The valproic acid rat model of autism present with gut bacterial dysbiosis similar to that in human autism

Authors: LIU, FANG - Ocean University Of China; HORTON-SPARKS, KAYLA - University Of California, Davis; HULL, VANESSA - University Of California, Davis; Li, Robert; MARTINEZ-CERDENO, VERONICA - University Of California, Davis

Submitted to: Molecular Autism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/26/2018
Publication Date: 12/10/2018
Citation: Liu, F., Horton-Sparks, K., Hull, V., Li, R.W., Martinez-Cerdeno, V. 2018. The valproic acid rat model of autism present with gut bacterial dysbiosis similar to that in human autism. Molecular Autism. 9:61. https://doi.org/10.1186/s13229-018-0251-3.
DOI: https://doi.org/10.1186/s13229-018-0251-3

Interpretive Summary: Parasite-related products, such as parasite eggs and excretory/secretory proteins, represent an innovative and promising strategy for treating autoimmune diseases and other conditions. For example, the whipworm Trichuris suis ova have been shown to have a beneficial effect on autoimmune inflammatory bowel disease and multiple sclerosis. Recently, several clinical trials have been set up to investigate their therapeutic potential in treating HIV infection and autism. Moreover, gut microbes play an important role in determining the therapeutic outcome. To understand molecular mechanisms of parasite-derived immune modulators in affecting disease progression as well as their safety and efficacy, a fully characterized animal disease model is essential. In this study, we characterized the gut microbiome of a rat autism model induced by a prenatal injection of valproic acid (VPA) using high-throughput sequencing and bioinformatics tools. We found that VPA administration during pregnancy reduced microbial diversity of the offspring and altered the composition and the metabolite potential of the gut microbial community, similar to that in the gut of humans with autism symptoms, in addition to behavioral and anatomical mimicking in the brain of patients with autism. We also provided further evidence of gender-specific alterations of gut microbiome by prenatal VPA administration in rodents. Together, our findings shall facilitate the development of unconventional and effective approaches, such as helminth therapy and probiotics, to treat autism spectrum disorder.

Technical Abstract: Background: Gut microbiome has the capacity to impact the regular function of the brain, which can in turn affect the gut microbial composition. Autism spectrum disorder (ASD) patients suffer from gastrointestinal problems and experience changes in the gut microbiome, however it is not yet clear whether the change in the microbiome associated to ASD and other disease states are a cause or a consequence of the disease. Methods: We have investigated the species richness and microbial composition in 400-E12 valproic acid (VPA) rat model for autism. Fecal samples from the rectum were collected at necropsy, microbial total DNA was extracted, 16 rRNA gene sequenced, and the global microbial co-occurrence network was constructed using a Random-Matrix theory-based pipeline. Collected data was compared to available data in autism human gut. Results: We found that VPA administration during pregnancy reduced fecal microbial richness, changed the gut microbial composition, and altered the metabolite potential of the fecal microbial community, in a pattern similar to that in the autism human gut. However, the global network property and network composition as well as microbial co-occurrence patterns were largely preserved in the offspring of rats exposed to prenatal administration of VPA. Conclusions: Our data on the gut microbiome of the 400-E12 rat indicate that this model, in addition to behavioral and anatomical mimicking the autism human brain as previously shown, also mimics the microbiome nature of autism, making it one of the best suited rodent models for the study of ASD.