TABLE 1.

Open questions and approaches in oral microbial ecology

Questions	Bottom-up approaches	Top-down approaches
How to build a simplified model system for oral microbiota? What are appropriate metrics for model evaluation?	Experimental model systems can be constructed at the species level (6, 17), genus level (6, 46), or functional level.	Quantitative approaches must be used to benchmark models using the human oral community (39, 42, 56).
What are the similarities and differences in community dynamics between supragingival and subgingival plaque?	Models can illuminate differences in microbial interactions between the two environments. For instance, the Zurich model suggested that the subgingival plaque model could be derived from the supragingival plaque model (62).	Comparative studies using sequencing and microscopy can show intrapatient and interpatient differences between environments.
What are the factors that drive the progression from healthy to diseased states or from diseased to healthy states? How do oral microbes colonize and invade different oral habitats?	Model systems can test the factors that lead to pathogen abundance and the production of virulence factors.	Detailed analyses of longitudinal studies in human patients can further show how communities change over time and which healthy communities become diseased.
How many microenvironments exist in the oral cavity? How do microenvironments impact biodiversity?	Perturbation of laboratory models can test the importance of different environmental factors.	In situ measurement of chemical gradients and oxygen levels can indicate different niches. Also, differential abundance of microbes can indicate site specialists with distinct niches (22).