BBSRC-NSF/BIO - The impact of public versus private metabolism on the stability of microbial communities within natural hosts

Why do microorganisms engage in cooperative nutrient consumption that is open to exploitation when an exploitation-free alternative is available? Our proposal will answer this fundamental yet unanswered question through a combination of synthetic biology, mathematical modelling and in vivo microbial community experiments.

Microorganisms play crucial roles in ecosystem functioning and the health of macro organisms. They form beneficial relationships with multicellular organisms, in environments ranging from animal guts to soil, and can be exploited to degrade industrial waste or produce useful chemicals. But they can also cause devastating damage by destroying our food sources and eliminating key plant species, thus preventing the absorption of hundreds of megatonnes of CO2.

Microorganisms do not exist in isolation, instead they form intricate communities of diverse strains and species where individuals participate in complex cooperative and competitive interactions. However, we lack a comprehensive understanding of how these interactions alter the function and stability of the community. This is crucial for predicting the evolution of microbial strategies that promote survival and growth in natural environments.

To survive and thrive, microorganisms must obtain nutrients from their environment and cooperative and competitive actions are key to the way that microbes feed. A common strategy to obtain nutrients involves secreting metabolic products into the external, "public" environment to break down or capture resources, before they are taken up into the cell. The metabolic products are considered to be cooperative public goods as they are generated externally and so benefit other cells in the shared environment. This seemingly successful strategy, termed "public metabolism", is used by a wide range of microbial species that inhabit diverse habitats, yet it has two obvious drawbacks. First, the public goods can easily be lost into the environment before they are successfully taken up by the cell that generated them. Second, the public-goods can be exploited by microbes that "cheat" by not contributing to their production but still reap the rewards. These shortcomings can threaten the success of public metabolism and the stability and functioning of microbial communities. Curiously, an exploitation-free strategy exists whereby microbes can secure nutrients by taking them directly into the cell, with digestion taking place "privately" inside the cell, instead of "publicly" in the environment. Yet despite this failsafe alternative, many microbes still feed by public metabolism. Our project will determine why this is the case and what benefits public metabolism provides.

Based on preliminary data we hypothesise that microbial feeding strategies involving either public or private metabolism represent two opposing approaches to survival, the success of which is environment-dependent. In particular, we hypothesise that sufficiently spatially structured environments will limit exploitation of public-metabolisers thus favouring them over private-metabolisers.

To test this, we have generated two well-defined and tractable synthetic systems involving the environmental yeast Saccharomyces cerevisiae and the plant pathogen Magnaporthe oryzae. These communities will be used to experimentally probe the fitness of different metabolic strategies in their natural environments and assess community stability and function. In parallel, we will develop dynamic, spatially explicit, genome-scale mathematical models to generate mechanistic understanding of how metabolic interactions and the degree of spatial structure support community stability. This will enable us to extrapolate general principles from the system-specific observation and to develop a classification of different types of biotic (e.g. host-pathogen and microbe-microbe) and abiotic (e.g. spatial structure) conditions that favour cooperative metabolism.

Microbial communities play essential roles in ecosystem processes and the health of macro organisms. To survive and thrive, microbes must acquire nutrients from their environment. Thus, metabolic interactions are key to the formation, stability and function of microbial communities. Yet we lack understanding of the fundamental rules governing how microbes feed. Nutrient acquisition frequently involves secretion of costly metabolic products that capture or break down resources in the external environment. This cooperative strategy, termed "public metabolism", is risky as the products can be lost into the environment or exploited by neighbours. So why do many diverse microbes engage in such cooperative nutrient consumption when an exploitation-free alternative, termed "private metabolism", is available? It involves microbes internalising substrates before being metabolised so all generated products are retained in the cell. Tackling this question requires an interdisciplinary approach that combines synthetic biology, microbial population ecology, molecular biology and mathematical modelling. Based on preliminary data, we hypothesise that feeding strategies involving either public or private metabolism represent two opposing approaches to survival, the success of which is environment-dependent. In particular, we predict that sufficiently spatially structured environments will limit exploitation of public metabolism, so favour it over private metabolism. To test this, we have generated two tractable synthetic systems with the environmental yeast Saccharomyces cerevisiae and the plant pathogen Magnaporthe oryzae. We will gain systematic understanding of the metabolic community interactions occurring within in vitro and in planta experiments by developing dynamic, spatially explicit, genome-scale metabolic models of both systems. This will allow us to extrapolate general principles governing microbial interactions and community stability from system-specific observation.

Microbial communities play essential roles in nutrient recycling, ecosystem processes and the health of macro-organisms. To survive and thrive, microbes need to acquire nutrients from their environment and frequently this is achieved through cooperation amongst community members. Our research will answer the fundamental question: why engage in cooperative nutrient consumption that is open to exploitation when an exploitation-free alternative is available? Adopting a truly interdisciplinary approach we will combine synthetic biology, mathematical modelling and microbial community experiments to address this question.

Who will benefit?

The impact of our research will be two-fold. First, it will contribute to understanding of basic questions in biosciences making an important contribution to the wider body of scientific knowledge available to researchers. Second, it will contribute to the much-needed long-term training of Bioscientists in quantitative disciplines as well as contribute to addressing underrepresentation of certain groups in STEM disciplines. Fundamental scientific knowledge is the bedrock that underpins technological innovation. Truly interdisciplinary research approaches such as those described in this proposal are still relatively rare but foster the skills mix and creativity required to identify and develop technological solutions to real-world problems. Underrepresented groups in STEM bring a different perspective, thus developing a better gender and minority balance in quantitative sciences will eventually lead to a fundamental shift in the diversity of research questions being studied and to broader range of approaches taken to address these questions. This in turn feeds the pipeline of ideas and solutions required to develop innovative technologies for industry and society.

How they will Benefit

Wider research community: Researchers will benefit by access to new knowledge and computational tools that underpin a mechanistic understanding of how different metabolic strategies affect microbial community composition, function and stability. This has far-reaching consequences as cooperative metabolism is prevalent amongst marine microbial communities, mammalian microbiota and plant pathogens.

Young researchers: A recent BBSRC review into vulnerable skills highlighted that "Maths, statistics and computational biology skills are lacking particularly at the postgraduate and postdoctoral levels, with many respondents reporting difficulties in recruiting adequately skilled researchers at these levels; shortages are not just restricted to the UK". Indeed, the same challenges exist in the US. Our interdisciplinary research project deploys data-driven mathematical modelling and computer simulations and the tools will be developed in a user-friendly way that is accessible to wide range of bioscientists. The quantitative training will be facilitated via a skills training workshop. In the long term this will increase employability of young researchers, not only in the academia but also in industries where quantitative skills are required alongside cutting-edge biological knowledge.

The wider public, including local schools: Wider society will benefit by access to new educational resources and knowledge about using mathematics, computer science and engineering to understand fundamental principles in biology. Promoting the importance of quantitative disciplines in solving topical problems in biology will help to address a long-standing gender gap in mathematics, computer science and engineering. In particular 63% of A-level Biology students are girls, while only 28% of A-level Further Maths students are girls. The underrepresentation of women studying mathematics, computer science and engineering continues into undergraduate HE. Introducing girls to the importance of mathematics in biology at an early age could help address this imbalance.