No Pain, No Gain: Commensal Bacteria Help Chemotherapy Through Painful Side Effects

Cancer is still an unmet clinical challenge. Tens of thousands of people are diagnosed with cancer every day. In the US alone, more than half a million people died from cancer in 2016. The progress in our knowledge of the underlying molecular mechanisms of cancer leads us to develop more effective and efficient therapies.

Chemotherapy, the use of one or more drugs that work throughout the whole body, is still one of the most routine treatments for most cancers. Oxaliplatin, for instance, is a medication used for the treatment of colorectal cancer. Chemotherapy is not without toxic side effects on the general health of patients. Indeed, owing to these adverse effects, patients who are diagnosed with cancers are more susceptible to infectious diseases, therefore, are routinely given antibiotics as part of their treatment. What distinguishes the therapeutic role of Oxaliplatin is its mechanism of action in regard to commensal bacteria; these peaceful microbes in our body have been shown to be required for an optimal response to cancers, yet in a painful manner. But, how could commensal bacteria affect the therapeutic role of cancer medications?

Back in November 2013, Goldszmid and colleagues at the National Cancer Institute, MD, found that intact commensal bacteria is required for the optimal efficacy of anticancer therapies. These “friendly” bacteria inhabiting our body had already been shown to influence development, metabolism, and immunity, yet their systemic effect on the inflammatory mechanisms had not been explained. Changing inflammation in the tumor microenvironment is the well-characterized mechanism to explain many tumor-killing effects of anticancer drugs. In their study, Goldszmid and colleagues revealed that commensal bacteria, especially those inhabiting our digestive system, independently from immune cells modulate the toxicity of chemotherapeutic drugs by changing the inflammatory tone required for response to different chemotherapeutic drugs. Thus, gut bacteria has been proved to be necessary for the tumor-killing effects of anticancer drugs such as Oxaliplatin, challenging the use of antibiotics in patients diagnosed with cancers.

On the other hand, 30% of chemotherapy procedures with Oxaliplatin are associated with peripheral neuropathy, a chronic pain state in response to changes in the inflammation in the tumor microenvironment. Peripheral nerves send sensory signals from the environment to the spinal cord. Pain signals will then be transmitted from the spinal cord to the brain, where they are being processed, resulting in the perception of sensory signals. Thanks to your healthy nervous system, for example, your feet feel the coldness in winter. So, you can imagine what damage to these peripheral nerves could cause: numbness, tingling, cramping, and in the worst case scenario, pain. The challenge for scientists is how to reduce the painful side effects of chemotherapeutic drugs, like Oxaliplatin, while maintaining their beneficial tumor-killing properties. The first step to find an answer to this question is to unravel the underlying mechanisms behind such pathological side effects.

Interestingly, Mao and colleagues at the Massachusetts General Hospital, MA, have recently pointed out that gut bacteria, beyond their significance in the treatment of cancers, also plays a key role in the development of pain after chemotherapy. In the absence of gut bacteria, Oxaliplatin is ineffective in stimulating the necessary inflammatory response required to manifest its tumor-killing properties. Gut bacteria is thus needed to permit the immune cells to mount an inflammatory response. This permissive signal, in the form of a bacterial cell wall component referred to as LPS, is sensed by a specific receptor, which then activates the underlying pain signals in the spinal cord, leading to the painful side effects. Therefore, commensal bacteria enable immune cells to manifest the inflammatory response required for cancer therapy and do so in a painful manner. In other words, exacerbating pain seems to be unavoidable when gut bacteria demonstrate their protective effects against cancers.

Gut bacteria seems to be more than just a normal flora in our bodies. Recent advances in our knowledge suggest that these bacteria are an integral part of different mechanisms with far-reaching effects. The significant role of gut bacteria in the perception of pain after chemotherapy opens up a new avenue for more comprehensive pain and cancer research, aiming to develop more efficient cancer therapies with minimal side effects.

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Written by Amin Kamaleddin

Illustrated by Jooyeun Lee

Translated by Reyna Ediss

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References

Iida, N., Dzutsev, A., Stewart, C. A., Smith, L., Bouladoux, N., Weingarten, R. A., . . . Goldszmid, R. S. (2013). Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. *Science, 342*(6161), 967-970. doi:10.1126/science.1240527

Shen, S., Lim, G., You, Z., Ding, W., Huang, P., Ran, C., . . . Mao, J. (2017). Gut microbiota is critical for the induction of chemotherapy-induced pain. *Nat Neurosci, 20*(9), 1213-1216. doi:10.1038/nn.4606