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

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2021 Apr 3

PMID 33807238

Citations 5

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

Affiliations

Soon will be listed here.

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 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.

Citing Articles

Characterization of a novel HDAC2 pathogenetic variant: a missing puzzle piece for chromatinopathies.

Di Fede E, Lettieri A, Taci E, Castiglioni S, Rebellato S, Parodi C Hum Genet. 2024; 143(6):747-759.

PMID: 38753158 PMC: 11186948. DOI: 10.1007/s00439-024-02675-0.

Sodium butyrate supresses malignant human mast cell proliferation, downregulates expression of KIT and promotes differentiation.

MacDonald C, Qian H, Pundir P, Kulka M Front Allergy. 2023; 4:1109717.

PMID: 36970068 PMC: 10036836. DOI: 10.3389/falgy.2023.1109717.

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

Righetto I, Gasparotto M, Casalino L, Vacca M, Filippini F Biomolecules. 2023; 13(1).

PMID: 36671555 PMC: 9855674. DOI: 10.3390/biom13010169.

Epigenetic disorders: Lessons from the animals-animal models in chromatinopathies.

Di Fede E, Grazioli P, Lettieri A, Parodi C, Castiglioni S, Taci E Front Cell Dev Biol. 2022; 10:979512.

PMID: 36225316 PMC: 9548571. DOI: 10.3389/fcell.2022.979512.

: Umbrella Gene for Multiple Diseases.

Castiglioni S, Di Fede E, Bernardelli C, Lettieri A, Parodi C, Grazioli P Genes (Basel). 2022; 13(3).

PMID: 35328068 PMC: 8949091. DOI: 10.3390/genes13030514.

References

Atlasi Y, Stunnenberg H . The interplay of epigenetic marks during stem cell differentiation and development. Nat Rev Genet. 2017; 18(11):643-658. DOI: 10.1038/nrg.2017.57. View

Fast D, Duggal A, Foley E . Monoassociation with Lactobacillus plantarum Disrupts Intestinal Homeostasis in Adult Drosophila melanogaster. mBio. 2018; 9(4). PMC: 6069112. DOI: 10.1128/mBio.01114-18. View

Iannitti T, Palmieri B . Clinical and experimental applications of sodium phenylbutyrate. Drugs R D. 2011; 11(3):227-49. PMC: 3586072. DOI: 10.2165/11591280-000000000-00000. View

Negri G, Milani D, Colapietro P, Forzano F, Della Monica M, Rusconi D . Clinical and molecular characterization of Rubinstein-Taybi syndrome patients carrying distinct novel mutations of the EP300 gene. Clin Genet. 2014; 87(2):148-54. DOI: 10.1111/cge.12348. View

Boot M, van Belzen M, Overbeek L, Hijmering N, Mendeville M, Waisfisz Q . Benign and malignant tumors in Rubinstein-Taybi syndrome. Am J Med Genet A. 2018; 176(3):597-608. PMC: 5838508. DOI: 10.1002/ajmg.a.38603. View

Astbury S, Corfe B . Uptake and metabolism of the short-chain fatty acid butyrate, a critical review of the literature. Curr Drug Metab. 2012; 13(6):815-21. DOI: 10.2174/138920012800840428. View

Louis P, Flint H . Diversity, metabolism and microbial ecology of butyrate-producing bacteria from the human large intestine. FEMS Microbiol Lett. 2009; 294(1):1-8. DOI: 10.1111/j.1574-6968.2009.01514.x. View

Bjornsson H . The Mendelian disorders of the epigenetic machinery. Genome Res. 2015; 25(10):1473-81. PMC: 4579332. DOI: 10.1101/gr.190629.115. View

Shin S, Kim S, You H, Kim B, Kim A, Lee K . Drosophila microbiome modulates host developmental and metabolic homeostasis via insulin signaling. Science. 2011; 334(6056):670-4. DOI: 10.1126/science.1212782. View

10.

Tarasenko N, Chekroun-Setti H, Nudelman A, Rephaeli A . Comparison of the anticancer properties of a novel valproic acid prodrug to leading histone deacetylase inhibitors. J Cell Biochem. 2017; 119(4):3417-3428. DOI: 10.1002/jcb.26512. View

11.

Akimaru H, Chen Y, Dai P, Hou D, Nonaka M, Smolik S . Drosophila CBP is a co-activator of cubitus interruptus in hedgehog signalling. Nature. 1997; 386(6626):735-8. DOI: 10.1038/386735a0. View

12.

Chan H, La Thangue N . p300/CBP proteins: HATs for transcriptional bridges and scaffolds. J Cell Sci. 2001; 114(Pt 13):2363-73. DOI: 10.1242/jcs.114.13.2363. View

13.

Yao T, P Oh S, Fuchs M, Zhou N, ChNg L, Newsome D . Gene dosage-dependent embryonic development and proliferation defects in mice lacking the transcriptional integrator p300. Cell. 1998; 93(3):361-72. DOI: 10.1016/s0092-8674(00)81165-4. View

14.

Tanaka Y, Naruse I, Maekawa T, Masuya H, Shiroishi T, Ishii S . Abnormal skeletal patterning in embryos lacking a single Cbp allele: a partial similarity with Rubinstein-Taybi syndrome. Proc Natl Acad Sci U S A. 1997; 94(19):10215-20. PMC: 23342. DOI: 10.1073/pnas.94.19.10215. View

15.

Fergelot P, Van Belzen M, Van Gils J, Afenjar A, Armour C, Arveiler B . Phenotype and genotype in 52 patients with Rubinstein-Taybi syndrome caused by EP300 mutations. Am J Med Genet A. 2016; 170(12):3069-3082. DOI: 10.1002/ajmg.a.37940. View

16.

Dutto I, Scalera C, Prosperi E . CREBBP and p300 lysine acetyl transferases in the DNA damage response. Cell Mol Life Sci. 2017; 75(8):1325-1338. PMC: 11105205. DOI: 10.1007/s00018-017-2717-4. View

17.

Alarcon J, Malleret G, Touzani K, Vronskaya S, Ishii S, Kandel E . Chromatin acetylation, memory, and LTP are impaired in CBP+/- mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration. Neuron. 2004; 42(6):947-59. DOI: 10.1016/j.neuron.2004.05.021. View

18.

Grunstein M . Histone acetylation in chromatin structure and transcription. Nature. 1997; 389(6649):349-52. DOI: 10.1038/38664. View

19.

Oike Y, Hata A, Mamiya T, Kaname T, Noda Y, Suzuki M . Truncated CBP protein leads to classical Rubinstein-Taybi syndrome phenotypes in mice: implications for a dominant-negative mechanism. Hum Mol Genet. 1999; 8(3):387-96. DOI: 10.1093/hmg/8.3.387. View

20.

Bassanini G, Ceccarani C, Borgo F, Severgnini M, Rovelli V, Morace G . Phenylketonuria Diet Promotes Shifts in Firmicutes Populations. Front Cell Infect Microbiol. 2019; 9:101. PMC: 6477998. DOI: 10.3389/fcimb.2019.00101. View