Epigenetics: the missing link between microbiota and colon epithelial cells
Short-chain fatty acids regulate gene expression in intestinal epithelial cells via histone post-translational modification. A promising objective for the development of new anti-tumoral agents, among others.
Histone post-translational modifications help regulate gene transcription by compacting the DNA more or less tightly. Crotonylation was discovered recently and joins the list of methylation, acetylation and other ubiquitinations: it involves the addition of a thioester group to histone lysines. This reaction is thought to depend particularly on the presence of short-chain fatty acids (SCFA). For the first time, an international team has demonstrated the role of SCFAs–and therefore of the microbiota–in gene regulation.
Positive regulation of butyric acid
The researchers first observed intense histone crotonylation activity in the intestinal epithelium of mice, as well as high activity in the brain, suggesting that this type of regulation has specific functions which may vary depending on the tissue. On the other hand, treating the mice with antibiotics, impairing their microbiota and therefore SCFA production, had the effect of reducing the level of histone crotonylation. Among SCFAs, butyric acid is known to be a histone deacetylase (HDAC) inhibitor. The team therefore assessed whether butyric acid acted on the crotonylation level through an HDAC-mediated effect. The hypothesis was validated: butyric acid increased histone crotonylation by inhibiting HDAC activity. The physiological basis of the influence of SCFAs, and therefore of the microbiota, on cell metabolism and immunity in the intestines, is therefore thought to be epigenetic in nature.
A new generation of epi-drugs*
The study also shows that the exact sites of crotonylation on the genome of colonic epithelial cells are found at the transcription start sites (TSS) of genes involved in metabolic cancer pathways in particular. This suggests that a disorder in the regulation of histone crotonylation could be associated with the presence of cancer. Moreover, depletion of the microbiota and of SCGA production also had the effect of increasing the expression of the HDAC2 gene, which is known to be linked to tumorigenesis in the colon. Along with butyric acid, the team observed a rise in crotonylation in presence of other HDAC inhibitors. This study therefore paves the way to the development of new HDAC inhibitors targeting the decrotonylase activity of these enzymes in order to expand their range of action. Another lead considered in the study was that of the brain, where the team also detected significant crotonylation, and where SCFA are also present. A role which remains to be elucidated, possibly by studying the gut-brain axis.
*Epi-drugs: drugs which act on epigenetic mechanisms to eliminate abnormal markings. Currently, they are divided into two main families of molecules: agents inhibiting DNA methylation (DNA methyltransferase inhibitors or DNMTi) and agents targeting histone modification (histone deacetylase inhibitors or HDACi).
R Fellows et al. Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases. Nat Comm 2018 ; Jan 9;9(1)