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A diverse metabolome exists on amphibian skin that mediates interactions between hosts and skin microbiomes. Tetrodotoxin is one such metabolite that occurs across a variety of taxa, and is particularly well studied in newts of the genusTarichathat are susceptible to infection with chytrid fungi. The interaction of tetrodotoxin with the skin microbiome, including pathogenic fungi, is not well understood, and here we describe these patterns across 12 populations ofTaricha granulosaandT. torosain Washington, Oregon, and California. We found no correlation of TTX andBatrachochytrium dendrobatidis(Bd) infection in eitherT. granulosaorT. torosa, a pattern inconsistent with a previous study. In addition, TTX, but not Bd, was significantly correlated with the skin microbiome composition inT. granulosa. InT. torosa, however, Bd, but not TTX, was correlated with the skin microbiome structure. The relationship between TTX and skin microbiome composition differed between species, with significant correlations observed only inT. granulosa, which exhibited higher TTX concentrations. We also detected significantly higher abundances of bacterial taxa (e.g., Pseudomonadaceae) associated with TTX production in newts with higher skin TTX. These taxa (ASVs matchingAeromonas, Pseudomonas, Shewanella, andSphingopyxis) were associated with all body sites of previously sampledT. granulosa, but not found in soil samples. Our results suggest that toxins can shape the newt skin microbiome and may influence pathogen infection through indirect mechanisms, as TTX showed no direct inhibition of Bd orB. salamandrivoransgrowth. 

Tetrodotoxin (TTX) is a potent neurotoxin that was first identified in pufferfish but has since been isolated from an array of taxa that host TTX-producing bacteria. However, determining its origin, ecosystem roles, and biomedical applications has challenged researchers for decades. Recognized as a poison and for its lethal effects on humans when ingested, TTX is primarily a powerful sodium channel inhibitor that targets voltage-gated sodium channels, including six of the nine mammalian isoforms. Although lethal doses for humans range from 1.5–2.0 mg TTX (blood level 9 ng/mL), when it is administered at levels far below LD50, TTX exhibits therapeutic properties, especially to treat cancer-related pain, neuropathic pain, and visceral pain. Furthermore, TTX can potentially treat a variety of medical ailments, including heroin and cocaine withdrawal symptoms, spinal cord injuries, brain trauma, and some kinds of tumors. Here, we (i) describe the perplexing evolution and ecology of tetrodotoxin, (ii) review its mechanisms and modes of action, and (iii) offer an overview of the numerous ways it may be applied as a therapeutic. There is much to be explored in these three areas, and we offer ideas for future research that combine evolutionary biology with therapeutics. The TTX system holds great promise as a therapeutic and understanding the origin and chemical ecology of TTX as a poison will only improve its general benefit to humanity.