Research Projects

Tryptophan is an essential amino acid required not only for protein synthesis but also as a precursor for several biologically significant metabolites, including serotonin, kynurenine, and nicotinamide. In eukaryotic cells, tryptophan is catabolized through three primary pathways: the kynurenine, serotonin, and tryptamine branches. Additionally, gut microbiota can convert tryptophan into indole and its derivatives, which have been implicated in both physiological and pathological processes. Using the nematode model Caenorhabditis elegans, we recently demonstrated that bacterial conversion of tryptophan to indole results in host toxicity. Indole exhibited marked toxicity to C. elegans, inhibiting egg hatching even at concentrations as low as 1 mM. Human gut bacteria are highly efficient at metabolizing tryptophan to indole, and fecal indole concentrations can reach several millimolar. Therefore, gut-derived indole may become toxic to human tissues, particularly under high-protein dietary conditions. Indeed, certain indole derivatives have been linked to human pathologies; however, the molecular mechanisms underlying indole-mediated cellular toxicity remain poorly defined. The proposed study aims to elucidate the molecular mechanisms of indole toxicity. Given that indole inhibits egg hatching in C. elegans, we hypothesize that it may interfere with eukaryotic cell division. While indole is known to inhibit bacterial cell division, its effects on eukaryotic mitotic processes are largely unexplored. To unbiasedly investigate the mechanisms of indole toxicity, we will employ forward genetic screens in C. elegans to identify the physiological changes induced by indole. Based on our transcriptomic data, we have developed a reporter strain activated by indole exposure. This strain will be used to screen for mutants that either phenocopy indole-induced physiological responses or suppress the transcriptional reprogramming caused by indole. These approaches will enable the identification of molecular targets and pathways contributing to indole toxicity. Finally, mechanisms uncovered in C. elegans will be validated in human cell lines to assess their relevance across species. This interdisciplinary framework, combining C. elegans genetics with mammalian cell biology, will provide comprehensive insights into the cellular and molecular basis of indole toxicity and may help in designing strategies for its mitigation in human health contexts.