On November 1, 2022, in a new study published in Cell, a research team led by researcher Cao Peng from the Beijing Institute of Life Sciences successfully established a sample to study toxin-induced retching in mice, mapping for the first time a detailed neural circuit involving the defense response of the gut-brain axis. The study provides new targets for the development of better anti-nausea chemotherapy drugs.
Vomiting is a very uncomfortable experience, but it is also the most important "life-saving" mechanism in the evolution of many mammals, including humans. Many foodborne bacteria produce toxins in the host when ingested. After sensing their presence, the brain initiates a series of defense responses, such as nausea, retching, and vomiting, to get rid of these toxic substances while developing a sense of aversion to foods that taste or look the same (taste avoidance).
Over the past few decades, scientists have conducted in-depth research on the neurobiology of toxin-induced defense responses. Because rodents don't vomit, scientists can't study this process in mice or rats. Studies using animal models with the ability to vomit, such as cats and dogs, have shown that the gut-brain axis is associated with toxin-induced nausea and vomiting. However, the mechanisms remain elusive.
In the new study, the research team noticed that while the mice did not vomit, they exhibited unusual mouth-opening behavior, similar to retching, after being infected with staphylococcal enterotoxin A. Staphylococcal enterotoxin A (SEA), a common bacterial toxin produced by Staphylococcus aureus, also causes food poisoning in humans.
In animal models of vomiting, the physiological feature of retching is the simultaneous activation of the diaphragm (inspiration) and abdominal (expiration) muscles. They found that SEA-induced mouth opening movements in mice were accompanied by synchronized burst-like electromyography (EMG) activity of the diaphragm and external oblique muscles of the abdomen; In control mice, normal ventilation parallels alternating EMG activity of these muscles.
In SEA-treated mice, the amplitude and frequency of diaphragm EMG in the open mouth stage were significantly higher than in the control group. These data provide physiological evidence that abnormal mouth opening movements in mice caused by staphylococcal enterotoxin A are retch-like behaviors. The neural mechanism of retching is similar to vomiting.
In this experiment, the team successfully established a paradigm for studying toxin-induced retching in mice. With this example, scientists can observe the brain's defense response to toxins at the molecular and cellular level.
In the intestinal epithelium, there is a class of intestinal endocrine cells called enteric chromaffin cells. Using the newly established research paradigm, the researchers found that enteric chromaffin cells play an important role in the "nausea-vomiting" response and may be "informants" that help the brain sense pathogen invasion. These cells synthesize serotonin (5-HT), which accounts for 90% of the body.
When the gastrointestinal tract is invaded by enterotoxin, enteric chromaffin cells may be activated and release 5-HT in large quantities. The released 5-HT binds to receptors located on intestinal vagus sensory neurons, which transmit signals from the gut along the vagus nerve to kinin gene (T ac1+) neurons in the dorsal vagus complex (DVC) of the brainstem. Tac1+ DVC neurons drive retching-like behavior and conditioned flavor avoidance by projecting divergent projections to the ventral respiratory group and lateral parabrachial nucleus, respectively.
When the researchers inactivated Tac1+DVC neurons, they could prevent pathogen invasion from triggering retching behavior and conditioned taste avoidance in mice.
In addition, the researchers investigated whether chemotherapy drugs activated the same neural circuits. Often, chemotherapy drugs also cause defensive reactions such as nausea and vomiting in the receptors. After injecting mice with the common chemotherapy drug doxorubicin, they triggered retching behavior in mice; But when the team inactivated their Tac1+ DVC neurons, or knocked out Tph1, a rate-limiting enzyme gene that synthesizes 5-HT in enteric chromaffin cells, the animals' retching behavior was significantly reduced.
Currently, some anti-nausea drugs used in chemotherapy patients, such as granisetron, work precisely by blocking 5-HT receptors. The study also explains why the drug works.
In summary, the team identified a set of moleculturally defined neural circuits of the gut-brain axis with the brain by developing an experimental paradigm based on "nausea-vomiting" induced by food poisoning in mice, suggesting that the immune neuroendocrine axis may be involved in toxin-induced defense responses. The research lays the groundwork for the development of better therapeutic drugs.
Paper Link:
https://doi.org/10.1016/j.cell.2022.10.001
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