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The role of the intestinal microbiome as driver between pesticide exposure and disease pathogenesis

We strives to unravel the complex relationship between chemical exposures, the intestinal microbiome, and host toxicity outcomes. MibiTox is strategically designed to assess the functional capacity of microbiomes from pesticide exposure to disease pathogenesis in zebrafish, mouse, and human hosts using both in vitro and in vivo systems.

It is widely understood that exposure to exogenous chemicals disrupts the community structure of host-associated microbes. Recent literature suggests that intestinal microbiota can biotransform chemicals. A major knowledge gap relates to whether xenobiotic-induced effects on microbial ecology and biotransformation causally alter the toxicity of environmental chemicals to the host organism. Until this question is answered, microbiota will not be considered in risk assessment strategies, although regulatory bodies are aware of its potential future relevance from both toxicokinetic and toxicodynamic perspectives. Here, we will move the science forward to illuminate the mode of action in microbiome-mediated toxicity.

Overview MibiTox
Conceptual workflow of PhD college MibiTox. Impact of anthropogenic exposure of pesticides to the intestinal microbiome.

MibiTox aims to evaluate the complex relationship between intestinal microorganisms and pesticides to ultimately analyze perturbations in microbiota structure and function that lead to adverse responses and disease pathogenesis in the host organism, with a focus on the developing immune and nervous systems. We will therefore assess the toxicological relevance of bacterial-xenobiotic interplay to the host organism.

To achieve this, we will determine the biotransformational capacity of intestinal microbes and the extent to which microorganisms influence pesticide exposures using zebrafish, mouse, and human (i.e. in vivo and in vitro) experimental systems. We will also determine the role of the microbiome as mediator between pesticide exposures and disease pathogenesis, specifically focusing on metabolic interactions and the nervous and immune systems.

This PhD project aims to elucidate the transformation potential of the intestinal microbiome using a suite of structurally diverse pesticides as study compounds (Figure 1). In vitro and in vivo models will be used for studying pesticide transformation and high resolution mass spectrometry (LC-HRMS) will be deployed to detect and to identify transformation products using suspect screening and non-target screening approaches. The project contributes to a systematic understanding of the interrelationship between the molecular structure of xenobiotics, their transformation by the intestinal microbiome, and microbiome composition.

The key questions are:
(1) What is the biotransformation potential of the human microbiome for pesticides? How does it alter chemical structure and exposure?
(2) How does the biotransformation potentials of humans compare to zebrafish and mouse? How does transformation by host-associated microorganisms compare to what is known from environmental systems?
(3) Can biotransformation be linked with enzyme activity or the activity of certain microbes and their relevant metabolic pathways?

PhD candidate:

Laura-Fabienne Fröhlich

Supervising team:

Prof. Dr. Thorsten Reemtsma

The influence of the microbiome on many diseases of the host, in humans especially those related to metabolic and immunological outcomes, has led to the question of the influence of chemicals on the microbiota-host interaction. Because xenobiotic exposures routinely disrupt the community structure of host associated microbes, the next fundamental data gap is: What are the functional consequences of microbiota disruption to the host?

The key questions are:
(1) What is the degradation potential of the microbiome for pesticides?
(2) How do chemical exposures change the bacterial composition and functional adaptation?
(3) Can we identify the type of interactions and interdependence within the microbiota that are affected by disturbances and quantifying their role in resilience?

PhD candidate:

Victor A. Castañeda-Monsalve

Supervising team:

Dr. Nico Jehmlich

Pesticide exposures are commonly associated with developmental neurotoxicity characterized by alterations in behavior (e.g. hyperactivity or hypoactivity). This PhD project will focus on the interaction between host-associated microbes, pesticide exposures, and the developing nervous system. By focusing on microbiota-chemical interactions that disrupt host neurodevelopment, this project will help reveal whether microbiota should be considered in current risk assessment paradigms.

The key questions are:
(1) Do non-teratogenic exposures to widely occurring pesticides disrupt the zebrafish microbiome (i.e. toxicodynamic hypothesis);
(2) Do pesticide-disrupted microbiomes bioactivate or detoxify the parent compound (i.e. toxicokinetic hypothesis);
(3) Do microbiota-chemical interactions influence host toxicity outcomes; and
(4) Can PBPK models be developed to describe microbiota-xenobiotic interactions?

PhD candidate:

Sebastian Gutsfeld

Supervising team:

Prof. Dr. Tamara Tal

This PhD thesis will examine the impact of maternal pesticide exposure using an established murine asthma model. Disease development in offspring and the underlying mechanisms will be characterized with a specific focus on the microbiome as a mediator between pesticide exposures and disease pathogenesis. In the case of glyphosate, the most widely used pesticide globally, acute toxicity effects are well characterized and accepted.

The key questions are:
(1) Does maternal pesticide exposure have an effect on the development of allergic asthma, weight, growth, or neurobehavior in offspring?
(2) Do pesticides affect the maternal and neonatal microbiota and to what extent does chemical-induced dysbiosis influence disease development?
(3) Are there pesticide-driven epigenetic alterations in offspring and is there a link between the chemical-induced dysbiosis and epigenetic changes?

PhD candidate:

Lisa Buchenauer

Supervising team:

PD Dr. Tobias Polte