The old adage reads “you are what you eat”, but a tasty new study turned that bland old phrase into “your histones are what you eat!”, and what’s more, those behind the study have worked the mechanistic link.
Some of our daily diet (i.e. coffee and candy) acts as an energy and carbon source for the mass of microbes that colonize the gut. Importantly, their “by-products” or metabolites greatly affect our physiology, alter disease development, and modulate therapeutic responses. But within this fact-sandwich, there remained a bit of a pickle: what is the mechanistic link!?
Now, in a Molecular Cell study, the labs of Federico E. Rey and John M. Denu have demonstrated that microbial metabolites modulate the activity of major histone-modifying enzymes and affect gene transcription in multiple organs. Furthermore, Krautkramer et al. discovered that this mechanism is sensitive to dietary changes.
The study assessed over 50 histone post-translational modifications via tissue-sample mass spectroscopy in mice and demonstrated that:
- Gut microbes can modify histone acetylation and methylation patterns via the production of metabolites which affect major histone-modifying enzymes and, therefore, transcriptional patterns
- Circulating metabolites include short-chain fatty acids (SCFAs), the major bacterial fermentation product of complex plant polysaccharides such (e.g. fiber)
- SCFAs can act as histone deacetylase (HDAC) inhibitors (e.g. butyrate) or can be converted into the histone acetyltransferase (HAT) co-activator acetyl-CoA (e.g. butyrate, acetate, and propionate)
- This link allows chromatin to respond to environmental changes
- Alterations occur within the gut (proximal colon) but also affect the liver, and white adipose tissue (WAT) via metabolite entry into the circulation
- Alterations to diet modifies patterns of histone modifications
- A western-style high-fat, high-sucrose “unhealthy” diet suppresses microbe-dependent SCFA production
- This prevents the formation of chromatin patterns observed under a healthy fiber-rich diet
- An unhealthy diet also produces “functionally relevant” alterations in liver gene expression (e.g. genes associated with PPAR signaling, insulin signaling, and diabetes mellitus)
- Germ-free mice fed with SCFAs attain both histone modifications and transcriptional patterns characteristic of mice with wild-type microbial gut colonization
Overall, these findings suggest that the metabolic end-products of our gut microbes chomping through the remains of our healthy, or indeed, unhealthy dietary intake promote alterations to gene expression patterns associated with normal and diseased tissue physiology.
However, while the SCFA-acetylation link seems direct and clear, what about other metabolites (e.g. bile acids, vitamins, choline metabolites, and lipids) and their mechanistic influence on other histone modifications (e.g. methylation)? We shall have to wait for the serving of the red hot and spicy next course to find out, so for now, ditch the donut, chomp on a cabbage, and read this tasty new study in Molecular Cell, Nov 2017.