Metaorganism Metabolomics: Hydra as a tool for understanding the role of bacterial metabolites in shaping the metabolic landscape of the host

With increased focus on host-microbe dynamics over the past decade, evidence that resident microbes affect host behaviour has mounted. Bacteria may be responsible for some of these effects as they produce a number of neuroactive compounds that could influence nervous system structure and function, leading to changes in behavioural phenotype. In the fresh water cnidarian Hydra, two behaviours are altered by microbiota: contraction frequency and feeding response duration. Here, I investigate the potential of resident microbiota to influence the structure and function of the nervous system in the early metazoan Hydra vulgaris AEP. I assess changes to nervous system structure by looking for altered neurogenesis and nerve cell density in adult polyps and find both unaltered in germ-free animals. This does not rule out the possibility of early-life alterations or smaller-scale changes to nervous system anatomy. Next, I present a metabolomics pipeline to aid in the identification of bacterially- derived, contraction-regulating compounds. Future work in identifying these compounds can take advantage of the new extraction process detailed here, which can easily be reproduced from the isolated stocks of Hydra’s five main colonizing bacterial strains. I demonstrate the utility of the metabolomics pipeline in bioactive molecule identification by identifying a dipeptide potentially responsible for the increased chemotaxis of bacterial colonizers towards germ-free Hydra. This may be a new mechanism for host-led shaping of microbial community composition. Finally, I assess the potential role of Hydra microbiota in influencing nervous system function by searching for in vitro neurotransmitter production by Hydra-associated microbes and find that the microbial community produces gamma-aminobutyric acid (GABA). Metabolic modelling confirmed the presence of GABA-synthesizing enzymes in the genomes of all five main colonizers, though only Duganella seems to possess secretory ability via a GABA transporter. Both GABA and Hydra microbiota are reported to increase the duration of the feeding response, so microbial GABA production may play a role in increasing feeding response duration. As GABA feeds into central carbon metabolism, I further analyse the role of the Hydra metabolite and GABA precursor putrescine on the growth of the bacterial colonizers, and find all colonizers are able to grow in a medium that contains putrescine as a sole carbon and nitrogen source. This suggests that any microbial manipulation of behaviour via GABA is a by-product of core metabolic processes in the bacteria. The work presented here demonstrates the utility of untargeted metabolomics for approaching a mechanistic understanding of host-microbe interactions.


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