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

Mar 8, 2026Toxicological sciences : an official journal of the Society of Toxicology

How a simplified human gut microbiome and zebrafish models show host responses to the fungicide azoxystrobin

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Abstract

Exposure to the fungicide azoxystrobin may alter gut microbiome composition and function, impacting neurobehavior.

Azoxystrobin exposure for 7 days at 10% of the acceptable daily intake led to significant changes in microbiota function.
Functional reprogramming was characterized by increased vitamin and cofactor biosynthesis, nutrient acquisition, and detoxification pathways.
There was a decrease in carbohydrate fermentation and amino acid turnover, correlating with reduced short-chain fatty acid levels.
Neurobehavioral testing revealed that azoxystrobin disrupted non-associative habituation learning regardless of microbiome presence.
In colonized larvae, azoxystrobin exposure resulted in hyperactivity during the dark phase, indicating a microbiome-dependent effect.
Lower serotonin levels were observed in microbiome-depleted larvae, and azoxystrobin exposure further reduced serotonin levels in colonized larvae.

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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 decreased 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.

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

Abstract

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