Gut microbiome profiling of Rubinstein-Taybi syndrome patients. human gut metagenome

Rubinstein-Taybi syndrome (RSTS, OMIM #180849, #613684) is a rare autosomal-dominant disease characterized by intellectual disability, postnatal growth deficiency with excessive weight gain in adolescence, distinctive dysmorphisms, and skeletal abnormalities with a wide spectrum of multiple congenital anomalies. RSTS is caused by pathogenic variants in one of two highly conserved genes: CREBBP (16p13.3), coding for cAMP response element binding and EP300 (22q13.2), coding for E1A-associated protein p300, both belonging to the lysine acetyl transferases family, acting as co-factors of transcription, and required in multiple pathways of cell growth control, DNA repair, cell differentiation, and tumor suppression. Preliminary studies supported the hypothesis that RSTS is caused by acetylation imbalance and that a key component can be represented by the role of gut microbiota (i.e. commensal microbial community) in protein acetylation. Among short chain fatty acids , endogenous butyrate is exclusively produced by commensal microorganisms and is the most potent histone deacetylase inhibitor among natural compounds. Indeed, besides SCFAs production, an altered gut microbiota could participate in the typical RSTS growth trend (weight deficit in infancy and excessive weight gain after puberty) and to comorbidities often associated to RSTS, such as gastrointestinal discomfort. We enrolled 23 RSTS subjects and 16 healthy siblings, as a control group and performed microbiota profiling by V3-V4 16S rRNA gene-targeted sequencing.

鲁宾斯坦-泰比综合征（Rubinstein-Taybi syndrome, RSTS, OMIM #180849, #613684）是一种罕见的常染色体显性遗传病，以智力障碍、出生后生长不足且青春期出现过度增重、特征性畸形表现，以及伴发多种先天性异常的广泛性骨骼异常为特征。RSTS由两个高度保守基因中的任意一个发生致病变异引发：CREBBP（16p13.3），编码cAMP反应元件结合蛋白，以及EP300（22q13.2），编码E1A相关蛋白p300；二者均隶属于赖氨酸乙酰转移酶（lysine acetyl transferases）家族，作为转录辅因子发挥作用，并在细胞生长调控、DNA修复、细胞分化及肿瘤抑制的多条通路中不可或缺。初步研究支持RSTS由乙酰化失衡所致的假说，且肠道菌群（gut microbiota，即共生微生物群落）在蛋白质乙酰化中的作用可作为其关键致病环节。在短链脂肪酸（short chain fatty acids, SCFAs）中，内源性丁酸仅由共生微生物产生，是天然化合物中活性最强的组蛋白去乙酰化酶抑制剂。事实上，除短链脂肪酸的产生外，肠道菌群失调还可能参与RSTS典型的生长模式（婴儿期体重不足及青春期后过度增重），以及RSTS常伴发的合并症，如胃肠道不适。本研究纳入23名RSTS患者与16名健康同胞作为对照组，通过靶向V3-V4区16S rRNA基因测序完成菌群谱分析。