Complex system modelling reveals oxalate homeostasis is driven by diverse oxalate-degrading bacteria

Decades of research have made clear that host-associated microbiomes touch all facets of health. However, effective therapies that target the microbiome have been elusive given its inherent complexity. Here, we experimentally examined diet-microbe- host interactions through a complex systems framework, centered on dietary oxalate. Using multiple, independent molecular, animal, andin vitroexperimental models, we found that microbiome composition influenced multiple oxalate-microbe-host interfaces. Importantly, administration of the oxalate-degrading specialist,Oxalobacter formigenes,was only effective against a poor oxalate-degrading microbiota background and gives critical new insights into why clinical intervention trials with this species exhibit variable outcomes. Data suggest that, while heterogeneity in the microbiome impacts multiple diet-host-microbe interfaces, metabolic redundancy among diverse microorganisms in specific diet-microbe axes is a critical variable that may impact the efficacy of bacteriotherapies, which can help guide patient and probiotic selection criteria in probiotic clinical trials.