The microbiome and drug toxicity

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In a report published yesterday (June 10) in the newspaper Cell, Researchers at Princeton University evaluated how a person’s gut microbial community affects oral drug metabolism.

The study differs from previous studies that looked at how a single species of gut bacteria can metabolize oral drugs because it assessed the entire gut microbial community at once.

“Basically, we don’t run around and hide from the complexity of the microbiome, but instead we embrace it,” said Mohamed S. Donia, assistant professor of molecular biology. “This approach allows us to gain a holistic and more realistic view of the contribution of the microbiome to drug metabolism.”

The team used this approach to assess the effect of the gut microbiome on hundreds of common drugs already on the market. The intestines are the main area where pills and liquid medicines are absorbed into the body.

Researchers have identified 57 cases in which gut bacteria can interfere with existing oral medications – 80% of these had not been reported before.

These alterations range from converting the drug into an inactive state – which can reduce its effectiveness – to converting the drug into a toxic form, which may cause side effects.

Systematic evaluation

The framework includes four steps to systematically assess the effect of the gut microbiome on drugs.

First, the researchers collected 21 fecal samples collected from anonymous donors and cataloged the bacterial species living in each individual. They found that donors each have a unique microbial community living in their gut, and that the majority of these personalized communities can be grown in a lab culture system they developed.

Next, they tested 575 FDA-approved drugs to see if they are chemically altered by any of the 21 cultured microbiomes, and then tested a subset of the drugs with all of the cultured microbiomes. Here, they found metabolites derived from the microbiome that had never been reported before, as well as those that have been reported in humans and associated with side effects, but their origins were unknown. They found cases where all of the donor microbiomes performed the same reactions to the drug, and others where only a subset did.

To understand exactly how the transformations happened, they traced the source of the chemical transformations to particular bacterial species and particular genes within those bacteria. They also showed that the microbiome-derived metabolic reactions that are discovered in this way can be summarized in a mouse model.

Round worm pattern

In another report, published on May 22 in Nature Communication, Scientists at the University of Virginia found that diet can cause microbes in the roundworm gut to trigger changes in the host’s response to a chemotherapy drug.

They found that common components in our daily diet (such as amino acids) could increase or decrease both the effectiveness and toxicity of drugs used for cancer treatment.

The team said their discovery, made using a new lab model with roundworms, could have major implications for predicting the right dose and better controlling the side effects of chemotherapy, the researchers report. The finding may also help explain the differences seen in patients’ responses to chemotherapy.

Researchers observed that probiotics and prebiotics and the microbiome previously affected the results of chemotherapy treatment. However, this is the first time that the underlying molecular processes have been fully dissected.

Dr. Eyleen O’Rourke, UVA College of Arts and Sciences, Department of Cell Biology, Faculty of Medicine and the Robert M. Berne Cardiovascular Research Center, said: “The first time we observed that changing the microbe or adding a single amino acid to the diet could turn a harmless dose of the drug into a highly toxic dose, we couldn’t believe our eyes.

“Understanding, with molecular resolution, what was going on required sifting through hundreds of genes from microbes and hosts. The answer was a surprisingly complex web of interactions between diet, microbe, drug, and host. “

The changes that diet triggers on microorganisms can increase the toxicity of a chemotherapy drug up to 100-fold, the researchers found.

Wenfan Ke, graduate student and lead author of the study, said: “The same dose of drug that does nothing on the control regimen kills the [roundworm] if one milligram of the amino acid serine is added to the diet. “

Additionally, data has shown that unique dietary changes can alter the microbe’s metabolism and, as a result, alter or even reverse the host’s response to a drug.

The researchers’ new model is a hugely simplified version of the complex microbiome found in humans. Roundworms serve as the host, and non-pathogenic E. coli bacteria represent microbes in the gut. In humans, the relationships between food, microorganisms and the host are much more complex, and understanding this will be a major task for scientists in the future.

They used this tractable system that enables molecular dissection of interactions between diet, drugs, microbes and the four-way host in vivo. With this four-way model system, they dissected the microbe and host response to FUdR (Floxuridine) and how they both change when serine is supplemented through diet.

They conclude: “Dietary thymidine and serine increase the toxicity of 5-fluoro 2′deoxyuridine (FUdR) in C. elegans through different microbial mechanisms. Thymidine promotes the microbial conversion of the prodrug FUdR to toxic 5-fluorouridine-5′-monophosphate (FUMP), resulting in increased host death associated with depletion of RNA and mitochondrial DNA and lethal activation of autophagy. On the other hand, serine does not alter the metabolism of FUdR.

“Instead, serine alters the 1C metabolism of E. coli, reduces the supply of nucleotides to the host, and exacerbates DNA toxicity and host death without depletion of RNA or mitochondrial DNA; furthermore, autophagy promotes survival in this condition. “

The authors predict that one day, doctors will give patients not only prescriptions, but also detailed dietary guidelines and personally formulated microbial cocktails to help them achieve the best results.

The team noted 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 determine whether the diet could cause microorganisms to produce substances, called metabolites, that could interfere with or facilitate the effects of drugs.

They suggest that the complexity of drug-host-microbiome interactions is likely “astronomical.” Many more studies are needed, but the resulting understanding, they say, will help doctors “realize the full therapeutic potential of the microbiota”.

O’Rourke added: “The potential for developing drugs that can improve treatment results by modulating the microbes that live in our gut is enormous.

“However, the complexity of the interactions between food, microbes, therapeutics and the host that we discovered in this study is humbling. We will need a lot of fundamental research, including sophisticated computer modeling, to reveal how fully exploit the therapeutic potential of our microbe. “

Source: Cell

Javadan. B., et al

“Personalized mapping of drug metabolism by the human intestinal microbiome”

DOI: https://doi.org/10.1016/j.cell.2020.05.001

Source: Nature Communication

Ke, W., Saba, JA, Yao, C. et al.

“Food serine-microbiota interaction improves chemotherapeutic toxicity without altering drug conversion”

https://doi.org/10.1038/s41467-020-16220-w


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