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Examining microbiota as a modifying factor for developmental neurotoxicity
Citation:
Tal, T. Examining microbiota as a modifying factor for developmental neurotoxicity. SOT, Baltimore, MD, March 10 - 14, 2019.
Impact/Purpose:
Intestinal microbes are thought to influence mood, anxiety, and increasingly, brain development. It has been proposed that microbiota, through bioactivation or detoxification, may mediate the developmental neurotoxicity of environmental chemicals. To determine the role of microbiota in zebrafish nervous system development, we used axenic (microbe-free) and colonized zebrafish. A standard locomotor behavioral assay was used as a functional readout of the microbiota-gut-brain axis. Using this system, we show that axenic zebrafish display a hyperactive swimming behavior and that antibiotic exposure mimics hyperactivity in colonized zebrafish. Data will be presented showing that xenobiotic-resistant microbes biotransform environmental chemicals, in some cases resulting in increased neurotoxicity to the host organism. To determine the functional requirements for bacterial colonization on neurobehavioral development, axenic zebrafish were colonized with single strains of bacteria isolated from 10 day old zebrafish. Zebrafish colonized with Actinetobacter, Comamonas, or Comamonadaceae developed control-like behavior. In contrast, colonization with Vibrio resulted in abnormal behavioral development that could be blocked by co-colonization with commensal bacteria. Collectively, this work supports the concept that microbiota modify the toxicokinetics and toxicodynamics of environmental chemicals. These data also suggest that recapitulation of a defined microbiota that contains sufficient diversity to reflect the full repertoire of interactions between xenobiotics and microbiota may be difficult.
Description:
Disruption of the community structure of host-associated microbes has been implicated in a number of behavioral disorders like anxiety, depression, and autism spectrum disorder. Complex bidirectional interactions between intestinal microbes and the nervous system may be vulnerable to perturbations via exposure to environmental chemicals, particularly during sensitive early life stages. For example, pharmacological or xenobiotic disruptions of intestinal microbiota harbors the potential to elicit secondary adverse effects on host brain development and function. Microbes are also known to biotransform drugs and environmental chemicals, thereby altering the toxicokinetics of chemical exposures. We developed a model comprised of conventionally colonized and microbe-free axenic zebrafish to test the hypothesis that microbiota modifies the developmental neurotoxicity of environmental chemicals. We also used axenic embryos colonized on day 1 with a diverse and variable mixture of fish facility microbes as a conventionalized control. A light/dark locomotor activity assay was used as a functional readout of neurodevelopment. We previously showed that axenic zebrafish are hyperactive relative to conventionally colonized or conventionalized zebrafish at 10 days post fertilization (dpf). To test the effect of chemical exposures on locomotor activity and microbiota community structure, we exposed conventionally colonized zebrafish to triclosan, triclocarban, bisphenol A (BPA), BPF, BPS, or estradiol (E2) on 1, 6, 7, 8, and 9 dpf and tested locomotor activity at 10 dpf. E2 treatment had no effect on microbiota while exposure to all other test compounds disrupted community structure. We next exposed conventionally colonized, axenic, and conventionalized zebrafish to triclosan, triclocarban, bisphenol A (BPA), BPF, or BPS and revealed that colonization status failed to modify chemical effects on locomotor activity. In comparison, E2 exposure caused hypoactivity in the light period in both colonized cohorts but had no effect on axenic zebrafish. One flaw of the experimental system is the inherent variability in conventionally colonized and conventionalized zebrafish microbiota. To further characterize neurobehavioral requirements for microbial colonization and potentially build a defined microbiota for zebrafish toxicology studies, we isolated strains of Actinetobacter, Vibrio, Comamonas, and Comamonadaceae from 10 dpf conventionally colonized zebrafish and used a combination of 16S rRNA and whole genome sequencing to identify isolates. Monocolonization of axenic zebrafish with the commensals Actinetobacter, Comamonas, or Comamonadaceae caused control-like behavioral development whereas colonization with pathogenic Vibrio provoked hypoactivity that was blocked by co-colonization with commensal strains. Taken together, these data show that colonization with specific strains of bacteria was required for control-like neurobehavioral development and that recapitulation of a defined microbiota that contains sufficient diversity to reflect the full repertoire of toxicodynamic and toxicokinetic interactions between xenobiotics and microbiota may be difficult. These data also suggest that, while environmental chemicals seem to uniformly disrupt the composition of host-associated microbes, microbial colonization status does not generally modify the neurobehavioral toxicity of multiple antimicrobial and industrial chemicals. This abstract does not necessarily reflect the views of the U.S. EPA.