Gut microbes transform common herbicide into previously unknown compounds

The human microbiome may play a critical role in determining the health impacts of chemical exposure from food, according to new research on the herbicide metazachlor.

Discussions about plant protection products in Switzerland often center on what happens after they leave the field: Can they reach rivers and groundwater? Do residues end up in food? Yet the fate of these chemicals inside the human body remains comparatively unexplored.

Researchers from the Laboratory of Toxicology at ETH Zurich set out to fill this knowledge gap by investigating whether microbes in the human gut can transform a commonly used herbicide into new compounds with potentially different biological effects.

Transformation of metazachlor in the human gut microbiome

Metazachlor is an herbicide primarily used in Switzerland to protect oilseed rape and some vegetable crops from weeds. While previous research has shown that metazachlor can be broken down by microorganisms in soils and aquatic environments, little was known about its fate in the human digestive tract.

Drawing on growing evidence that the gut microbiome acts as a powerful chemical processing system, the researchers exposed microbial communities from human fecal samples to metazachlor under conditions designed to mimic the oxygen-free environment of the gut. Using advanced mass spectrometry techniques, they tracked how the compound was transformed and identified the resulting metabolites.

The results revealed that the human gut microbiome extensively metabolizes metazachlor. In total, the team identified 22 transformation products, 17 of which had never been reported before. The findings provide the first detailed picture of how this herbicide is processed by human gut microbes and were recently published in Environmental Science & Technology.

Toxicological relevance of transformation products

Identifying these previously unknown metabolites raised an important question: do they behave differently from the original herbicide once they are formed in the body? To investigate this, the researchers examined whether selected metabolites could be absorbed through the intestinal barrier and whether they affected human cells. They tested metazachlor and four selected metabolites in two human colon-derived cell lines.

The results showed that not all metabolites have the same biological activity. Two of the tested metabolites did not cause measurable toxic effects in either cell line. In contrast, metazachlor and two other metabolites reduced cell viability at micromolar concentrations. Notably, those two metabolites were more toxic than the parent compound itself. The researchers also found that one of these metabolites displayed a high capacity to cross an intestinal barrier model, suggesting that it could be readily absorbed following its formation in the gut.

"An interesting aspect of the finding is how gut microbes generate a chemical signature completely distinct from environmental aerobic organisms, which is key because potential host effects ultimately depend on these specific metabolite structures.", says Prof. Shana Sturla, Laboratory of Toxicology, ETH Zurich.

Toxicokinetic model for improved human health risk assessment

Together, these findings reveal that metazachlor is extensively transformed by the human gut microbiome into a diverse range of metabolites, some of which may have biological properties distinct from the original herbicide. The study highlights an often-overlooked aspect of chemical exposure and suggests that microbial metabolism should be considered more systematically in human health risk assessments.

To support this goal, the researchers developed a microbiome-competent physiologically based kinetic (PBK) model, based on previously published frameworks. This is an emerging approach that integrates microbial metabolism into simulations of chemical absorption, distribution and elimination within the body.

When applied to metazachlor, the model predicted that the herbicide itself is rapidly eliminated, while simultaneously undergoing extensive transformation by gut microorganisms. Incorporating these microbial processes provides a more complete picture of internal exposure and may help explain differences in how individuals respond to the same chemical exposure.

The researchers view this work as an important step toward microbiome-informed safety assessment approaches. In the future, such models could improve predictions of human responses to chemicals present in food and the environment and help identify individuals or populations that may be particularly susceptible to adverse effects.

"Gut microbial biotransformation is emerging as a key contributing factor to bioactivity, and quantitative computational and in vitro approaches are pivotal to addressing this in chemical risk assessment.", says Dr. Georg Aichinger, Laboratory of Toxicology, ETH Zurich.

Looking ahead

This study is one example of the broader work underway within the Addressing Environmental and Human Health Risk Research Program of the World Food System Center, investigating how chemicals move through food systems and how they interact with both human biology and the environment.

Ongoing projects work to expand this work to other classes of compounds, including fluorinated chemicals used in pharmaceuticals and agrochemicals, and look at pathways of contamination in the food value chain. By combining mapping of chemical flows in food value chains, microbiome research, and predictive modelling, the projects aim to better understand how these substances are transformed from field to food and ultimately within the human body.

» Original publication

Source: ETH Zürich