Insights into the Role of the Microbiota and of Short-Chain Fatty Acids in Rubinstein–Taybi Syndrome

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.

Exogenous Players in Mitochondria-Related CNS Disorders: Viral Pathogens and Unbalanced Microbiota in the Gut-Brain Axis

“…Pharmacological therapy with HDAC inhibitors was shown to attenuate chromatin impairment, improving the clinical phenotype. By analyzing the overall composition of bacterial metabolites from commensal gut microbiota, RSTS patients compared to healthy siblings showed significant depletion in butyrate [122]. Accordingly, ameliorative effects of butyrate, relative to other HDAC inhibitors, have been reported in both in vitro and in vivo models of RSTS.…”

KMT2A: Umbrella Gene for Multiple Diseases

“…Indeed, the microbial community within the intestine can produce metabolites such as short-chain fatty acids (SCFAs) with a known role of histone deacetylase (HDAC) inhibitors. These compounds or diets able to increase them were recently used as possible therapeutic approach for several diseases, including drug-resistant epilepsy [ 91 , 92 ], cancer [ 93 ], neurodegenerative disease [ 94 ], heart failure [ 95 ], and diabetes mellitus [ 96 ], and their effect was even studied in experimental models of chromatinopathies, i.e., Kabuki syndrome [ 97 ] and Rubinstein–Taybi syndrome [ 98 ]. Furthermore, bacteria synthetize essential vitamins, fundamental for immune systems, such as B12, but also folate, required for DNA, histone and protein methylation [ 99 , 100 ].…”

Epigenetic disorders: Lessons from the animals–animal models in chromatinopathies

“…Conversely, a Drosophila model for EP300-related RSTS phenotype does not exist, leaving the study of dCBP mutant flies, named nejire (nejP/ +), as the only option for Drosophila studies of RSTS. Hemizygous nej are embryonic lethal (Akimaru et al, 1997;Di Fede et al, 2021), while nejire mutants affect the eye specification and cell fate determination (Kumar et al, 2004).…”

“…Conversely, a Drosophila model for EP300-related RSTS phenotype does not exist, leaving the study of dCBP mutant flies, named nejire (nejP/+), as the only option for Drosophila studies of RSTS. Hemizygous nej are embryonic lethal ( Akimaru et al, 1997 ; Di Fede et al, 2021 ), while nejire mutants affect the eye specification and cell fate determination ( Kumar et al, 2004 ). Similarly to what happens in mouse, knockdown of dCBP causes behavioral alterations ( Boyles et al, 2010 ; Sethi et al, 2019 ), affects nervous system development ( Kirilly et al, 2011 ) and learning, due to altered development of mushroom bodies, associative center in invertebrate brains ( Li et al, 2018 ).…”