When we eat contaminated food, we often feel the urge to give it up shortly afterwards. Vomiting is an important defense reaction of the body to get rid of bacterial toxins. However, how exactly our brain learns that there are toxins in our gastrointestinal tract in order to produce nausea was previously unclear. Researchers have now used mice to investigate which molecular and neuronal mechanisms play a role. The results may also help design better medicines for patients suffering from nausea during chemotherapy.
Many foodborne bacteria produce toxins that harm our bodies. One of the most common toxins responsible for foodborne illness is Staphylococcus enterotoxin A (SEA), which is produced by the common germ Staphylococcus aureus and cannot be destroyed by cooking. After sensing the presence of the toxins, the brain triggers a series of biological responses, including vomiting and nausea, to get rid of the substances and preemptively develop an aversion to foods that taste or look similar.
Choking Mice
“However, little was known about how the brain recognizes ingested toxins and coordinates the various defense reactions,” writes a team led by Zhiyong Xie from the National Institute of Biological Sciences in Beijing. An important reason for this: The classic test animals, mice, did not seem to be suitable for such investigations, because rodents cannot vomit. Some studies have therefore already been carried out on dogs and cats, but a detailed model has not yet existed.
However, Xie and his team found that although mice cannot vomit, they appear to still feel nauseous and gag. When they gave the animals Staphylococcus enterotoxin A, they opened their mouths unusually often and wide, contracting their diaphragm and abdominal muscles at the same time — a pattern seen in dogs when they vomit. Mice that received saline instead did not show these reactions. If the animals were given a sugar solution to drink shortly before the toxin was administered, they subsequently avoided the taste, which they had previously perceived as tasty. The researchers take this as a clear sign that, like humans, the mice are developing an aversion to foods that they associate with experiencing nausea.
gut to brain
After the researchers had demonstrated with these experiments that, contrary to what was previously assumed, mice are a suitable model organism for researching nausea, they examined in detail how the relevant information is transmitted from the intestine to the brain. The result: In the intestine, the so-called enterochromaffin cells, which are located on the inner wall of the intestine, register the presence of the toxin. They then release the messenger substance serotonin, which then binds to receptors on certain neurons in the intestine.
The nerve cells in the gut transmit the signal along the vagus nerves to the brainstem. The so-called Tac1+ DVC neurons are responsible for processing there, as the team reports. In another experiment with the mice, Xie and his colleagues showed that these neurons do indeed play a key role: when they blocked the Tac1+ DVC neurons, the mice stopped gagging, even when given the bacterial toxin. This suggests that both the enterochromaffin neurons in the gut and these brain cells are critically involved in nausea and vomiting.
Same mechanism in chemotherapy
The results could also help cancer patients suffering from nausea due to chemotherapy. “Paradoxically, the body’s defenses against toxins are the main cause of serious side effects of chemotherapy drugs,” the researchers explain. To prove this, they injected some mice with a common chemotherapy drug instead of bacterial toxins. As expected, these animals also reacted by gagging. However, when the researchers switched off the Tac1+ DVC neurons, the gagging behavior was significantly reduced.
In some cases, chemotherapy patients are already being treated with anti-nausea drugs that work by blocking serotonin receptors. The current study helps explain why these drugs work. “With this study, we can now better understand the molecular and cellular mechanisms of nausea and vomiting, which will help us to develop even better drugs,” says Xie’s colleague Peng Cao. In future studies, the researchers want to investigate exactly how the toxins affect the enterochromaffin cells in the intestine. They also want to uncover other mechanisms of how the body reacts to pathogens and how it tries to remove them.
Source: Zhiyong Xie (National Institute of Biological Sciences, Beijing, China) et al., Cell, doi: 10.1016/j.cell.2022.10.001