biostudies-literatureBuffington SANIDDK NIH HHSNIEHS NIH HHSNIAID NIH HHSNHLBI NIH HHSNIMH NIH HHSNIHNIGMS NIH HHS1740-1756.e16https://www.ebi.ac.uk/biostudies/studies/S-EPMC8996745biostudies-literatureUnknown184(7)The core symptoms of many neurological disorders have traditionally been thought to be caused by genetic variants affecting brain development and function. However, the gut microbiome, another important source of variation, can also influence specific behaviors. Thus, it is critical to unravel the contributions of host genetic variation, the microbiome, and their interactions to complex behaviors. Unexpectedly, we discovered that different maladaptive behaviors are interdependently regulated by the microbiome and host genes in the Cntnap2^-/- model for neurodevelopmental disorders. The hyperactivity phenotype of Cntnap2^-/- mice is caused by host genetics, whereas the social-behavior phenotype is mediated by the gut microbiome. Interestingly, specific microbial intervention selectively rescued the social deficits in Cntnap2^-/- mice through upregulation of metabolites in the tetrahydrobiopterin synthesis pathway. Our findings that behavioral abnormalities could have distinct origins (host genetic versus microbial) may change the way we think about neurological disorders and how to treat them.CellDissecting the contribution of host genetics and the microbiome in complex behaviors.PMC8996745R01 DK114034R25 GM056929R01 HL122593P30 ES030285R01 MH112356T32 AI060537Dooling SWCosta-Mattioli MSgritta MMurillo ODNoecker CFelice DFBuffington SATurnbaugh PJfalseDissecting the contribution of host genetics and the microbiome in complex behaviors.The core symptoms of many neurological disorders have traditionally been thought to be caused by genetic variants affecting brain development and function. However, the gut microbiome, another important source of variation, can also influence specific behaviors. Thus, it is critical to unravel the contributions of host genetic variation, the microbiome, and their interactions to complex behaviors. Unexpectedly, we discovered that different maladaptive behaviors are interdependently regulated by the microbiome and host genes in the Cntnap2^-/- model for neurodevelopmental disorders. The hyperactivity phenotype of Cntnap2^-/- mice is caused by host genetics, whereas the social-behavior phenotype is mediated by the gut microbiome. Interestingly, specific microbial intervention selectively rescued the social deficits in Cntnap2^-/- mice through upregulation of metabolites in the tetrahydrobiopterin synthesis pathway. Our findings that behavioral abnormalities could have distinct origins (host genetic versus microbial) may change the way we think about neurological disorders and how to treat them.2021-01-01T00:00:00Z2021 Apr2026-05-10T01:35:48.968Z2025-02-19T01:10:48.736ZS-EPMC89967453370568810.1016/j.cell.2021.02.009