New study describes “language” bacteria use to control genes, development

Bacteria in the gut do far more than help digest food. They can also tell genes what to do, according to a new study published today in the journal Cell.

The study, conducted at Case Western Reserve University School of Medicine in Cleveland, Ohio, describes a form of "interspecies communication" in which bacteria secrete a specific molecule, nitric oxide, that allows them to communicate with and control their hosts' DNA. The study’s authors suggest that the conversation between the two may broadly influence human health.

Researchers tracked nitric oxide secreted by gut bacteria inside C. elegans, tiny worms commonly used in laboratory models. Nitric oxide secreted by gut bacteria attached to thousands of host proteins, completely changing a worm's ability to regulate its own gene expression.

The study is the first to show gut bacteria can tap into nitric oxide networks ubiquitous in mammals, including humans. Nitric oxide attaches to human proteins in a carefully regulated manner, a process known as S-nitrosylation, and disruptions are broadly implicated in diseases such as Alzheimer's, Parkinson's, asthma, diabetes, heart disease, and cancer.

The findings suggest nitric oxide is a general mechanism by which gut bacteria can communicate with its hosts, according to researchers, who published a press release last week.  

Previous work to untangle communication lines to and from gut bacteria has primarily focused on rare molecules that bacteria secrete, researchers say. The new findings are akin to uncovering a chemical language common across species, as opposed to single words, according to senior author Jonathan Stamler, MD, director of the Institute for Transformative Molecular Medicine at Case Western Reserve University School of Medicine and president of the Harrington Discovery Institute at University Hospitals Cleveland Medical Center.

"There is tremendous complexity in the gut, and many researchers are after the next unusual substance produced by a bacterium that might affect human health," he said.

With trillions of bacteria in the average gut, Stamler said he decided to look for a common language that all bacterial species might use.

"The enormity of the gut bacteria population and its relationship to the host predicts there will be general means to communicate that we humans can recognize,” he said.

The researchers demonstrated the phenomenon by feeding developing worms bacteria that produce nitric oxide. They then selected argonaute protein, or ALG-1, a protein that is highly conserved from worms to humans and silences unnecessary genes, including genes critical for development. When nitric oxide secreted by the bacteria attached to ALG-1, they developed malformed reproductive organs and died. Too much nitric oxide from bacteria commanded the worms' DNA silencing proteins and impaired healthy development, researchers said.

Practically, animals will not let this happen, according to Stamler. Instead, the authors speculate a mammalian host outside of a laboratory setting will adjust to accommodate changing nitric oxide levels.

"The worm is going to be able to stop eating the bacteria that make the nitric oxide, or it will begin to eat different bacteria that makes less nitric oxide, or change its environment, or countless other adaptations,” he said. “But by the same token, too much nitric oxide produced by our microbiome may cause disease or developmental problems in the fetus."

The study adds to a growing body of evidence that bacteria living in the gut, determined by diet and environment, have a tremendous influence on overall health.

Stamler said he imagines nitric oxide may represent an opportunity to manipulate this symbiotic relationship. Just as probiotics are designed to improve digestion, inoculating a person's gut with bacteria to improve nitric oxide signaling is conceivable.

"I now think of this therapeutically, as a drug,” he said. “There are tremendous opportunities to manipulate nitric oxide to improve human health."

However, more research is needed, and while nitric oxide and S-nitrosylation may be a general mode of interspecies communication with broad health implications, this is just one of potentially many general strategies of communication.