Anti-cancer drugs affect gut bacteria, which in turn can influence how well treatment works. Now, researchers have found that the microbiota plays a key role in how cancer patients respond to the drug capecitabine and can impact both treatment efficacy and side effects. 

The findings, published in mBio, suggest that targeting the gut microbiota could help predict, prevent or reduce chemotherapy-related toxicity.

Capecitabine (CAP) is a common chemotherapy drug used to treat colorectal cancer. In the body, CAP is converted to a cancer-fighting compound called 5-fluorouracil, which works by stopping cancer cells from making DNA and RNA. However, only about 40% of people who take CAP see good results, and up to 57% have to reduce or stop treatment due to side effects. 

Studies in mice have shown that gut bacteria can affect CAP’s efficacy and its side effects, so Lars Hillege at Maastricht University in the Netherland and his colleagues set out to investigate how gut bacteria influence the effects of CAP in 56 people with colorectal cancer.

Protective effect

The researchers found that, after three treatment cycles, certain bacterial species—including Clostridiales—increased, while others such as Actinomycetaceae decreased. More than 250 biological pathways were altered, especially those related to the production of menaquinol, a form of vitamin K2 produced by Escherichia bacteria. 

Further analyses showed that certain gut bacteria can protect themselves from the harmful side effects of chemotherapy drugs by producing vitamin K2. People with higher levels of vitamin K2-producing bacteria in their gut microbiotas were less likely to experience nerve pain—a common chemotherapy side effect, when compared to those with lower levels of these bacteria. 

Lab and animal tests confirmed that vitamin K2 could reduce nerve damage caused by chemotherapy without causing other toxic effects. These results suggest that gut bacteria, as well as the compounds they produce, may play a protective role during cancer treatment, the researchers say.

Treatment results

By focusing on specific microbial genes, the team trained machine-learning models to predict which patients were more likely to experience toxic effects and thus needed dose adjustments. 

The models showed moderate accuracy when tested on a group of people with colorectal cancer. Certain gut bacterial genes were linked to fewer dose adjustments and lower risk of side effects, while lower levels of vitamin K2-producing bacteria were associated with a higher risk of nerve pain, the researchers found.

“These results suggest that treatment-associated increases in bacterial vitamin production protect both bacteria and host cells from drug toxicity,” the authors say. This finding, they add, opens chances for new treatments and highlights the importance of understanding how diet and gut bacteria’s production of nutrients such as vitamin K2 affect cancer treatment.