Crosstalk Between the Microbiome and Gestational Immunity in Autism-Related Disorders

Abstract

The etiologies of most neurodevelopmental disorders, including autism spectrum disorder (ASD), remain incompletely understood. However, recent epidemiological and experimental data suggest that dysregulated maternal immune activation (MIA) can impede normal brain maturation and promote the development of autism-related phenotypes. Indeed, our studies and work by others demonstrate that offspring born to pregnant animals that were exposed to immune activators develop many of the defining behavioral features of ASD, including abnormalities in social preference, communicative impairments, and repetitive/stereotyped behaviors. Although mounting evidence implicates key roles for hyperactive gestational inflammatory responses in neurodevelopmental disorders, the specific immune pathways that provoke autism-related phenotypes remain poorly described. The microbiome is recognized as a key modulator of immune responses, and emerging studies suggest that microbiota composition is a pivotal regulator of central nervous system function and disease. There has been growing speculation that changes in human microflora diversity contribute at some level to the recent rise in autism incidence. This has largely stemmed from reports of dysbiosis and gastrointestinal inflammation in autistic individuals. Given these clinical findings and the well-described role of the microbiome in calibrating the immune system, our group and others have recently become interested in investigating how changes in microbiota landscape influence neurodevelopmental disorder pathogenesis. In this review, we highlight emerging data describing roles for microbiota in the development of autism-related behavioral abnormalities. These recent findings identify the immune system as a link between gut microbiota and the brain in neurodevelopmental disorders, and suggest that targeting the microbiome and maternal immune responses during gestation may offer strategies to limit autism development in at-risk pregnancies.

Keywords: IL-17a; autism; dysbiosis; maternal immune activation; microbiota; neurodevelopmental disorders.

FIG. 1.

Dysregulated maternal immune responses can lead to impaired neurodevelopment and autism-related disorders. Immune-mediated inflammation in pregnant mothers can promote the acquisition of autistic-like behaviors in offspring. Autism-provoking inflammation in the pregnant mother can result from infection, autoimmune disease, obesity-induced inflammation, and disruptions in microbiome homeostasis (dysbiosis). The release of inflammatory mediators by the maternal immune system perturbs proper neurodevelopment and promotes the development of autistic-like behaviors.

FIG. 2.

Microbiota-mediated calibration of maternal IL-17a responses affects neurodevelopmental disorder susceptibility in the MIA model of autism. (A) Pregnant animals that harbor segmented filamentous bacteria (SFB) or other commensals capable of promoting robust IL-17a responses produce higher levels of IL-17a in response to MIA induction with the viral analog PolyI:C, and offspring from these mothers develop autism-related behavioral abnormalities. Previous studies have shown that IL-6 is critical in this process and contributes to the activation of IL-17a-secreting immune cells. (B) In contrast, MIA offspring from mothers possessing microflora communities that are poor inducers of systemic IL-17a responses do not exhibit abnormalities in autism-related behaviors or cortical development. MIA, maternal immune activation; PolyI:C, polyinosinic-polycytidylic acid; IL, interleukin.