring with the cardinal behavioral and neuropathological symptoms of human ASD. In this study, we find that offspring of immune-activated mothers display altered immune profiles and function, characterized by a systemic deficit in CD4+ TCRβ+ Foxp3+ CD25+ T regulatory cells, increased IL-6 and IL-17 production by CD4+ T cells, and elevated levels of peripheral Gr-1+ cells. In addition, hematopoietic stem cells from MIA offspring exhibit altered myeloid lineage potential and differentiation. Interestingly, repopulating irradiated control mice with bone marrow derived from MIA offspring does not confer MIA-related immunological deficits, implicating the peripheral environmental context in long-term programming of immune dysfunction. Furthermore, behaviorally abnormal MIA offspring that have been irradiated and transplanted with immunologically normal bone marrow from either MIA or control offspring no longer exhibit deficits in stereotyped/repetitive and anxiety-like behaviors, suggesting that immune abnormalities in MIA offspring can contribute to ASD-related behaviors. These studies support a link between cellular immune dysregulation and ASD-related behavioral deficits in a mouse model of an autism risk factor.

119. Modeling an autism risk factor in mice leads to permanent changes in the immune system

Increasing evidence suggests a role for the immune system in autism spectrum disorders (ASD) pathogenesis. Studies have reported immune dysregulation in the brain, periphery and gastrointestinal tract in ASD. Furthermore, maternal infection (immune activation, MIA) is a risk factor for ASD. Modelling this risk factor in mice yields offspring with the cardinal behavioral and neuropathological symptoms of human ASD. In this study, we ask if MIA offspring also exhibit abnormal neural, peripheral or enteric immunity. We find that these offspring display altered immune profiles and function. In addition, hematopoietic stem cells (HSCs) from MIA offspring exhibit altered lineage potential and differentiation. To examine whether immune dysfunction contributes to ASD pathogenesis, we behaviorally assess MIA offspring that have been repopulated with naive bone marrow. To explore the potential for prenatal programming of long-term immune dysfunction, we examine whether transferring HSCs from MIA offspring into naive mice can induce cell-autonomous immune abnormalities.