Microbiota regulate short chain fatty acids and influence histone acylations in intestinal epithelial cells

The intestinal microbiota have a vital role in aiding digestion by metabolising dietary fibres. In this process, they produce short chain fatty acids (SCFAs) such as butyrate, an important energy source for intestinal epithelial cells. SCFAs are chemically related to histone acylations, a growing number of post-translational modifications that include histone acetylation, butyrylation and crotonylation. Histone post-translational modifications are thought to be involved in the regulation of gene expression as they can specifically recruit transcription factors and chromatin remodellers. Histone acylations are abundant in the intestine and are associated with active chromatin. In this project, I have identified that butyrate can upregulate histone acylations in both colon carcinoma cells and intestinal organoids in a dynamic manner. In addition, I identified that class I histone deacetylases (HDACs) are efficient histone decrotonylases. I have achieved this through a combination of biological analysis of the effects of treatment with HDAC inhibitors and in vitro analysis of purified proteins, which enabled determination of kinetic parameters. When investigating how SCFAs could influence histone acylations in vivo, I identified that antibiotic induced depletion of the microbiota in mice caused reduction in luminal SCFA concentration and global changes in histone acetylation and crotonylation, particularly those at histone H4. RNA-sequencing of these mice identified changes in the expression of genes which were involved in many important biological processes, such as cell signalling, energy generation and metabolism. Further to this, I studied lysine crotonylation and H4K8 acetylation at dysregulated genes to understand the how the presence of these modifications at the promoter influences gene expression in this context. These intriguing findings suggest that histone acylations could act as a nutrient sensors to couple changes in microbiota composition to that of gene expression and cellular function.