WIKIMEDIA, CHRISTOPH BOCKShortly after we finish a good meal, our resident microbes spring into action. The bacteria, viruses, and fungi that inhabit our guts send out metabolites that prepare our organs for the incoming nutrients. But the details of this symbiotic communication remain a mystery. Now, a November 23 study in Molecular Cell describes how microbes in mice send messages to a wide range of digestive tissues. The findings suggest that three specific short-chain fatty acids—acetate, propionate, and butyrate—act on histones to influence gene transcription epigenetically.
“The gut microbiome influences the host epigenome on a global scale,” said coauthor John Denu, an epigeneticist at the University of Wisconsin School of Medicine and Public Health. “We discovered key communicators, or key molecules that communicate this information, to the host.”
Gut microbes produce a wide variety of metabolites, from bile acids to vitamins. Through fermentative reactions, gut microbes can also metabolize complex carbohydrates to form short-chain fatty acids, such as butyrate, which has been implicated in cardiovascular disease and diabetes. Previous studies have demonstrated that certain diets can spur gut bacteria to produce more short-chain fatty acids, which prompted Denu to ask: “Since these microbes are changing and they’re a large percentage of the metabolites produced by the bacteria, could those be sufficient to drive some of the changes we’re seeing in the host tissues?”
The researchers first compared germ-free to normal, colonized lab mice. Consistent with the results of prior research, they found that mice fed a high-fiber diet, as opposed to a low-fiber, Western–type diet, produced the most short-chain fatty acids, causing “pretty profound changes in the chromatin—or epigenome—of germ-free versus colonized mice,” Denu said.
“Diet provides a lot of nutrients for the microbes, and we see a lot of genes are regulated by these microbes,” added coauthor Federico Rey, also of the University of Wisconsin. “What this paper shows is that the communication that happens between microbes and the host is modified by the diet that the host consumes.”
In other words, the preliminary findings suggested that a high-fiber diet led the mouse microbiome to produce specific short-chain fatty acids, which then acted as messenger molecules, impacting histones in far-off tissues.
The tricky part was determining whether these metabolites were indeed messengers. To test that theory, the researchers spiked the water given to germ-free mice with three prominent metabolites, finding that, even when they cut out the microbial middlemen, between 50 percent and 75 percent of the previously identified epigenomic changes still occurred.
“This work shows a clear connection between the gut microbiota and epigenetic regulation through histone modification,” Martin Blaser, a microbiologist at New York University School of Medicine who was not involved in the study, wrote in an email. “The work was carefully done and well-controlled, so these findings are quite credible. . . .All in all, [this is] pioneering work that can lead to new ways to modify human physiology.”
In future studies, Denu, Rey, and colleagues intend to focus on understanding the mechanism by which short-chain fatty acids influence gene expression. They also hope to uncover other histone-modifying metabolites produced by the microbiome.
“If you think of this as a language, this is sort of like first contact,” Denu told The Scientist. “The bugs are creating this language that the host tissues are trying to respond to. We have some of the language, and we think we know what they’re saying, but it’s like having a verb and maybe a subject, but no predicate. It’s not the whole story.”
K.A. Krautkramer et al., “Diet-microbiota interactions mediate global epigenetic programming in multiple host tissues,” Molecular Cell, doi:10.1016/j.molcel.2016.10.025