A growling stomach represents a clear sign that you must eat something tasty; however, sometimes, your digestive system is where the message needs to go! An exciting epigenetics study reveals that our gut microbiota employs a histone code via histone acylations to influence gene expression in intestinal cells, forcing these cells to speak their language!
A communicative crew headed by Leah A. Gates (Case Western Reserve University School of Medicine) knew that high levels of metabolites generated by gut microbiota could induce post-translational modifications in histone proteins in neighboring cell types to regulate the expression of associated genes. Their new study sought to evaluate whether specific metabolites – short-chain fatty acids specifically – generated by gut microbiota could induce the acylation (acetylation, butyrylation, crotonylation, or propionylation) of histone proteins to regulate intestinal gene expression in female mice.
Let’s hear more from Gates and Colleagues on how the gut microbiota make intestinal cells speak their language:
- The caecum and large intestine display high histone butyrylation and propionylation levels compared to other tissues, consistent with these tissues being major sites of microbial fermentation and short-chain fatty acid production
- Mass spectrometry analysis of histones extracted from caecal tissue identifies butyrylation and propionylation on histone H3 lysine 27 (H3K27bu and H3K27pr) and histone H3 lysine 9 (H3K9bu and H3K9pr)
- Evaluating H3K27bu reveals elevated levels in caecal intestinal epithelial cells in regions harboring fermenting bacteria
- Germ-free mice or conventional mice treated with antibiotics display reduced levels of butyrylation and propionylation, suggesting that histone acylations display sensitivity to microbiota alterations
- Administration of tributyrin (a stable, rapidly absorbed form of butyric acid) to antibiotic-treated mice rescues caecal histone butyrylation, suggesting that this metabolite regulates this post-translational modification in the intestine
- Tributyrin treatment also induces robust changes in gene expression in caecal intestinal epithelial cells, with genes mainly related to metabolic programs
- ChIP-seq for H3K27bu reveals overlap with active (H3K27ac and H3K4me3) but not repressive histone modifications (H3K27me3) and H3K27bu enrichment at active gene-regulatory elements
- These findings suggest an association between H3K27bu, active gene-regulatory elements, and gene expression in caecal intestinal epithelial cells
Overall, this highly codified new study communicates a critical point – that guy microbiota and metabolites can dynamically influence the expression profiles of mouse caecal intestinal epithelial cells by influencing their histone modification profiles – specifically through modifications such as butyrylation and propionylation. Additional explorations of transcription-factor-mediated responses and reader proteins (effectors for histone post-translational modifications) for butyrylation and propionylation and their potential impact on chromatin structure represent noted future directions for this research.
For more on how the gut microbiota employs the histone code to force intestinal cells to speak their language, see Nature Metabolism, February 2024.