I was looking forward to a session on the microbiome during the 2018 Annual Meeting and ToxExpo. The panel of experts for the Workshop Session "Microbiota as a Target or Mediator of Adverse Effects: Implication for Toxicology" did not disappoint! Speakers Karsten Beekmann, Wageningen University & Research; Shana Sturla, ETH Zürich; Tamara Tal, US Environmental Protection Agency; Matthew Redinbo, University of North Carolina at Chapel Hill; and Christina Behr, BASF and Wageningen University & Research, highlighted emerging concepts in the microbiome field and how they relate to toxicology.
One emerging theme was the appreciation that the metabolic function of the microbiome can no longer be ignored in the field of toxicology. Traditionally, it has been the liver that gets all the attention from toxicologists. However, trillions of gut microbiota encounter xenobiotics and may either activate or deactivate them by producing metabolic intermediates. Although the composition of microbiota varies between people, the metabolic pathways of the microbiota are particularly stable. The products of these metabolic pathways affect drug efficacy, carcinogenesis, organism development, etc.
Another theme from this session was the development of in vitro assays to assess the microbiotic metabolism of xenobiotics. Dr. Beekmann’s laboratory uses an in vitro fecal incubation assay that can be amended with specific nutrients to measure metabolic intermediates produced by the microbiome. These measurements are used to create physiologically-based kinetic (PBK) models. Dr. Sturla’s laboratory uses in vitro gut fermentation models to assess the gut’s microbiome transformation of chemical carcinogens. She focuses on heterocyclic amines that are produced during the high-temperature cooking of meat. These amines have a genotoxic mode of action in the colon. However, gut biota conjugate activated glycerol to the amines, protecting them from activation in the liver and their subsequent mutagenic mode of action. Comparison of the metabolomes between colon cancer patients and healthy individuals show a reduction of the enzymes needed to conjugate glycerol onto the heterocyclic amines in colon cancer patients.
The targeted control of microbial enzymes was the third theme. Dr. Redinbo explained how the colon cancer drug irinotecan produces severe gastrointestinal toxicity in 30–70% of cancer patients. This limits the use of the drug. This gastrointestinal toxicity is a function of the gut microbiome’s beta-glucuronidase enzymes that reactivate the drug after it has been inactivated in the liver and targeted for secretion. By developing specific inhibitors to the glucuronidase enzymes and administering them along with the irinotecan in mice, the Redinbo laboratory observed an increased efficacy of the drug by blocking the toxic side effects. It will be exciting to see if this is replicated in clinical trials.
Lastly, the fourth theme was the development of other models to study chemical-microbiota interactions. Dr. Tal’s laboratory developed a zebrafish model to study the gut microbiota’s role in neurodevelopment and the disruption of normal development with environmental compounds. Ms. Behr uses MetaMap®Tox, developed by BASF, that contains more than 800 compounds’ metabolic profiles. The database helps to identify plasma metabolite patterns and similar mode of actions between chemicals that affect microbiome metabolism.
It is an exciting time to study the microbiome’s role in toxicology. It is apparent that the microbiome plays a key role in the metabolism of xenobiotics. I look forward to hearing about new developments at future SOT meetings.
This blog was prepared by an SOT Reporter. SOT Reporters are SOT members who volunteer to write about sessions and events they attend during the SOT Annual Meeting and ToxExpo. If you are interested in participating in the SOT Reporter program in the future, please email SOT Communications Director Michelle Werts.