Today's "Cell": What's going on? Chinese scientists have solved three mysteries of the "nausea-vomiting" reaction

▎WuXi AppTec content team editor

Today, the authoritative academic journal Cell published a paper
by a Chinese research team online.
The study, led by Cao Peng's team at the Beijing Institute of Biological Sciences, used innovative animal models to solve multiple mysteries about the nausea-vomiting response
.
The research results have opened up a new direction for the study of the molecular cell mechanism and neural circuit mechanism of the "nausea-vomiting" response, and are also expected to provide new targets for the development of new chemotherapy antiemetics
.

"Nausea-vomiting" is a reaction
that almost everyone experiences in their daily lives.
The most common is after eating spoiled food
.
Through vomiting, the body excretes the ingested toxic food from the digestive tract to prevent pathogens from further invading the body; Through the disgust of nausea, the brain deepens long-term memories of the characteristics of toxic foods so that they do not ingest them again
in the future.
It can be seen that the "nausea-vomiting" response is a kind of self-protection defense response produced by the human body after encountering the invasion of pathogens, which is of great significance
for survival.

However, this innate reaction can also cause us inconvenience and even pain.

For example, passengers with motion sickness will have a "nausea-vomiting" reaction due to prolonged bumps, and "expectant mothers" who are pregnant will have different degrees of "nausea-vomiting" reactions
.
At this time, we need safe antiemetics to help suppress excessive "nausea-vomiting" responses
.

There is another group of people who are in urgent need of safe antiemetics, and that is cancer patients
undergoing chemotherapy.
Chemotherapy drugs can kill rapidly dividing tumor cells, but they also have a strong killing effect
on normal cells.
Nausea and vomiting are the main side effects of cancer chemotherapy, and cancer patients must take large doses of antiemetic drugs to survive the chemotherapy process
.

Image source: 123RF

"Because the specific mechanism of the 'nausea-vomiting' reaction is unknown, there are only a few
antiemetics that can be used clinically.
Only by deeply analyzing the delicate mechanism of the body's "nausea-vomiting" response can it be possible to develop more effective chemotherapy antiemetics
.
Professor Cao Peng pointed out
.

For more than three decades, limited by technical and experimental methods, people's understanding of its mechanisms has been limited
.
Researchers introduced that previous people used dogs, ferrets and other animals with vomiting behavior to find that cutting the vagus nerve can block the vomiting response, vomiting depends on the "gut-brain" axis between the gastrointestinal tract and the brain, and identified some brain regions involved in the vomiting response, and found that some serotonin receptors or neurokinin receptor antagonists can inhibit the vomiting response
.

However, there are three long-unsolved mysteries about the "nausea-vomiting" response that plague scientists: First, after the gastrointestinal tract is invaded by pathogens, what kind of intestinal cells give this important information to the vagus nerve? Second, what are the identities and characteristics of sensory neurons in the vagus nerve responsible for docking with intestinal "informants"? Third, after receiving information about pathogenic invasion from the vagus nerve, how can the brain quickly and synchronously initiate a series of defensive responses such as nausea and vomiting?

In this new study, Chinese scientists solved the mystery one by one, elucidating the molecular cell and neural circuit mechanisms
that trigger the "nausea-vomiting" response when the brain perceives the pathogen invasion.

▲ Mice "yue": After ingesting enterotoxin, mice showed retching behavior of "opening their mouths wide" (video source: provided by the research team).

In this study, the research team first established a research paradigm for food poisoning in mice
using enterotoxins produced by Staphylococcus aureus.
The researchers observed that mice ingested enterotoxin, although they did not vomit, exhibited "open mouth" yue behavior
.

The mice "yue", the researchers were pleasantly
surprised.
This is because rodents commonly used in laboratories such as mice and rats may be because the smooth muscles of the digestive tract are not developed enough to spit out the food in the stomach, and this "vomiting defect" has become an important reason for
the long-term lack of suitable animal models and research paradigms in the field of "nausea-vomiting".

But now, researchers have found that the retching behavior of mice can mimic the "vomiting" defense response after food poisoning in humans; In addition, ingestion of enterotoxin also caused mice to develop "nausea" similar to "nausea", forming conditioned taste avoidance
of beverages containing enterotoxin.
As a result, the researchers have successfully established a new research paradigm for food poisoning in mice
.

On this basis, the researchers found that enterochrome cells play an important role in the "nausea-vomiting" response and may be "informants"
that help the brain sense pathogenic invasion.
Intestinal chromaffin cells are intestinal endocrine cells distributed in the intestinal epithelium and synthesize serotonin
, which accounts for 90% of the body.
When the gastrointestinal tract is invaded by enterotoxins, these cells may be activated and release large amounts of serotonin
.
After knocking out the rate-limiting enzyme Tph1, which synthesizes serotonin in enterochromephilic cells, the "nausea-vomiting" response caused by enterotoxin is greatly reduced
.

Around enterochromaffin cells, vagus nerve sensory endings expressing the serotonin type 3 receptor gene (Htr3a+) receive important information
about pathogenic invasion by responding to serotonin.
This information is transmitted through the vagus nerve to the solitary tract nucleus of the brainstem, where it is received by a group of neurons expressing the tachykinin gene (Tac1+
).

Using optogenetics and chemogenetics, the researchers artificially activated these solitary nucleus Tac1+ neurons and found that they could directly trigger retching behavior and conditional taste avoidance
in mice.
Conversely, inactivating this group of neurons, or knocking out the Tac1 gene, prevents the "nausea-vomiting" behavior caused by the pathogen invasion
.

Further analysis can be seen that these solitary nucleus Tac1+ neurons "divide into two ways": on the one hand, they activate the disgust center in the pons and produce disgust related to "nausea"; On the other hand, activation of the respiratory center of the medulla oblongata may trigger retching motor behavior
by regulating the "retching" neurons responsible for simultaneous contraction of the diaphragm and abdominal muscles.

▲ Research schematic: The neurobiological mechanism by which the brain senses toxins and initiates the "nausea-vomiting" response (Image source: Reference [1]).

It is worth noting that experiments carried out by Cao Peng's team using the chemotherapy drug doxorubicin and others also proved that the above molecular cells and neural circuit mechanisms are also involved in the "nausea-vomiting" side effects
caused by chemotherapy drugs.
"This finding suggests that the 'nausea-vomiting' side effects caused by chemotherapy drugs may have been achieved by kidnapping evolutionarily conservative food poisoning mechanisms
.
" The researchers concluded
.

The Cao Peng Research Group of Beijing Institute of Biological Sciences warmly welcomes graduate students and postdocs who are passionate and motivated for scientific research to join the research team and explore the neural mechanism
of the brain's defense response triggered by the invasion of perceived pathogens.
For details, please refer to the Study Group homepage:

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Resources:

[1]: Xie et al.
, The gut-to-brain axis for toxin-induced defensive responses, Cell (2022), https://doi.
org/10.
1016/j.
cell.
2022.
10.
001