Interplay between genetic disorders and gut microbial community: Rubinstein-Taybi syndrome as a model

Background: Rubinstein-Taybi syndrome (RSTS) is a genetic disorder affecting 1 out of 125,000 newborns characterized by intellectual disability, skeletal and gastrointestinal anomalies and growth deficiency. RSTS is caused by mutations in the genes CREBBP, encoding for CBP protein, or EP300, encoding for p300 protein. As CBP and p300 are lysine acetyl-transferases, RSTS patients show an imbalance between histone acetylation and deacetylation. Preclinical studies have shown that histone deacetylase inhibitors (HDACi) may attenuate the chromatin impairment improving the phenotype. As microbial-derived shortchain fatty acids, especially butyrate, display HDACi activity, the aim of this study was to assess the endogenous level of butyrate and the relative abundance of butyrate-producing taxa in a RSTS cohort. Materials/methods: We enrolled 23 RSTS patients and 16 healthy siblings (HC), as control group to minimize environmental factors having a well-recognized role on gut microbiota. We assessed dietary intake and performed gut microbiota analysis by next-generation sequencing using V3–V4 hypervariable 16S rRNA genomic region. Fecal SCFAs were quantified by gas chromatography. Exogenous HDACi effect on acetylation of lymphoblastoid cell lines (LCLs) derived from RSTS patients was assessed by Alpha LISA technology. Results: The biodiversity of gut communities (alpha-diversity) was similar for all the assessed metrics (Observed species, chao1, Shannon index, PD-whole tree) between RSTS and HC. Conversely, a clear difference among HC and RSTS subjects was highlighted in beta-diversity analyses, as both unweighted and weighted Unifrac distances revealed a significant separation between groups (p=0.022 and p=0.013, respectively). We found several significant differences in taxa relative abundance between groups across all phylogenetic levels. In particular, RSTS were depleted in major butyrate-producing genera Faecalibacterium and Roseburia. Fecal SCFA concentrations were similar except for butyrate that was found reduced in RSTS. Sodium butyrate (HDACi) appeared to restore acetylation levels in RSTS LCLs. Conclusions: Despite sharing diet habits and the environment, RSTS gut microbiota is depleted in major butyrate-producing taxa, resulting in a decreased butyrate production. Deepening our knowledge of RSTS gut microbiota alterations could offer new hints to explore strategies aimed at restoring a normal microbial community, and potentially improving some co-morbidities associated to RSTS, such as gastrointestinal discomfort.