Entering Defense Mode! The Gut-Brain Response To Perceived Toxins
By Zahraa Chorghay, Montréal
It’s an uncomfortable feeling, your insides pushing upwards through you, making you retch, sometimes resulting in you vomiting the contents of your digestive system, and other times, just persisting within you. When you’re nauseous, it’s difficult to think about anything, much less do something. You just hang in there, praying for that sensation to disappear (either on its own or with medication), or ffs to just throw up already, so you can finally stop feeling utterly disgusting.
Nausea is a common complaint not only in people with inflammatory bowel disease (IBD) but across many different conditions like “stomach flu” and other infections, sensitivity to strong smells, morning sickness during pregnancy, or even in response to certain medical treatments (such as in cancer). There is a lot of advice floating out there on what you should or shouldn’t do to deal with your nausea (e.g., NHS, accessed 2024).
Here, I focus on the why and how of retching, nausea, and vomiting by discussing [just some of] the basic neurobiology underlying these uncomfortable symptoms.
Defending against toxins
When a toxin is sensed in your gut, your brain goes into defense mode and orchestrates retching, nausea, and vomiting behaviours. This coordinated response does not only expel the toxin from your body, but also helps prevent future exposure to that toxin by forming an unpleasant association between the toxic substance and your bodily response.
Typically, a toxin will get into your gut through contaminated food that has toxin-producing bacteria, or through direct ingestion of a harmful substance. For example, during excessive drinking, your liver can get overloaded and unable to successfully filter out all of the alcohol from your blood (Cleveland Clinic, accessed 2024). Sensing the elevated blood alcohol levels, your brain triggers its coordinated motor responses such that you throw up, removing excess alcohol from your body. Furthermore, earlier episodes of inebriation teach you how much alcohol is too much for you (i.e. how many drinks does it take before you start throwing up or pass out?), so you are less likely to consume excessive liquor in the future.
Additionally, in autoimmune diseases like IBD, the body mistakes its own tissue as pathogenic, so the nausea you experience in IBD may be from your body mistakenly assuming you were exposed to toxins. In response, as it does during toxin exposure in an otherwise healthy body, the brain triggers retching, nausea, and vomiting.
The gut-brain pathway
The defensive response relies, firstly, on receptors in your gut and other peripheral regions of your body detecting the toxin, such as when the toxin has a chemical structure that can bind to a chemoreceptor (chemical receptor), changing its conformation (shape). This change then leads to a cascade of chemical signals in your gut cells, which then relay the information through the vagus nerve to the brainstem. In the brainstem, a region called the dorsal vagal complex (DVC) acts as the brain’s relay centre, receiving information from your organs as well as sending information to other brain regions, including the ventral medulla and hypothalamus (Hornby, 2001). These areas of the brain coordinate retching, nausea, and vomiting behaviours.
For example, Xie et al. (2022) studied the toxin-induced defensive response by injecting mice with a bacterial toxin called Staphylococcal enterotoxin A (SEA). In these mice, in response to SEA, gut enterochromaffin cells release a molecule called serotonin. (Yes, this is the same serotonin you may have heard of as the “feel good” chemical in the brain! But here, serotonin has a different function as a gut messenger.) Serotonin release then activates sensory neurons in the vagus nerve, which carry the information to a specific subset of neurons in the DVC. These brainstem DVC neurons in turn activate a specific neuronal population in the medulla. Together, the DVC and medullary neurons coordinate motor signals, sent also via the vagus nerve to the site of action in the body, thus inducing the mouse’s retching behavior.
Keeping this cascade of signals in mind, newer medications to prevent nausea or vomiting are designed to act on receptors in vagal nerve endings or in the DVC. For example, you can prevent vomiting through blocking neurokinin-1 receptors (NK1R) in the DVC or by activating cannabinoid receptors (CB1R) – also in the DVC – using the active component of marijuana called THC (delta(9)-tetrahydrocannabinol).
Importantly, while scientists have made strides to understand the gut-brain pathway, including the impact of the gut microbiome, we still have many knowledge gaps. The mechanisms underlying gut sickness responses are a subject of active investigation, and can lead to recognizing new therapeutic targets to dissipate the discomfort of nausea in IBD, infection, oncology, and beyond.
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