The microbiome, often considered to be “the second genome,” has become increasingly recognized as relevant to human health over recent years. The microbiome is composed of bacteria, archaea, fungi, and viruses. In the gastrointestinal tract, it contributes over 200-thousand unique genomes linked to 171 million proteins, totaling to a microbial cell count of approximately 10^13. Each person is estimated to house several hundred microbial species.
Given the complexity of the microbiome, there is much that has yet to be discovered, and uncertainty remains regarding some of its functions that are already known. An example of one such uncertainty is whether the microbiome is capable of mediating the toxicity of environmental chemicals. This was the topic of a spirited debate between Dr. Tamara Tal (Helmholtz Centre for Environmental Research) and Dr. Karsten Beekmann (Wageningen University and Research) at the 2024 SOT Annual Meeting during the Featured Session “SOT/EUROTOX Debate: Can the Microbiome Mediate the Toxicity of Environmental Chemicals?”
To kick off the debate, Dr. Tal presented her stance that xenobiotic toxicity is in fact mediated by the microbiome. To demonstrate this, she provided examples for each of three principles that support a chemical-microbiome interaction framework: (1) chemical-selected microbiome, (2) altered toxicokinetics, and (3) toxicodynamic effect on host.
Chemical-Selected Microbiome (chemical alters microbiome structure)
There are various well-known examples of chemical exposures that have the ability to alter the composition of microorganisms associated with a host, such as alcohol, antibiotics, other drugs, age, diet, and pets. Furthermore, a recent analysis that evaluated studies from the past 10 years identified 124 examples of chemicals that selected for an altered microbiome in experimental systems. These chemicals included a variety of metals, herbicides, fungicides, insecticides, mycotoxins, detergents, and dyes, among many others.
Chemical-Selected Microbiomes Have Altered Function (toxicokinetic interaction)
Digoxin, a drug used to treat cardia arrhythmias, can be biotransformed and inactivated by the bacteria Eggerthella lenta through a reductive reaction. This reaction was later attributed to a single gene (cgr2), and since this bacterial species is differentially present among the population, this provides an explanation for why some individuals are metabolizers of digoxin and some are not.
Another study determined that of 271 drugs evaluated, 176 (64.9%) were found to be biotransformed by at least 1 of 76 tested bacteria, thereby demonstrating that many drugs have toxicokinetic interactions with the microbiome.
Furthermore, structure-activity relationships have been identified to elucidate the rules of toxicokinetic impacts of microbes on xenobiotics. Some of these structural features include the presence of hydrolyzable esters and amides and nitro and azo groups that are prone to reduction.
Change in Structure and Function Leads to Toxicodynamic Effect on Host
The topoisomerase inhibitor, irinotecan, is one example that provides evidence of a causal link between the microbiome and toxicity outcomes. Irinotecan is a prodrug that is activated within the host, followed by subsequent inactivation via glucuronidation in the liver. However, it then re-enters the gut lumen via biliary clearance and interacts with gut microbial ß-glucuronidases which deglucuronidate the inactive drug, thereby reactivating it. This results in a dose-limiting toxicity in mammalian models. It was later determined that coadministration of irinotecan with a ß-glucuronidase inhibitor (to inhibit bacterial ß-glucuronidase activity) prevented this dose-limiting toxicity.
Taking the opposing viewpoint, Dr. Beekmann argued that there is currently insufficient evidence to prove a causal relationship between the microbiome as a mediator of environmental chemical toxicity and stressed that our understanding of the microbiome is still limited. He stated that contact of xenobiotics with the microbiome is often insignificant, especially if the substance is absorbed in the stomach or small intestine. Furthermore, microbiome composition, which is not necessarily a predictor of function, varies immensely across individuals, thereby complicating the ability to prove causation. The microbiome is extremely dynamic and resilient, and even after drastic measures such as antibiotic administration, microbial colonies are capable of restoring their populations; therefore, xenobiotics would not be expected to have lasting effect on the microbiome either.
Following the debate, the audience asked questions and raised several important points, which included mention of an existing field of study called toxicomicrobiomics, the importance of maintaining focus on the clinical relevance of any potential microbiome-mediated xenobiotic toxicity, and consideration of the skin and lung microbiomes in addition to the gut microbiome, which may be just as relevant. Dr. Tal noted that as of now, the best data is available for the gut microbiome, although it is known that the skin microbiome is capable of transforming various polyaromatic hydrocarbons (PAHs) that have potential to lead to toxicologically relevant adverse effects.
After this lively debate, the audience voted with a resounding “yes” when asked whether or not they believed there was adequate evidence to support the microbiome’s ability to mediate chemical toxicity. Dr. Tal and Dr. Beekman noted that they would be reversing roles in the upcoming iteration of this debate at the EUROTOX 2024 meeting.
This blog reports on the Featured Session titled “SOT/EUROTOX Debate: Can the Microbiome Mediate the Toxicity of Environmental Chemicals?” that was held during the 2024 SOT Annual Meeting and ToxExpo. An on-demand recording of this session is available for meeting registrants on the SOT Online Planner and SOT Event App.
This blog was prepared by an SOT Reporter and represents the views of the author. SOT Reporters are SOT members who volunteer to write about sessions and events in which they participate during the SOT Annual Meeting and ToxExpo. SOT does not propose or endorse any position by posting this article. If you are interested in participating in the SOT Reporter program in the future, please email SOT Headquarters.
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