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The joint contribution of cannabinoid/serotonergic pathways in chemotherapy-induced diarrhoea.

If you’re a long term subscriber to this blog, you may be aware that embarrassing and painful side effects are a major downside of cancer therapy, however they must be endured by recipients of this otherwise life-saving treatment. For decades, scientists have searched for a solution to this problem, however have had little success, directly exemplified by the absence of an effective treatment for gastrointestinal mucositis (injury to the lining of the gut) and its subsequent clinical manifestation, chemotherapy induced-diarrhoea (CID). This symptom is particularly debilitating, as it not only prevents people from indulging in their favourite foods, participating in beloved hobbies, and engaging with friends and family, but it places them at a heightened risk of infection, dehydration and malnutrition; all of which are potentially deadly to someone with cancer. This can be extremely frustrating, impacting a patients willingness and fundamental ability to complete treatment, leaving these patients with more than just the literal shits! While minor advances in this field have been made, more can and should be done, to combat these nasty side effects and to reduce the psychosocial, clinical and economic burdens that unavoidably reside with CID.

So far, the approaches taken to understand the mechanisms behind CID have been rational and thoughtful (as all science should be), but also conventional, perhaps revealing a limiting factor that explains the current lack of translational, clinical outcomes emerging from mucositis research. A slightly more controversial approach that is currently under investigated but holds extraordinary promise in the field, is the role of cannabinoid and serotonergic pathways in CID.

But what exactly are these pathways?

Well, as their name suggests, cannabinoid (CB) receptors are a part of the endocannabinoid system, which the drug cannibas acts on to produce its infamous, psychotropic effects. However, no bodily system is entirely one-dimensional, so the CB pathway can do more than just heighten one’s senses or cause feelings of euphoria. For example, and more therapeutically relevant, the CB pathway has been shown to be involved in inflammation (a damaging gut response to chemotherapy), gut motility (how quickly food moves through the gut), and gut secretion (how well food is absorbed by the digestive system). As inflammation is a hallmark feature of mucositis, and gut motility and secretion are key mechanisms behind diarrhoea, we are now interested in how this pathway can be exploited to prevent injury to the intestine, caused by chemotherapy. Secondly, CB receptor expression is altered in human and animal models of inflammatory bowel disease (IBD). While differences exist between IBD and mucositis, such as the chronic and acute nature of each condition respectively, they share a common underlying mechanism in inflammation. Thus, IBD data can be used to draw parallels to, and make predictions about mucositis. Hence, knowing IBD alters CB receptor expression, it is plausible to speculate that CB receptor expression will also be implicated during mucositis.

Just like the CB system, it is understood that the serotonergic pathway is involved in diarrhoea and events that are relevant to mucositis. Now, for a long time the gut has been referred to as our other brain and this is simple because, just like the cells in our brain, gut the is able to produce its own hormones. Serotonin is an example of one of these hormones, and it is known to control things like motility (how fast food moves through your gut), secretion (which controls water movement and diarrhea) and inflammation (a hallmark feature of mucositis). Unsurprisingly, this pathway has also been implicated in human and animal models of IBD, and is thus suspected to play a similar role in a mucositis associated-inflammation. Furthermore, careful consideration and collation of the following information, allows us to predict that mucositis, caused by chemotherapy, will impact the production of serotonin in the gut;

1) enterochromaffin cells produce 90% of the gut’s serotonin

2) the microbiome regulates enterochromaffin cells

3) chemotherapy alters the microbiome

Another important concept to consider is how CB and serotonergic systems might interact in the gut to propagate mucositis. It is already known that these pathways interact in other parts of the body, such as the brain, and as has already been described, regulate common gastrointestinal events (secretion, motility and inflammation). This information further advocates for the investigation into these two systems in mucositis pathogenesis.

If you’re still unconvinced that these pathways need to be explored, consider this...

On top of governing mucositis-related gut function s, the CB system has also been shown to boost appetite and mood, whether modulated by medical cannabis use or my modulating these receptors with pharmacological agents. Importantly, chemotherapy severely impacts appetite, cognitive function and mood, each of which severely impacts patient quality of life during and after cancer therapy. Thus, in a best case scenario, investigating the CB pathway in mucositis will ultimately reveal a potential for medicinal cannabis to be used in a ‘joint’ (excuse the pun) effort, with anti-cancer treatments, to not only improve patient quality of life, but to target the key mechanisms behind diarrhoea.

In summary, exploring the role of CB and serotonergic pathways in mucositis pathogenesis may lead to a more sophisticated understanding of the mechanisms behind CID, resulting in a novel and holistic supportive care option, that could help stop cancer from giving people the shits.

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