The urge to vomit after eating contaminated food is the body’s natural defensive response to get rid of bacterial toxins. Researchers headed by a team at the National Institute of Biological Sciences in Beijing have now mapped out the detailed neural pathway of the defensive responses from the gut to the brain in mice, which can retch, but not vomit. Their results could help scientists develop better anti-nausea medications for cancer patients undergoing chemotherapy.

“The neural mechanism of retching is similar to that of vomiting,” said Peng Cao, PhD. “In this experiment, we successfully build a paradigm for studying toxin-induced retching in mice, with which we can look into the defensive responses from the brain to toxins at the molecular and cellular levels … With this study, we can now better understand the molecular and cellular mechanisms of nausea and vomiting, which will help us develop better medications.” Cao is corresponding author of the researchers’ published paper in Cell, which is titled “The gut-to-brain axis for toxin-induced defensive responses.”

Many foodborne bacteria produce toxins in the host after being ingested. The brain, after sensing their presence, will initiate a series of biological responses, including motor reflexes such as retching and vomiting, to get rid of the substances, as well as the unpleasant sensation of nausea, which serves as what the authors noted is a “teaching signal” for conditioned flavor avoidance (CFA), to help prevent ingesting the same toxin in the future. And, as the authors further commented, “Paradoxically, these defensive responses for protecting the body from toxins are the main cause of severe side effects of chemotherapeutic drugs.”

While the neurobiology of toxin-induced defensive responses has been intensively studied in the past several decades, the process of how our brain initiates these biological reactions has remained elusive. “The mechanisms underlying the detection of toxins and coordination of defensive responses are poorly understood,” the team continued. As Cao commented, “ … details on how the signals are transmitted from the gut to the brain were unclear, because scientists couldn’t study the process on mice.” Rodents cannot vomit, likely because of their long esophagus and weaker muscle strength compared to their body size. And so, the authors noted, “The major obstacle hampering addressing these questions is the lack of mouse-based experimental paradigm.”

With rodents being unable to vomit, scientists have been studying this defensive response in other animals such dogs and cats, but these animals are not comprehensively studied and have failed to reveal the mechanism of nausea and vomiting.

Cao and his team noticed that while mice don’t vomit, they do retch, meaning that they also experience the urge to vomit, albeit without the ability to throw up. “… mice do exhibit conditioned flavor avoidance (CFA) and potentially retching-like behavior,” the scientists pointed out. For their study the team carried out a series of experiments in mice to investigate more closely the gut-brain mechanisms and cell types that underpin the toxin-induced defensive responses, such as retching.

The team first demonstrated that mice receiving Staphylococcal enterotoxin A (SEA)—a bacterial toxin produced by Staphylococcus aureus that also leads to foodborne illnesses in humans—quickly developed episodes of unusual mouth opening. Mice that received SEA opened their mouths at angles wider than those observed in the control group of animals that received saline water. Moreover, during these episodes of mouth opening, the diaphragm and abdominal muscles of the SEA-treated mice contracted simultaneously, a pattern that is also seen in dogs when they are vomiting. During regular breathing an animal’s diaphragm and abdominal muscles would contract alternatively.

In mice given SEA, the team found that the toxin activated the release of the neurotransmitter serotonin (5-HT) by enterochromaffin (EC) cells on the lining of the intestinal lumen. The studies indicated that the released serotonin binds to the receptors on the vagal sensory neurons located in the intestine, which transmits the signals along the vagus nerves from the gut to a specific type of neurons in the dorsal vagal complex—Tac1+ (DVC) neurons—in the brainstem. When Cao and his team then inactivated the Tac1+DVC neurons, SEA-treated mice retched less than did mice with normal Tac1+DVC neuron activities.

The authors explained, “We identified a molecularly defined gut-to-brain circuit composed of a subset of Htr3a+ vagal sensory neurons that functionally link Tac1+ DVC neurons to 5-HT+ intestinal EC cells … We showed that ablation of 5-HT synthesis in intestinal EC cells impaired retching-like behavior and CFA, suggesting EC cells are gut chemosensors for toxin-induced defensive responses.”

In addition, the team investigated whether chemotherapy drugs might activate the same neural pathway. They injected doxorubicin, a common chemotherapy drug, into mice. The drug made the mice retch, but when the team inactivated their Tac1+ DVC neurons or serotonin synthesis by the enterochromaffin cells, the animals’ retching behaviors were significantly reduced.

Cao says that some of the current anti-nausea medications that are given to chemotherapy recipients—an example is Granisetron—work by blocking the serotonin receptors. The newly reported study helps to explain why these drugs work. Cao and his colleagues next want to explore how toxins act on enterochromaffin cells. Preliminary research shows that enterochromaffin cells don’t sense the presence of toxins directly. The process likely involves complex immune responses of damaged cells in the intestine.

“In addition to foodborne germs, humans encounter a lot of pathogens, and our body is equipped with similar mechanisms to expel these toxic substances,” said Cao who suggested that future research may reveal new and better targets for drugs, including anti-nausea medicines. “For example, coughing is our body’s attempt to remove the coronavirus. It’s a new and exciting field of research about how the brain senses the existence of pathogens and initiates responses to get rid of them.”