Supplementation of Clostridiales affects microbial profile and induces sex- specific social behavior deficits in mice following prenatal immune insult

Background: Autism spectrum disorder (ASD) is a heritable and complex neurodevelopmental disorder with both genetic and environmental risk factors, with a male:female diagnosis ratio of 3:1. ASD can be modeled in rodents using Maternal Immune Activation (MIA). In this model, pregnant mice undergo an immune challenge that leads to ASD-relevant phenotypes in their offspring. Previous work in male mice has shown that the microbiota of the gastrointestinal tract drives the development of abnormal behavior in the MIA model. In this study, we tested whether modulating the microbial composition of the MIA mice could induce behavioral deficits and if these deficits were sex specific. To modulate the microbial community, we supplemented MIA offspring with oral Clostridium celatum, a gut commensal bacterium found to be enriched in autistic children. We then compared behavioral phenotypes and the microbial structure of the mice that received the bacteria to those which did not. Results: We found that exposure to Clostridium resulted in sex-specific social preference impairment, affecting only male MIA mice. 16S rRNA gene amplicon analysis of the duodenum and colon microbiota showed that the MIA model as well as C. celatum addition altered the gut microbiota in a sex-specific manner, and that specific taxa were associated with social behavior outcomes. Conclusions: These data reveal that sex-specific disruptions of the gut microbiota may play a role in social behavior and the efficacy of the MIA model of ASD, and further support the important of female inclusion in autism and gut microbiota research.