Integrated culturing, modeling and transcriptomics uncovers complex interactions and emergent behavior in a three-species synthetic gut community

Abstract

The composition of the human gut microbiome is well resolved, but predictive understanding of its dynamics is still lacking. Here, we followed a bottom-up strategy to explore human gut community dynamics: we established a synthetic community composed of three representative human gut isolates ( Roseburia intestinalis L1-82, Faecalibacterium prausnitzii A2-165 and Blautia hydrogenotrophica S5a33) and explored their interactions under well-controlled conditions in vitro. Systematic mono- and pair-wise fermentation experiments confirmed competition for fructose and cross-feeding of formate. We quantified with a mechanistic model how well tri-culture dynamics was predicted from mono-culture data. With the model as reference, we demonstrated that strains grown in co-culture behaved differently than those in mono-culture and confirmed their altered behavior at the transcriptional level. In addition, we showed with replicate tri-cultures and simulations that dominance in tri-culture sensitively depends on the initial conditions. Our work has important implications for gut microbial community modeling as well as for ecological interaction detection from batch cultures.

eLife digest

Our gut is home to trillions of microorganisms, most of them bacteria, which have an important impact on our body. During healthy periods, these microorganisms help our digestion, protect our cells, and compete against disease-causing bacteria. But specific communities of gut bacteria are linked to many diseases.

We already have a good knowledge of the bacterial composition present in a wide range of human guts, but how the different bacterial species within such communities affect each other, has so far been unclear. Future disease treatments may be able to steer ‘bad’ communities to healthier mixtures. For this to happen we need to know how species interact and how these interactions change the behavior of the whole community.

To investigate this further, D'hoe, Vet, Faust et al. studied three common species of gut bacteria under controlled conditions in the laboratory. The different species were either grown alone, in pairs or together, and the number of bacteria and the concentration of nutrients were measured over time. The results showed that when grown alone or together, their behavior changed.

D'hoe et al. then used a mathematical model to estimate the rates at which species multiplied and consumed nutrients. This model was able to predict the dynamics of each of the species grown alone. However, the data from bacteria grown in pairs was needed to predict the dynamics of bacteria grown as a group of three. Next, D'hoe et al. compared the activity of genes between bacteria grown alone or together, and discovered several differences.

This suggests that bacterial species affect each other greatly, and community behavior cannot be predicted from knowledge of its members alone. Therefore, studying bacteria in isolation is not enough to understand the complex environments of our guts, which are inhabited not by three but hundreds of bacterial species. In future, interactions between bacteria will need to be studied to ultimately be able to shift the gut community into better shapes.