| Summary: | Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by deficits in social interaction and communication, and repetitive behaviors. In addition, co-morbidities such as gastro-intestinal problems have frequently been reported. Mutations and deletion of proteins of the SH3 and multiple ankyrin repeat domains (<i>SHANK</i>) gene-family were identified in patients with ASD, and <i>Shank</i> knock-out mouse models display autism-like phenotypes. SHANK3 proteins are not only expressed in the central nervous system (CNS). Here, we show expression in gastrointestinal (GI) epithelium and report a significantly different GI morphology in <i>Shank3</i> knock-out (KO) mice. Further, we detected a significantly altered microbiota composition measured in feces of <i>Shank3</i> KO mice that may contribute to inflammatory responses affecting brain development. In line with this, we found higher <i>E. coli</i> lipopolysaccharide levels in liver samples of <i>Shank3</i> KO mice, and detected an increase in Interleukin-6 and activated astrocytes in <i>Shank3</i> KO mice. We conclude that apart from its well-known role in the CNS, SHANK3 plays a specific role in the GI tract that may contribute to the ASD phenotype by extracerebral mechanisms.
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