BacArena: Individual-based metabolic modeling of heterogeneous microbes in complex communities

Recent advances focusing on the metabolic interactions within and between cellular populations have emphasized the importance of microbial communities for human health. Constraint-based modeling, with flux balance analysis in particular, has been established as a key approach for studying microbial metabolism, whereas individual-based modeling has been commonly used to study complex dynamics between interacting organisms. In this study, we combine both techniques into the R package BacArena (https://cran.r-project.org/package=BacArena) to generate novel biological insights into Pseudomonas aeruginosa biofilm formation as well as a seven species model community of the human gut. For our P. aeruginosa model, we found that cross-feeding of fermentation products cause a spatial differentiation of emerging metabolic phenotypes in the biofilm over time. In the human gut model community, we found that spatial gradients of mucus glycans are important for niche formations which shape the overall community structure. Additionally, we could provide novel hypothesis concerning the metabolic interactions between the microbes. These results demonstrate the importance of spatial and temporal multi-scale modeling approaches such as BacArena.Author summary: In nature, organisms are typically found in near proximity to each other, forming symbiotic relationships. Particularly bacteria are often part of highly organized communities such as biofilms. In this study, we integrate the detailed knowledge about the metabolic capabilities of individual organisms into an individual-based modeling approach for simulating the dynamics of local interactions. We provide a fast and flexible framework, in which established computational models for individual organisms can be simulated in communities. Nutrients can diffuse in an area where cells move, divide, and die. The resulting spatial as well as temporal dynamics and metabolic interactions can be analyzed as well as visualized and subsequently compared to experimental findings. We demonstrate how our approach can be used to gain novel insights on dynamics in single species biofilm formation and multi-species intestinal microbial communities.