Dysregulated Microbiome in People and Mice with Autism-Associated Genetic Mutations

Friday, May 12, 2017: 12:00 PM-1:40 PM
Golden Gate Ballroom (Marriott Marquis Hotel)
L. Tabouy1, O. Ziv1, O. Koren1 and E. Elliott2, (1)Bar Ilan University, Safed, Israel, (2)Bar Ilan University, safed, Israel
Background:  The gut microbiome may influence brain development and behavior, mainly through the modulation of physiological metabolism and the immune system. Recent studies have highlighted a possible role for microbiome dysregulation in the development of autism spectrum disorders. However, according to current data, over half of the risk of autism is due to genetics. Therefore, knowledge of the interaction between the genetic disposition to autism and the microbiome is necessary to understand the exact role of microbiome in autism development.

Objectives: Our main objectives are to determine the dysregulation of the microbiome in people with the autism associated chromosome 16p11.2 deletion, as well as microbiome dysregulation in the chromosome 16 deletion mouse model. A second objective was to determine the dysregulation of microbiome in the Shank3 mouse model and to correlate microbiome dysregulation to immune dysregulation.

Methods: Using 16S high-throughput sequencing of stool samples, we have determined the gut microbiome community of 26 individuals with the chromosome 16p11.2 deletion, and their non-affected siblings. Real Time PCR is used to verify dysregulation of specific bacterial species in the people, and to study their dysregulation in the mouse model. 16S high-througput sequencing was also performed on stool samples from Shank3 knockout mice. The immune system profile of the mice was performed to determine the correlation between microbiome dysregulation and immune dysregulation.

Results:  We have identified specific bacteria which are increased in individuals with the chromosome 16p11.2 deletion. In addition, we have found that some of these species are also dysregulated in the chromosome 16p11.2 deletion mouse model, further suggesting that genetic changes directly lead to microbiome dysregulation. In the case of the shank3 mice model, we verified the dysregulation of several bacterial genus and species by real-time PCR. Some of these species overlapped with those found in the individuals with chromosome 16p11.2 deletion. Of particular interest, we found that a few specific species within the bacterial genus lactobacillus, which has previously been implicated in social behavior, is dysregulated in all of our experimental groups (people with chromosome 16p11.2 deletion and both mouse models included in this study) In addition, we identified a correlation between levels of specific bacterial species and dysregulation of blood cytokine levels, as well as neurotransmitter receptor levels in the brain.

Conclusions:  These studies determine that genetic differences associated with autism can induce changes in the microbiota profile. While most work has focused on the role of the microbiome in environmental factor-induced susceptibility to autism, this study highlights the role of genetics in establishing the microbiome. These studies will further help us understand the role of the microbiome in autism and if probiotics may helpful in a subset of affected individuals.

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See more of: Miscellaneous