BBSRC-DFG 23/24: MIMICC - Modelling microbiome dynamics in continuous culture

Over the past decade, advances in DNA sequencing methodologies have revolutionised microbiome research, facilitating the genomic characterisation of microbial communities inhabiting diverse ecosystems. They have unveiled the novelty, complexity, and functional repertoire of microbes housed therein, while also highlighting the critical role played by the microbiota in both health and disease of humans, animals and plants. However, studies have largely focused on descriptive differences between two or more conditions and not analysed causality due to inherent experimental limitations, such as complexity of host-associated microbial communities, large variation between individuals/samples, and sample destruction during the experiment. Nevertheless, well-studied communities like the human gut microbiome have provided a nascent picture of a representative microbial community. Coupled with the large-scale efforts to cultivate microbes, there now exist isolates for a large fraction of the most abundant members of the human gut microbiome, which has facilitated the construction of synthetic communities (SynComs). Most SynComs generated so far have been grown in batch cultures - a fixed volume, rich media system, where the microbes are grown for a short time until they exhaust the nutrients and reach a stationary growth phase. To overcome this limitation and study complex communities under conditions more closely mimicking the natural environment, we propose to develop a continuous culturing system using a representative human gut core microbiome via the following objectives: (1) Establish the requisite conditions for a continuous culturing platform using a representative SynCom, coupling this to sequencing and informatics analysis to develop a rapid community composition monitoring system; (2) Leverage this continuous system to obtain insights into community dynamics via strain competition and introduction of an archaeon capable of methanogenesis; (3) Assess the impact on an established community of temperature fluctuation and introduction of a lytic virus. Real-time monitoring of the community will be used to guide selection of samples for further analysis. Metatranscriptomics will be used to understand gene expression in response to abiotic or biotic stresses and metagenomics to monitor the impact of the virus at a genomics level. We will use this data to develop mechanistic models for understanding community dynamics. Our project will facilitate hypothesis-driven research, thus importantly addressing a key issue raised in a recent Microbiome Innovation Network report, which highlighted the need for researchers to move beyond purely descriptive towards more causal studies. We will perform the technical and experimental developments required to routinely establish continuous culture systems for complex communities typically found in animal guts. Such systems can be used to assess, for example, the broader impact of antimicrobials on a microbiome, the impact of viruses on the microbiome structure, or the role of the microbiome in food and nutrition, such as the influence of methane-suppressing feed products on the composition of methane-producing archaea or the breakdown of complex carbohydrates by microbial communities. Leveraging our collaborative networks, we will determine the applicability of this system to plant biomes to help acquire insights into the mechanisms behind how microbial communities influence plant health in the future. Finally, this proposal will address three highlighted challenges in the area of integrative microbiome research, namely understanding variation in microbiome composition, the impact of disturbance of the microbiome, and the functional properties of the microbiome.