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Chemotherapy-induced peripheral neuropathy (CIPN) is a relatively common side-effect of some types of chemotherapy, affecting between 19 to 85% of people. It refers to a few different conditions involving damage to the peripheral nervous system. The peripheral nervous system sends signals back to the central nervous system (brain and spinal cord) as well as other parts of the body. The symptoms of CIPN occur mainly in the hands and feet and include tingling, burning, numbness, weakness, pain and cramping. Severity ranges widely in people, from being annoying to being completely disabling. Sometimes CIPN will last for a few weeks after treatment finishes, but in other cases it can last for many years. Unfortunately, there are currently no effective treatments for CIPN, leading to a reduced quality of life.
The mechanisms of CIPN are still being determined, but a role for the connections between our intestine and our brain, known as the gut-brain axis, has recently been hypothesised. A new paper by Ramakrishna and colleagues in the journal Scientific Reports has investigated the role of the gut microbiome and the gut-brain axis having a key role in the development of CIPN.
Connections between gut bacteria and the brain? Looking into the gut-brain axis
The gut-brain axis is composed of the biochemical signalling pathways that bidirectionally link the central nervous system and the gastrointestinal system. The gut-brain axis has many connections and communications between the endocrine and immune systems. A simple example of gut-brain interactions is the release of secretions that prepare the stomach for food to enter, triggered just by the sight or smell of food.
It has long been suggested that abnormal changes in the brain or gut can lead to negative changes in the other, including changes in behaviour or mood or increased levels of intestinal inflammation. More recently, we have begun to understand the role of the gut microbiome in mediating the effects of the gut-brain axis. The gut microbiome, the collection of bacteria and other microorganisms living in the intestine, has a variety of beneficial functions in the body; however, altering its composition can lead to negative health effects. It is thought that specific types of bacteria, as well as the metabolic products they release, can alter the neural signalling reaching the brain.
Investigating CIPN and the microbiome
The recent paper hypothesised that the gut microbiome may play a key role in the development of CIPN. We already know that the composition of the gut microbiome changes due to chemotherapy, and we also know that chemotherapy causes damage to the lining of the intestine. This study used a mouse model of CIPN to test the role of the microbiome. Two strains of mice were used, one of which is known to develop CIPN following treatment with the chemotherapy drug paclitaxel (C57BL/6 mice, known as B6) and one which does not (129 mice). These two types of mice are known to have a different baseline microbiome composition. In mice, the development of CIPN can be assessed with some key tests, including measuring how quickly heat or cold temperature are sensed in the extremities (i.e. in the paws), and how sensitive the paws are to the touch of a flexible wire-type filament.
In order to assess whether the microbiome was responsible for the differences in the mice in CIPN development, two key experiments were carried out. First, the gut microbiome of the mice was wiped clean using antibiotics, and paclitaxel was given. B6 mice, which usually develop CIPN, had less CIPN when they had lowered levels of gut bacteria. This suggests the microbiome has a key role in the development of CIPN. The second key experiment involved replacing the microbiome of the B6 mice with the microbiome of the 129 mice (and vice-versa). Surprisingly, when their microbiome was swapped, the 129 mice developed CIPN and the B6 mice did not, showing that the B6 mice-specific microbiome composition was required to develop CIPN.
How does your gut microbiome actually affect your nervous system?
This paper was able to show that a specific microbiome composition was required to develop CIPN. These are really promising findings; however, in order to be able to translate this into a benefit for people suffering from CIPN, we need to think about how this occurred. This way, we could find a way to target and prevent CIPN before it becomes disabling. The researchers also investigated changes in microglia, which are immune cells that reside in the central nervous system. In their experiments, mice with the B6 microbiome (prone to CIPN) treated with paclitaxel had more microglia than mice who had the 129 microbiome. In addition, it was found that some specific types of bacteria correlated with microglia levels and pain responses. One of these was Akkermansia muciniphila, which has a role in maintaining the functioning of the intestinal barrier. This supports the idea that chemotherapy causes damage to the intestine and changes to microbiome composition, leading to increased central nervous system exposure to different bacterial products and metabolites, leading to systemic inflammation that causes pain sensitivity.
Can this be translated into a treatment for humans? Not yet….
These are really interesting results, which open up a new line of research in this area. However, a key issue with microbiome studies in pre-clinical models (i.e. not humans), is that the microbiome in animals is extremely different to that of humans. In fact, one study showed that 85% of bacterial sequences seen in a mouse represents genera not detected in humans. Therefore, caution needs to be taken when working with these results. These results still show that the microbiome has a role in the development of CIPN, but it is difficult to pin the results to specific bacteria. Before this occurs, more clinical studies in humans are required, as well as an exploration into how we could block central nervous system exposure to potentially harmful bacterial metabolites.
Edited by Sara Musetti
Ramakrishna C, Corleto J, Ruegger PM, et al. Dominant Role of the Gut Microbiota in Chemotherapy Induced Neuropathic Pain. Sci Rep. 2019;9(1):20324. Published 2019 Dec 30. doi:10.1038/s41598-019-56832-x