Investigating the role of the gut-brain axis in defense reactions

Investigating the role of the gut-brain axis in defense reactions

In a recently published study in Cell Reports The researchers examined the function of the gut-brain axis in defense reactions induced by toxins.

Lernen: Die Darm-Hirn-Achse für Toxin-induzierte Abwehrreaktionen. Bildnachweis: Pikovit/Shutterstock

background

In recent decades there has been a lot of research into the neurobiology of toxin-induced defense reactions. Studies show that a gut-brain axis is linked to toxin-induced vomiting and nausea. There are important questions that need to be addressed regarding the mechanics underlying the gut-brain axis.

First, it is still unknown which essential core of the solitary tract (NTS) neuronal subtypes and efferent networks coordinate toxin-induced protective responses. Second, extensive research is needed to understand the molecular structure and physiological properties of the vagal sensory neurons that form the gut-brain axis.

Thirdly, cellular mechanisms in the intestine that are essential for toxin-induced defense reactions also need to be further researched.

About studying

In the present study, researchers assessed defense responses elicited by bacterial toxins using a mouse-based paradigm.

The team used mice to create a model of the defense responses produced by toxins. Food poisoning in emetic animals is caused by staphylococcal enterotoxin A (SEA), an exotoxin produced by Staphylococcus aureus. After intraperitoneal injection of SEA, the behavior of mice was observed for three hours. The open mouth angle of the mice was observed and the time course of this angle was recorded to define the mouth opening movements. The period when the opening angle was more than 0.13 peak angle was called the “open” phase of mouth opening in SEA-treated mice. The maximum angle and duration of mouth opening activities in mice treated with saline or SEA were also quantified. The team also observed the actions of these muscles in the subjects.

The team conducted two control studies to learn more about choking behavior. Mouth opening movements are also part of the gaping response elicited by intraoral administration of bitter stimuli such as quinine. Next, the researchers examined whether different emetic drugs could cause mice to exhibit gagging-like behavior. As part of the study paradigm for SEA-induced CFA, the conditioned flavor avoidance index (CFA) was determined, which is derived from dividing the time spent consuming the conditioned flavor by the total time spent drinking. Additionally, the similarity between SEA-induced retching-like behavior and CFA with toxin-induced vomiting in emetic species was evaluated.

Results

All SEA-treated mice exhibited aberrant mouth-opening behavior, whereas saline-treated mice did not. The mouth opening movements of the saline-treated mice showed a small amplitude sporadically and did not last long. Two clusters of mouth opening behaviors were observed in SEA-treated mice. The spontaneous mouth opening behavior of saline-treated mice was mimicked by one movement cluster, but the other cluster showed stronger amplitude and longer duration. Early research compared SEA-induced mouth opening behavior to “choking in mice.”

Omics eBook

Compilation of the top interviews, articles and news from the last year. Download a free copy

The team also discovered that the diaphragm, along with the external obliques, were involved in simultaneous bursting electromyogram (EMG) activity due to SEA-triggered mouth opening activity. Normal breathing occurred simultaneously with the alternating EMG activity of these muscles in control mice. The diaphragm EMG frequency and amplitude during the “open” phase of mouth opening activities in SEA-treated mice were significantly higher than those during the “closed” phase. These results provide physiological evidence that the unique mouth opening behavior caused by SEA in mice is gagging-like movements.

The team discovered that when mice were exposed to these enterotoxins, they exhibited gagging behavior, with the amount of time they spent opening their mouths being influenced by the dosage of each enterotoxin. Additionally, the mice exhibited gagging-like behavior in response to additional emetic agents such as copper sulfate and protoveratrine A. Furthermore, mice treated with SEA developed CFA in a dose-dependent pattern.

Pretreatment with an antiemetic neurokinin-1 receptor (NK1R) antagonist called CP-99994 reduced SEA-induced nausea-like behavior and CFA. Granisetron, a 5-HT3R antagonist, also reduced SEA-induced CFA and gagging-like behavior. These results imply that SEA triggers defense responses in mice that rely on NK1R- and 5-HT3R-mediated signals. Therefore, the researchers investigated the mechanisms behind toxin-induced defense responses in mice using the developed experimental paradigm.

When these neurons were chemogenetically inactivated with an intraperitoneal dose of clozapine N-oxide (CNO), SEA-induced choking behavior as well as CFA was inhibited. These results demonstrated that SEA-induced defense responses in mice involve a gut-brain axis. Doxorubicin-induced defense responses were significantly reduced when chemogenetically inactivated by Tac1+ DVC neurons. The Tac1 gene deletion in the DVC or the Slc17a6 deletion in the Tac1+ DVC neurons both strongly reduced doxorubicin-induced defense responses. Deletion of Tph1 in Vil1+ intestinal epithelial cells prevented 5-HT production in EC cells, which greatly reduced doxorubicin-induced defense responses.

In contrast to CFA, doxorubicin-induced gagging behavior was selectively reduced by chemogenetic inhibition of rVRG-projecting Tac1+ DVC neurons. Instead of affecting choking behavior, chemogenetic ablation of LPB-projecting Tac1+ DVC neurons specifically reduced doxorubicin-induced CFA. These results imply that Tac1+ DVC neurons may also be crucial in the immune responses induced by chemotherapy in mice.

Overall, the study results highlighted that the paradigm developed by the researchers was able to efficiently identify distinct brain circuits involved in the coordination of toxin-induced defense responses in mice and a molecularly defined gut-to-brain circuit involved in the transmission of toxin-related signals.

Reference:

• Zhiyong Xie, Xianying Zhang, Miao Zhao, Fengchao Wang, Congping Shang, Peng Cao. (2022). Die Darm-Hirn-Achse für Toxin-induzierte Abwehrreaktionen. doi: https://doi.org/10.1016/j.cell.2022.10.001 https://www.cell.com/current-biology/fulltext/S0092-8674(22)01314-9

.