We all know how important it is to eat fiber, whether in the form of fruits and veggies, or even a big bowl of fiber-rich cereal. Now, research from Ben Garcia’s lab (WUSTL) gives us one more reason to eat our Wheaties—our gut microbiome needs it to acetylate histones and possibly ward off diseases like colitis.
Organisms in the microbiome ferment fiber, producing short-chain fatty acids, such as butyrate, which can directly inhibit histone deacetylases (HDACs). But butyrate has more tricks up its sleeve—it can bind to cell-surface and intracellular receptors to regulate conditions in the gut. It can also lead to acetyl-coenzyme A (acetyl-CoA) production, indirectly activating histone acetyltransferases (HATs).
Previously, other teams used radioactive isotopes to track carbons from butyrate to the TCA cycle, but they didn’t look at contributions to histone acetylation via acetyl-CoA. With stable isotope labeling, another team showed that many compounds from microbes can be incorporated into host tissues. But Garcia’s team were hungry to investigate what was going on with an intact gut microbiome. So, the group performed deep profiling of histone mods with mass spectrometry and ChIP-seq, along with in vivo isotope tracing with 13C-labeled fiber and untargeted metabolomics methods.
Here’s the digest:
- Histone H4s of gut epithelial cells from germ-free mice are only acetylated at promoter regions, revealing that microbes are needed for histone acetylation throughout most of the genome
- Carbons from dietary fiber and butyrate end up in mouse histone acetyl groups, so microbes are contributing to host histone modifications through metabolism, not just inhibiting HDACs
- In vivo stable isotope tracing showed that microbial metabolism contributes to many acylated molecules in mice
- Inflammation in a colitis mouse model alters the connection between the microbiome and fatty acid metabolism
Taken together, these findings show that carbon flows from diet to microbiome to the host, with histone acetylation being a key endpoint. If this flow is disrupted, diseases like colitis can develop.
Take a bite out of this one over at Cell Reports, December 2022