Cognitive and autism-like abnormalities are associated with gut microbiome alterations in a mouse model of Neurofibromatosis type I
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Neurofibromatosis type 1 (NF1) is a common genetic condition presenting with variable symptomatology, however most individuals will demonstrate cognitive and behavioural difficulties including autism. Currently, it is unknown whether individuals with NF1 present with alterations in their gut microbiota, despite accumulating evidence for a role of gut microbiota in the pathophysiology of many brain disorders. Using a heterozygous germline knockout mouse model of NF1 (Nf1 +/-), we performed an in-depth behavioural evaluation encompassing all relevant domains: learning and memory, stereotypy, social interaction, anxiety- and depression-like behaviour. Anatomical and functional studies of the brain and gastrointestinal tract were also performed, followed by the first investigation of gut microbiota composition (via full-length 16S rRNA sequencing) in a Nf1 +/- mouse model. Our findings indicate that the cognitive and autism-like behavioural phenotype seen in Nf1 +/- mice is accompanied by a striking increase in relative brain size which is highly relevant to clinical NF1. Furthermore, brain size was correlated with behaviour, supporting a potential mechanistic link. Nf1 +/- mice showed significant alterations in gut microbiota composition, with males additionally showing significant changes to species abundance of the Clostridium and Blautia genera, and the Lachnospiraceae family, findings which partially overlap with those in preclinical and clinical autism. These findings significantly expand our understanding of brain and behavioural abnormalities in this preclinical model of NF1 and, importantly, have uncovered gut microbiota as a highly promising new area of research and a novel therapeutic target for cognitive and behavioural symptom clusters.
