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.
Highlights
Altered gut microbiota could itself affect the endogenous levels of SCFAs in patients, it could participate in their typical Rubinstein–Taybi syndrome (RSTS) growth trend, characterized by a deficit in infancy and excessive weight gain after puberty, and/or it could contribute to the comorbidities often associated with RSTS, such as gastrointestinal discomfort [8]
In the present study, we compared butyrate to other HDAC inhibitors (HDACi) molecules in vitro on lymphoblastoid cell lines (LCLs) derived from RSTS patients
Considering HDACi applications as anticancer drugs for their role in cell cycle arrest, cell death, and immune-mediated mechanisms [25], we studied NaB and other HDACi effects on cell proliferation and apoptosis, performing Ki67 and Tunel assays upon exposure of LCLs with HDACi (Figures S2 and S3)
Summary
Altered gut microbiota could itself affect the endogenous levels of SCFAs in patients, it could participate in their typical RSTS growth trend, characterized by a deficit in infancy and excessive weight gain after puberty, and/or it could contribute to the comorbidities often associated with RSTS, such as gastrointestinal discomfort [8]. On these premises, in the present study, we compared butyrate to other HDACi molecules in vitro on lymphoblastoid cell lines (LCLs) derived from RSTS patients. Our work points to the importance of the microbiome in the pathogenesis and treatment of ultra-rare diseases
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