Dataset Information

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

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 integrated a simplified human gut microbiota model (SIHUMIx) with 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-colonized 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.

INSTRUMENT(S):

ORGANISM(S): Bacteroides Thetaiotaomicron Thomasclavelia Ramosa Anaerostipes Caccae Blautia Producta Atcc 27340 = Dsm 2950 Clostridium Butyricum Dsm 10702 Escherichia Coli (strain K12) Lactobacillus Plantarum Subsp. Plantarum Bifidobacterium Longum Ncc2705

SUBMITTER: Nico Jehmlich

LAB HEAD: Nico Jehmlich

PROVIDER: PXD070601 | Pride | 2026-04-27

REPOSITORIES: Pride

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

Wray Chloe C Castañeda-Monsalve Victor V Engelmann Beatrice B Rolle-Kampczyk Ulrike E UE Schweiger Nicole N Gutsfeld Sebastian S Ghosh Debjyoti D Kader Siraz S Tyler Charles R CR Jehmlich Nico N Tal Tamara T

Toxicological sciences : an official journal of the Society of Toxicology 20260401 4

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 zebra ...[more]

PMID: 41795836

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Project description:“Dysbiosis" of the maternal gut microbiome, in response to environmental challenges such as infection, altered diet and stress during pregnancy, has been increasingly associated with abnormalities in offspring brain function and behavior. However, whether the maternal gut microbiome regulates neurodevelopment in the absence of environmental challenge remains unclear. In addition, whether the maternal microbiome exerts such influences during critical periods of embryonic brain development is poorly understood. Here we investigate how depletion, and selective reconstitution, of the maternal gut microbiome influences fetal neurodevelopment in mice. Embryos from antibiotic-treated and germ-free dams exhibit widespread transcriptomic alterations in the fetal brain relative to conventionally-colonized controls, with reduced expression of several genes involved in axonogenesis. In addition, embryos from microbiome-depleted mothers exhibit deficient thalamocortical axons and impaired thalamic axon outgrowth in response to cell-extrinsic guidance cues and growth factors. Consistent with the importance of fetal thalamocortical axonogenesis for shaping neural circuits for sensory processing, restricted depletion of the maternal microbiome from pre-conception through mid-gestation yields offspring that exhibit tactile hyposensitivity in select sensorimotor behavioral tasks. Gnotobiotic colonization of antibiotic-treated dams with a limited consortium of spore-forming bacteria indigenous to the gut microbiome prevents abnormalities in fetal brain gene expression, fetal thalamocortical axonogenesis and adult tactile sensory behavior associated with maternal microbiome depletion. Metabolomic profiling reveals that the maternal microbiota regulates levels of numerous small molecules in the maternal serum as well as the brains of fetal offspring. Select microbiota-dependent metabolites – trimethylamine N-oxide, 5-aminovalerate, imidazole propionate, and hippurate – sufficiently promote axon outgrowth from fetal thalamic explants. Moreover, maternal supplementation with the metabolites during early gestation abrogates deficiencies in fetal thalamocortical axons and prevents abnormalities in tactile sensory behavior in offspring from microbiome-depleted dams. Altogether, these findings reveal that the maternal gut microbiome promotes fetal thalamocortical axonogenesis and select tactile sensory behaviors in mice, likely by signaling of microbially modulated metabolites to neurons in the developing brain.

Project description:Background: Toll-like receptor 2 (TLR2) plays a pivotal role in innate immunity and has recently emerged as a criti-cal regulator of host-microbiome interactions. However, how TLR2 influences host transcriptional responses to colonized microbiome and microbial community dynamics remains largely unclear. Germ free (GF) and conven-tionalized zebrafish (Danio rerio) model provides a valuable system to study microbiome functions. Results: RNAseq analysis revealed that transcriptomic alterations resulted from tlr2 mutation were more extensive in the presence of the microbiome than under the GF condition, indicating that tlr2 mutation has a more pro-nounced impact on host transcriptional responses when microbial signals are present. KEGG enrichment analyses showed an enhanced host response to the energy metabolism in the presence of microbial stimuli resulting from tlr2 deficiency. In addition, microbiome colonization elicited a broader transcriptional response in tlr2 wild-type larvae than in the mutants, highlighting the essential role of tlr2 in regulating host transcriptomic programs in re-sponse to microbial signals. In terms of how tlr2 influences microbial composition, 16S rRNA gene sequencing showed that tlr2 mutants exhibited higher microbial diversity during early development, whereas adult microbial diversity was highest in wild-type males, indicating a developmental stage- and sex-specific restructuring of the gut microbiome. For larvae at the genus level, tlr2 mutant larvae showed increased Chryseobacterium and Flecto-bacillus but reduced Gracilibacteria abundance relative to wild-type controls. For adult gut samples, the relative abundance of Cetobacterium was lower, while genera such as Romboutsia, Aeromonas and Pseudarthrobacter were more abundant in tlr2 wild-type male group compared to other groups. Predicted functional analyses revealed that tlr2 deficiency induced complex alterations in microbial metabolic pathways, with distinct pathway enrichments observed between larval and adult stages. Conclusions: TLR2 not only modulates host transcriptional responses to microbial colonization but also shapes gut microbial diversity, composition, and metabolic potential. Our findings highlight the critical role of TLR2 in orchestrating immunometabolic homeostasis and provide new insights into its broader function in maintaining host-microbiota symbiosis across developmental stages.

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