Integration of human microbiota (SIHUMIx) and zebrafish models reveals microbiome-mediated host responses to azoxystrobin.

Overview

1. Department of Ecotoxicology, Chemicals in the Environment Research Section, Helmholtz-Centre for Environmental Research—UFZ, 04318 Leipzig, Germany
2. Biosciences, University of Exeter, Exeter, Devon EX4 4QD, United Kingdom
3. Department of Molecular Toxicology, Chemicals in the Environment Research Section, Helmholtz-Centre for Environmental Research—UFZ, 04318 Leipzig, Germany
4. Medical Faculty, University Leipzig, 04103 Leipzig, Germany

Abstract

The gut microbiome is essential for neurodevelopment via bidirectional gut–brain axis signaling, yet environmental chemicals can potentially disrupt this communication by altering community structure and xenobiotic metabolism. In this study, we investigated whether the fungicide azoxystrobin, a known metabolic disruptor, modulates microbiome composition and function to influence neurobehavior. We utilized a simplified human gut microbiota model (SIHUMIx) and a vertebrate host model (larval zebrafish) to elucidate microbiome-mediated mechanisms of xenobiotic neurotoxicity. SIHUMIx was exposed to azoxystrobin for 7 days at 10% of the acceptable daily intake, followed by recovery. Integrated metaproteomic and metabolomic analyses revealed functional reprogramming of the microbiota, characterized by upregulation of vitamin and cofactor biosynthesis, nutrient acquisition, and detoxification pathways, and decreases in carbohydrate fermentation and amino acid turnover, consistent with reduced short-chain fatty acid levels. Microbiome-depleted and SIHUMIx-inoculated larvae were exposed to azoxystrobin at 4 days post fertilization, and neurobehavioral outcomes were assessed after 24 h using the Visual and Acoustic Motor Response assay. Azoxystrobin exposure disrupted non-associative habituation learning independent of microbiome status but induced dark-phase hyperactivity only in colonized larvae, indicating a microbiome-dependent phenotype. Targeted metabolomics revealed lower serotonin levels in microbiome-depleted larvae relative to colonized controls and that azoxystrobin exposure reduced serotonin in colonized larvae toward depleted levels. These results suggest that microbiota-dependent serotonergic signaling may modulate host responses to azoxystrobin. This integrated ex vivo–in vivo approach supports the concept that the microbiome is a key determinant of neurotoxic responses and underscores the importance of incorporating microbiome-mediated effects into chemical risk assessment frameworks.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• doi:10.17632/97f3yffwz9.1, at the source; found in the references
• zenodo:18433571, at Zenodo; found in the references

Other data links

• ncbi.nlm.nih.gov/sra, NCBI; found in “Data availability”

Data availability

The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE (Perez-Riverol et al. 2022) partner repository with the dataset identifier PXD070601. 16S rRNA sequencing data are deposited in the NCBI Sequence Read Archive (https://www.ncbi.nlm.nih.gov/sra/) under BioProject accession PRJNA1364743. Underlying code and data used to generate figures are available at https://doi.org/10.5281/zenodo.18433571 (Wray et al. 2026).

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 11 authors, 5 keywords, 11 MeSH terms, 5 funders, 106 references.

Cite

This paper

Wray, C., Castañeda-Monsalve, V., Engelmann, B., Rolle-Kampczyk, U. E., Schweiger, N., Gutsfeld, S., Ghosh, D., Kader, S., Tyler, C. R., Jehmlich, N., & Tal, T. (2026). Integration of human microbiota (SIHUMIx) and zebrafish models reveals microbiome-mediated host responses to azoxystrobin. Toxicological sciences : an official journal of the Society of Toxicology, 209(4), kfag022. https://doi.org/10.1093/toxsci/kfag022

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