Single amino acid enough to trigger catastrophic microbiome change in chemotherapy patients

08 Jun 2020 --- Cancer patients’ responses to chemotherapy drugs can be changed by microbes in the gut. This is according to a study from the University of Virginia (UVA), which revealed that common components of a daily diet, for example amino acids, could either increase or decrease both the effectiveness and toxicity of the drugs used for cancer treatment. The researchers note that this discovery opens an important new avenue of medical research and could have major implications for predicting the right dose and better controlling the side effects of chemotherapy. This could also help explain differences seen in patient responses to chemotherapy that have baffled doctors until now.

“Changing the microbe or adding a single amino acid to the diet could transform an innocuous dose of the drug into a highly toxic one. Understanding, with molecular resolution, what was going on took sieving through hundreds of microbe and host genes. The answer was an astonishingly complex network of interactions between diet, microbe, drug and host,” says Dr. Eyleen O’Rourke of UVA’s College of Arts & Sciences and the School of Medicine’s Department of Cell Biology.

The lab model, which used roundworms, found that microbiome changes triggered by diet can increase the toxicity of a chemotherapeutic drug up to 100-fold. Notably, single dietary changes can shift the microbe’s metabolism and, consequently, change or even revert the host response to a drug.

“The same dose of the drug that does nothing on the control diet kills the roundworm if a milligram of the amino acid serine is added to the diet,” says Wenfan Ke, a graduate student and lead author of the scientific paper outlining the findings.

The researchers say this is the first time that the underlying molecular processes have been fully dissected.A simplified version of the microbiome
The researchers’ roundworm model is an extremely simplified version of the complex microbiome found in people. The roundworms serve as the host, while non-pathogenic E. coli bacteria represent the microbes in the gut. In people, the relationships among diet, microorganisms and host is vastly more complex, and understanding this will be a major task for scientists going forward.

While previous investigations revealed that microbes and diet can affect treatment, the researchers say this is the first time that the underlying molecular processes have been fully dissected.

Addressing the future outlook for this space, the researchers note that drug developers will need to take steps to account for the effect of diet and microbes during their lab work. For example, they will need to factor in whether diet could cause the microorganisms to produce substances, called metabolites, that could interfere or facilitate the effect of the drugs.

They also suggest that the complexity of the interactions among drug, host and microbiome is likely “astronomical.” While more research is needed, the scientists say that the resulting findings will help doctors “realize the full therapeutic potential of the microbiota.”

“The potential of developing drugs that can improve treatment outcomes by modulating the microbes that live in our gut is enormous. However, the complexity of the interactions between diet, microbes, therapeutics and the host that we uncovered in this study is humbling. We will need lots of basic research, including sophisticated computer modeling, to reveal how to fully exploit the therapeutic potential of our microbes,” concludes Dr. O’Rourke.

In the same space, a separate research project recently developed Harvey and Harvetta, who are virtual humans to aid personalized research into the microbiome. They are touted as enabling the creation of personalized whole-body metabolic models using an individual’s physiological, genomic, biochemical and microbiome data. Meanwhile, a collaboration between Danone Nutricia Research and the University of California, San Diego’s Microsetta Initiative is recruiting hundreds of US citizens to map their gut microbiomes. 

As part of its World Cancer Day coverage, NutritionInsight previously noted how nutrition can have a notable impact on cancer – and vice versa. Meanwhile, a collaboration including over 1,300 scientists and clinicians from 37 countries recently uncovered an “unprecedented” amount of new insights into the disease.

Edited by Katherine Durrell