What tells our gut to vomit? Scientists think they've found a clue that could help chemo patients

It’s probably not the top thing on your mind when you’re doubled over the toilet after eating some questionable-looking lettuce. But nonetheless, the question remains: How does the gut tell the brain that it needs to get something out, stat?

The answer lies in a set of vagal sensory neurons that transmit toxin-related signals from intestinal cells back to the brain, according to a new study published Nov. 1 in Cell by researchers from Beijing’s National Institute of Biological Scientists. Their work marks the first time scientists have fully characterized the mechanism behind the vomiting response to toxins—an accomplishment that could lead to better treatments for the side effects of chemotherapy.

“With this study, we can now better understand the cellular mechanisms of nausea and vomiting, which will help us develop better medications,” Peng Cao, Ph.D., corresponding author, said in a press release.

While previous work had shown a cellular pathway between the gut and the brain that stimulates vomiting, it wasn’t clear what types of cells were involved. That’s because there wasn’t a well-defined model to study. Rodents can’t throw up because their stomachs aren’t strong enough to push contents up their lengthy esophagi. And although cats and dogs can puke, their neuroanatomy is less characterized, making it difficult to elucidate the brain mechanisms behind vomiting.

Despite the limitations, Cao’s team thought they could make a model out of a mouse anyway. They noticed that while the animals couldn’t throw up, they did dry heave. That suggested that the mice were experiencing the urge to vomit, even if they were anatomically incapable of doing so.

To see if they could pin down a set of mouse behaviors that mimicked vomiting in humans, the researchers infected a set of mice with Staphylococcal enterotoxin A, or SEA, a bacterial toxin from a microbe that causes food poisoning. When they got sick, the mice that received SEA would open their mouths wider, a different angle and for a longer period than those who did the action spontaneously. The same thing happened when the researchers gave the mice other vomit-inducing drugs.

By measuring this angle and the duration the mice kept their mouths open, the scientists developed a paradigm with which to study the relationship between the gut and brain in vomiting. Armed with their new model, the researchers set out to find the responsible cells. They found that cutting the vagus nerve eliminated the dry heaving behavior in the mice, consistent with other studies that had shown it to be critical to vomiting due to toxins.

Cells from the vagus nerve send signals to the medulla, the bottom-most part of the brain and command center for basic functions like breathing, swallowing and digestion. The scientists found that a set of neurons there receives signals from cells in the gut. Stimulating those neurons directly caused the mice to dry heave.

Tracing the pathways back down into the gut revealed that cells on the lining of the intestine, known as enterochromaffin cells, appeared to respond to the presence of SEA—and to the chemotherapy drug doxorubicin—by releasing serotonin. The serotonin then bound to receptors on vagal sensory neurons that sent signals back up to the neurons in the medulla. When the scientists inhibited the medulla neurons, either by impairing serotonin synthesis or inactivating them with a chemical, the mice didn’t dry heave in response to SEA or doxorubicin.

Looking closer at the gut-brain circuitry, the scientists found that the enterochromaffin cells weren’t responding to SEA or doxorubicin directly. Instead, they released the cytokine IL33, which ultimately drove serotonin release.

“These findings support the hypothesis that SEA and doxorubicin may recruit the gut-to-brain circuit via an immune-neuroendocrine axis,” the scientists wrote in the paper. They plan to focus future research on understanding the connection between enterochromaffin cells and the immune system.

IL33 or other targets along the pathway may be the key to developing better drugs to treat or prevent nausea and vomiting in chemotherapy patients, Cao told The New York Times. Most current treatments, such as GSK’s Zofran, work by inhibiting serotonin release. Others, like Heron Therapeutics’ Cinvanti and Merck’s Emend, block the brain’s neurokinin-1 receptors. And Insys’ drug Syndros, a synthetic form of THC, is also approved for treating nausea and vomiting in chemo patients.