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Getting gut bacteria to improve cancer treatment

There is an ever increasing plethora of information about our gut microbes, with these little critters thought to be involved in things from obesity to Parkinson's disease. It is therefore not surprising that their involvement in cancer is an area of intense interest, with oncology journals busting at the seams with new information.

The microbiome has an increasingly evident role in the aetiology of cancer, as well as cancer risk, as the gut microbiome co-develops with the host, sitting at the interface of multiple anti-neoplastic, carcinogenic, immune and inflammatory pathways. However, an emerging focus of ‘oncomicrobiome’ research is now defining its role in the efficacy and toxicity of treatment.

You see, the bacteria that inhabit your gut do much more than digesting your food and creating gas. They are able to produce hormones we ourselves are unable to. They communicate with our immune system, and most importantly for cancer, they are able to metabolise all sorts of drugs, including those that are found in chemotherapy - the mainstay treatment for cancer. ![endif]--![endif]--

This directly places your gut bacteria at the forefront of cancer treatment, and new research is trying to understand how we can exploit our gut microbes to enhance the outcomes of cancer treatment.

So ... do our microbes actually cause cancer?

As interesting as that would be, the science does not quite suggest that. For cancer development, the most important role of the gut microbiome is its ability to modulate the host's immune system, as this is ultimately what identifies mutated cancer cells and eliminates them. The interaction that exists between the host microbes and immune system is bidirectional, meaning each affects one another in different ways. For example, high levels of bad bacteria will promote an immune response characterised by high levels of molecules called pro- inflammatory cytokines. A microbiome with lots of good bacteria, called commensal bacteria, will promote low levels of these pro-inflammatory cytokines, replacing them with anti-inflammatory cytokines that calm the body's immune system.

However, research has also shown that mice that are genetically altered to have high levels of these anti-inflammatory cytokines actually have higher levels of bad bacteria. Most importantly, these mice were at a higher risk of developing bowel cancer. This is most likely because their immune system was not able to identify and eliminate cancer cells.

The most interesting part of this study was that the scientists were able to prevent the development of bowel cancer by a faecal transfer from a healthy mouse. This involves collecting the poo from a donor mouse and feeding it to a recipient mouse. Poo from the donor mouse is rich in good bacteria. Once transferred to the recipient mouse, these new bacteria flourish in the gut changing the composition of the microbiome, and altering their risk of developing cancer.

Although this has not been directly studied in humans, it is understood that disruption to the normal ecosystem of the gut can affect the risk of cancer. One study recently reported that long-term antibiotic use increased the risk of bowel cancer. This is because antibiotics kill the good bacteria in your gut, just like the mice in the experiment explained above.

So, although in its infancy, the gut microbiome seems to play a role in the development of cancer through its ability to regulate and change the way in which our immune system detects and kills cancer cells. But how we manipulate, or exploit these bacteria to prevent cancer still remains a challenge.

What about the treatment of cancer?

Cytotoxic drugs such as chemotherapy continue to be the mainstay treatment for many cancers, yet they have an unpredictable treatment response and are associated with unwanted side effects. Both the response to treatment (i.e. whether the person achieved remission) and the toxic side effects of chemotherapy remain very variable. Take for example, two people with cancer. They are given the same chemotherapy drug, at the same dose. It is not uncommon for one person to respond very well, and the other show no improvement. It is also likely that one will experience very severe side effects, and the other none.

The disparity that exists in these responses has baffled scientists and oncologists for decades. Much of the research in this area has focused on the genetic factors that determine a patient's response to treatment, and research has certainly shown different genetic factors do play a role in their development. However, they don't account for all the differences, thus other determinants of treatment response must exist.

BUT, a recent review published in Nature suggests that the gut microbiome might be the culprit for determining an individual's response to treatment.

One of the best ways to investigate the gut microbiome is using mice that lack any bacteria at all. These "germ-free" mice are bred in completely sterile conditions, and have no bacteria anywhere in their body. Research has shown that chemotherapy is less effective in these mice, compared to normal mice, and their tumours therefore grow much more quickly.

This is because many chemotherapy agents rely on particular bacteria to convert them into their active forms, and without them much of the chemotherapy drug remain in their inactive state. However, we also know that this response is also due to these germ-free mice having different immune responses, which are unable to kill tumour cells in a process called inflammation. In this study, these germ-free mice had much lower levels of pro-inflammatory cytokines in their tumours compared to normal mice.

Once again, by supplementing these mice with the poo from healthy mice, their response to chemotherapy is greatly improved and reflects that of the normal mice.

The importance of the immune system in chemotherapy efficacy has also been shown in mice that are genetically modified. Research has shown that when an immune receptor (called TLR4) is genetically deleted, mice respond poorly to chemotherapy and their tumours grow much faster than normal. TLR4 is an immune receptor that is found in the gut. It acts as the interface between the gut bacteria and the immune system, hence when it is deleted the gut microbiome cannot communicate with the immune system.

Interestingly, these mice have also been used to investigate the side effects of chemotherapy, showing less severe diarrhoea compared to normal mice. Diarrhoea remains a significant side effect of chemotherapy. It is acutely life threatening as it starves patients of vital nutrients and makes them susceptible to infection and death.

Like cancer development and treatment, diarrhoea is associated with changes in the gut microbiome, but we now think that the levels of bacteria found in a person's gut before they start chemotherapy might be important in how they respond. We have shown that mice with high levels of Proteobacteria (before chemotherapy), had much worse diarrhoea compared to mice with low levels of these bacteria.

This research supports growing evidence in human trials showing that the levels of gut bacteria in the poo of patients before they start cancer treatment predicts their likelihood of developing diarrhoea.

So what does this mean for the treatment of cancer?

This exciting new research suggests that modifying the microbiome might be a powerful to optimise cancer treatment outcomes. This could be in the form of poo transfer, probiotics or even something as simple as changing someone’s diet.

And the ability to understand someone’s risk, and modify it before chemotherapy starts, can ensure the perfect balance between chemotherapy response and toxicity is achieved.

Work is currently being performed in Adelaide to identify the specific bacteria that are critical in determining chemotherapy response. Once this has been achieved, methods of mitigating risk can be evaluated and translated to patients.


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