The mammalian gut is a complex ecosystem inhabited by diverse microbial communities, which are highly dynamic throughout life and can substantially vary between individuals. Nevertheless, individual taxa within bacterial communities form organized metabolic networks, which is considered essential for overall ecosystem functionality. Microbial metabolite networks are influenced by three mechanisms: (i.) Compositional changes can alter the representation of metabolic pathways. (ii.) Variability arises by transcriptional alterations, for example in response to diet or during disease. (iii.) Evolutionary changes such as mutational events and horizontal gene transfer modify the genomic content and metabolic capabilities of individual taxa. Currently, little is known on how within-host evolution of the microbiome can result in functional changes.
In EvoGutHealth, we will address this question using a synthetic bacterial model community, termed Oligo-Mouse-Microbiota (OMM). Our previous work demonstrates that the OMM recapitulates central physiologic and functional traits of a complex mouse microbiome and exhibits long-term stability in gnotobiotic mice. Therefore, the model is exceptionally suited to study microbial community evolution in its native host. Our preliminary work shows that several taxa accumulate multiple, non-synonymous mutations in metabolic and transport functions during long-term co-colonization of the murine gut. Transplanting germ-free mice with “evolved” and original communities allowed us to reveal functional differences related to nutrient breakdown, metabolite production and host phenotypes. Therefore, the underlying hypothesis of EvoGutHealth is that within-host evolution of microbial communities in the gut shapes the metabolic interactions between microbial populations and their host and with this impact on microbiome functions. The specific objectives are
• to discern environmental and host factors governing microbial community evolution in the gut
• to identify pathways and functions of different taxa under selection during within-host evolution
• to assess global metabolic and disease-relevant phenotypes of evolved microbial communities using systems biology approaches, metabolic phenotyping and mouse disease models
• to characterize phenotypes of evolved strains by metabolite profiling, metabolic network models and generation of targeted mutations
• to verify and extend results to the human gut microbiota
EvoGutHealth will lead to fundamental and ground-breaking insights into mechanisms and functional implications of within-host microbiome evolution in the mammalian gut.
