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I believe that many people have experienced the impact of the first wave of the new crown epidemic this winter and are on the road
from "yang" to "yin".
Although the high fever has subsided, the coughing sound is still rising and falling, and this is a self-protection mechanism of the human body, through coughing and sputum, the secretions in the throat, trachea and bronchi are excreted, cleaning up the "first battlefield"
with the virus.
Similarly, nausea and vomiting are a self-protection mechanism
for the body.
When we eat food that may be contaminated with parasites or pathogens, vomiting is one of the important ways for the body to expel toxins, so how does the human body "know" and "direct" the gastrointestinal tract to vomit? Among the side effects of cancer chemotherapy, nausea and vomiting are also one of the most disgusting phenomena for patients, can we find a target to block this phenomenon and allow patients to have a better treatment experience?
Recently, a team from the Institute of Life Sciences in Beijing, China, tracked a similar vomiting process from the intestine to the brain in mice, and although the mice did not really vomit because of their long esophagus and weak muscles, at the molecular and cellular level, the researchers still established a complete gut-brain defense response
to toxins.
The results are "The gut-to-brain axis for toxin-induced.
"
defensive responses" was published in Cell
.
Figure 1 Research results (Source: [1])
understood.
To this end, the researchers developed a mouse-based vomiting paradigm to answer
the above three questions.
Retching and "nausea" researchers performed staphylococcal enterotoxin A on mice SEA) to cause food poisoning
.
Although the mice did not actually vomit, the SEA-treated mice showed unusual mouth-opening movements
in control saline-treated mice.
This retching-like behavior is associated with simultaneous activation of the diaphragm and abdominal muscles, and the neural mechanism is similar
to vomiting.
The researchers measured the angle and length of time at which the mice's mouths opened to determine whether retching occurred
.
In addition, SEA induces conditioned flavor avoidance (CFA) that reflects "nausea," defined as the time to drink the conditioned taste divided by the total drinking time
.
Figure 2 Retching behavior in mice (Source: [1])
Tac1+ DVC neurons
Past studies have shown that the vagus nerve is critical in toxin-induced vomiting, and the target brain area of the vagus afferent nerve is the dorsal vagal complex (DVC)
in the medulla.
The researchers labeled
neurons that expressed the Fos gene.
Fos genes begin to be expressed within a short period of time when neurons are activated and can be used as a marker of neuronal activation
.
The results showed that a large number of neurons in DVC of SEA-treated mice were labeled, and the chemical genetic inactivation of these neurons would impair gagging-like behavior and CFA, indicating the involvement
of the gut-brain axis in it.
Further quantification of the expression of several neuropeptide-coding genes in DVC found that preprotachykinin 1 (Tac1) expressed Fos 3 h after SEA treatment and was highly likely involved in retching-like behavior and CFA
.
Subsequent inactivation of Tac1+ DVC neurons impairs retching-like behavior but does not impair CFA
.
The photoinduced postsynaptic current through Tac1+ DVC neurons can be blocked by glutamate receptor antagonists, while GABA A receptor antagonists have no effect on it, and it can be found that the neurotransmitter released by Tac1+ DVC neurons is glutamate rather than GABA
.
Knocking out the Tac1 gene or the Slc17a6 gene expressing the vesicle glutamate transporter both impairs retch-like behavior and CFA, suggesting that glutamate released by Tac1+ DVC neurons and Tac1-encoded neuropeptides do indeed participate.
Gut-brain circuit
To determine the entero-brain circuit that innervates Tac1+ DVC neurons, the researchers performed retrograde tracing using recombinant rabies virus and found that Tac1+ DVC neurons were innervated
by ipsilateral vagus sensory neurons and single synapses in several brain regions.
The mucosal end of the intestinal villi mucosa of vagus nerve sensory neurons is close to enterochromaffin (EC) cells
.
EC cells are responsible for the synthesis and secretion of serotonin (5-HT), so do vagus sensory neurons respond to 5-HT?
The researchers further knocked out genes necessary for the synthesis of 5-HT in mouse EC cells, resulting in impaired gagging-like behavior and CFA
.
Fluoxetine alone (a common antidepressant that blocks neuronal reuptake of 5-HT) alone does not cause retch-like behavior, but promotes SEA-induced retching-like behavior, suggesting that rapid reuptake of 5-HT may be involved in the regulation
of toxin-induced vomiting.
Tac1+ DVC neurons were imaged using fluorescent indicators and found that when mice exhibited gagging-like behavior, fluorescence increased instantaneously, and the fluorescence signal was able to align with gagging-like behavior in time and mouth amplitude, indicating that Tac1+DVC neurons encoded
the amplitude and duration of gagging-like behavior.
Both the severation of the vagus nerve or the use of HT3R antagonists significantly reduced the amplitude of the fluorescent signal, indicating that this signal was transmitted from the gut to Tac1+ DVC neurons from vagus sensory neurons
.
Artificially activating Tac1+DVC neurons using optogenetics can also induce gagging-like behavior in mice, and the time depends on the frequency of photostimulation and laser power
.
Chemical genetic activation of Tac1+DVC neurons was also able to induce gagging-like behavior and CFA, indicating that activation of Tac1+DVC neurons was sufficient to make mice respond.
Video S1 optogenetically-induced retching behavior (Source: [1])
Investigating the downstream of Tac1+DVC neuronal projection, it was found that some Tac1+DVC neurons projected to the ventral respiratory group (rVRG) of the ventrolateral medulla oblongata, and the other part was projected to the lateral parabrachial nucleus (LPB)
of the pons 。 Past studies have shown that rVRG is associated with vomiting and LPB is associated with aversion to taste memory, and subsequent experiments have also verified that the two groups of Tac1+ DVC neurons projected into these two different regions are indeed involved in retching and CFA
, respectively.
Testing how SEA and the chemotherapy drug doxorubicin evoke the gut-brain circuitry identified in this study found that SEA and doxorubicin do not directly activate intestinal EC cells, but first cause inflammatory damage in the intestine, and intestinal epithelial cells then release the alarm cytokine IL33 to indirectly induce EC cells to release 5-HT.
At this point, toxins - intestinal epithelial cells - IL33 - EC cells - 5-HT - vagus nerve sensory neurons - Tac1 + DVC neurons - rVRG/LPB—/CFA
。
Figure 3 Entero-brain circuit inducing vomiting by toxins (Source: [2])
This study identifies the gut-brain circuits involved in toxin-induced defense responses at the molecular and cellular levels, contributing to a better understanding of the side effects
of food poisoning and chemotherapy.
This study opens up a new path for the development of anti-vomiting drugs in the future, and the corresponding author of the study, Dr.
Cao Peng of the Beijing Institute of Life Sciences, said: "In addition to foodborne bacteria, humans encounter many pathogens, and our bodies are equipped with similar mechanisms to expel these toxic substances, and studying how the brain senses the presence of pathogens and initiates a response to clear them is an exciting new area of research
.
" ”
Written by | Wind Standing Night
Typesetting| Qiao Weijun
End
Resources:
[1] Xie Z, Zhang X, Zhao M, et al.
The
gut-to-brain axis for toxin-induced defensive responses.
Cell.
2022 Nov
10; 185(23):4298-4316.
e21.
doi: 10.
1016/j.
cell.
2022.
10.
001.
Epub 2022 Nov 1.
PMID: 36323317.
[2] Jane Y.
Chen, Richard D.
Palmiter, A
gut-retching discovery, Cell, Volume 185, Issue 23, 2022, Pages 4249-4251, ISSN
0092-8674, https://doi.
org/10.
1016/j.
cell.
2022.
10.
015.
