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Insights into the Role of the Microbiota and of Short-Chain Fatty Acids in Rubinstein–Taybi Syndrome
Authors:Elisabetta Di Fede  Emerenziana Ottaviano  Paolo Grazioli  Camilla Ceccarani  Antonio Galeone  Chiara Parodi  Elisa Adele Colombo  Giulia Bassanini  Grazia Fazio  Marco Severgnini  Donatella Milani  Elvira Verduci  Thomas Vaccari  Valentina Massa  Elisa Borghi  Cristina Gervasini
Abstract:The short-chain fatty acid butyrate, produced by the gut microbiota, acts as a potent histone deacetylase (HDAC) inhibitor. We assessed possible ameliorative effects of butyrate, relative to other HDAC inhibitors, in in vitro and in vivo models of Rubinstein–Taybi syndrome (RSTS), a severe neurodevelopmental disorder caused by variants in the genes encoding the histone acetyltransferases CBP and p300. In RSTS cell lines, butyrate led to the patient-specific rescue of acetylation defects at subtoxic concentrations. Remarkably, we observed that the commensal gut microbiota composition in a cohort of RSTS patients is significantly depleted in butyrate-producing bacteria compared to healthy siblings. We demonstrate that the effects of butyrate and the differences in microbiota composition are conserved in a Drosophila melanogaster mutant for CBP, enabling future dissection of the gut–host interactions in an in vivo RSTS model. This study sheds light on microbiota composition in a chromatinopathy, paving the way for novel therapeutic interventions.
Keywords:Rubinstein–  Taybi syndrome, butyrate, microbiota, HDACi, histones
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