Ulcers after Cancer Therapy – New Directions

Reading time: 5 minutes

Kate Secombe

Cancer treatment- it’s not fun! The treatment can take hours in the hospital, it makes you feel fatigued and has a range of difficult side-effects, including nausea, vomiting, hair loss, and memory problems. But today, I want to focus on one, in particular, mucositis, and look at the research that is currently going on in this area. Mucositis is the ulceration and injury of the gastrointestinal tract and mouth stemming from cancer treatment, which can lead to bleeding, abdominal pain, and diarrhea. This results in increased hospital stays and the need to administer nutrition through an intravenous route. These interventions, as well as the use of pain management medication, results in a significantly increased economic cost, with Medicare data from Australia suggesting a cost of $1500 AUD per episode of severe diarrhea.

Cancer treatment can lead to diarrhea by damaging the cells lining the intestine. This allows bacteria to move into the body and cause infection, leading to pain, bleeding and diarrhea. Image created using BioRender
How cancer treatment can lead to diarrhea?

Mucositis can affect up to 4 in 5 patients, depending on the treatment regimen.  The currently available evidence is likely to substantially underestimate the larger societal burden and loss of quality of life caused by mucositis. This can be in the form of loss of productivity, the need for informal care arrangements and increases in anxiety and depression levels. Severe complications associated with toxicity to the digestive tract induced by chemotherapy, such as sepsis (an extreme reaction to infection throughout the body), can cause chemotherapy dose reductions. In profound cases, treatment cessation, relapse- a period when signs and symptoms of cancer reappear, and increased mortality are common as well.

Mucositis is an issue for many types of cancer treatments, but it is especially so for chemotherapy. It was widely thought that mucositis was caused simply due to chemotherapy killing the rapidly growing cells on the lining of the intestine. This would lead to the thinning of the intestinal wall causing ulceration and infection. However, we now know things are much more complex than this, and involves inflammation, gut bacteria, and even connections to our central nervous system.

We understand that transcription factors, which are proteins that control the rate of transcription from DNA to RNA, are activated differently by chemotherapy, allowing small signaling proteins called cytokines to be produced in higher numbers. These cytokines can promote inflammation and gaps in the intestinal barrier, which can lead to ulceration and infection- key to mucositis. We still don’t know why some people are affected much more severely than others though!

Currently, mucositis can be difficult to treat (especially as we don’t really understand what causes it). Recently, new guidelines were released by the Multinational Association for Supportive Care in Cancer (MASCC) on the best and new ways to deal with mucositis in the mouth and gut. Along with these guidelines, a publication describing current research highlights was also released. The key areas of interest this article highlighted were: the role of the microbiome – the complex ecological community of microorganisms that reside within us, host immune responses, and  connections between the nervous and immune systems. The major findings are described below:

The gut microbiome

The gut microbiome is a really hot topic at the moment in the scientific community. As you may already know, it refers to the billions of bacteria and other microorganisms that live in your intestine. We know that chemotherapy causes a change in the amounts and types of species living in your intestine. There’s an increasing amount of evidence to show that people’s individual microbiome composition- which could be tuned by chemotherapy, could affect the severity of their mucositis.

The intestinal nervous system

Connections between the nervous system and immune system are also becoming more thoroughly researched in this area. Did you know that you have a division of the nervous system in your intestine? It’s called the enteric nervous system, and is important for the secretion of enzymes to digest food, to keep intestinal contents moving and for communication with the brain. It’s believed that cells called glia in the enteric nervous system may change in number and function following chemotherapy treatment. This may lead to functional changes, contributing to pain and diarrhea. In models of disease where cells are grown in lab dishes, enteric glia cells have been shown to be useful in stopping changes in the permeability of the intestinal tract following chemotherapy. We still need to see more studies about this in humans to start understanding how treatments could fix these problems.

Immune response

The host immune response is really important as well. This refers to how our own body deals with the chemotherapy treatment – does it cause a big and potentially unnecessary reaction (sort of like an allergic reaction)? Or does it have no response at all?  Specific immune proteins called Toll-Like Receptors have been shown to be important in animal models of diseases in determining severity of mucositis. In one study, mice who were deficient in Toll-Like Receptor 4 and given chemotherapy had less diarrhea, less weight loss and gastrointestinal damage than normal mice having the same treatment. However, this may be difficult to translate into humans, as Toll-Like Receptor signaling is really important in ensuring that our body can fight off a tumor.

Treating cancer is so complex, and sometimes, what works to treat cancer has really negative effects on quality of life and other body systems. It takes time and research to balance these two factors. Now we know that more research is required in understanding how the gut microbiome can affect your risk of developing mucositis, and also working out how inflammation may cause the enteric nervous system to change. Researchers are looking at these ideas in animal models, cell culture models, and clinical trials. Hopefully one day, cancer treatment without risk of diarrhea and extreme pain will be within reach.

Edited by Manisit Das

Works Discussed

Bowen, J., Al-Dasooqi, N., Bossi, P., Wardill, H., Van Sebille, Y., & Al-Azri, A. et al. (2019). The pathogenesis of mucositis: updated perspectives and emerging targets. Supportive Care In Cancer, 27(10), 4023-4033. doi: 10.1007/s00520-019-04893-z

Cheadle, G., Costantini, T., Lopez, N., Bansal, V., Eliceiri, B., & Coimbra, R. (2013). Enteric Glia Cells Attenuate Cytomix-Induced Intestinal Epithelial Barrier Breakdown. Plos ONE, 8(7), e69042. doi: 10.1371/journal.pone.0069042

Secombe, K., Coller, J., Gibson, R., Wardill, H., & Bowen, J. (2018). The bidirectional interaction of the gut microbiome and the innate immune system: Implications for chemotherapy‐induced gastrointestinal toxicity. International Journal Of Cancer, 144(10), 2365-2376. doi: 10.1002/ijc.31836

Stringer, A., Gibson, R., Bowen, J., Logan, R., Ashton, K., & Yeoh, A. et al. (2009). Irinotecan-induced mucositis manifesting as diarrhoea corresponds with an amended intestinal flora and mucin profile. International Journal Of Experimental Pathology, 90(5), 489-499. doi: 10.1111/j.1365-2613.2009.00671.x

Wardill, H., Gibson, R., Van Sebille, Y., Secombe, K., Coller, J., & White, I. et al. (2016). Irinotecan-Induced Gastrointestinal Dysfunction and Pain Are Mediated by Common TLR4-Dependent Mechanisms. Molecular Cancer Therapeutics, 15(6), 1376-1386. doi: 10.1158/1535-7163.mct-15-0990

Image Credits

Cover Image- https://unsplash.com/photos/O7ibntiR6kI

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