biostudies-literatureUnknownMukherjee SDNIDDK NIH HHSDecades 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, and <i>in vitro</i> experimental models, we found that microbiome composition influenced multiple oxalate-microbe-host interfaces. Importantly, administration of the oxalate-degrading specialist, <i>Oxalobacter formigenes,</i> 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 bioRxiv : the preprint server for biology2024.10.28.620613https://www.ebi.ac.uk/biostudies/studies/S-EPMC11565779biostudies-literatureComplex system modelling reveals oxalate homeostasis is driven by diverse oxalate-degrading bacteria.PMC11565779R01 DK121689Dearing DBatagello CAAgudelo JMukherjee SDZampini ANguyen AMonga MAdler AOrr TMiller AWSuryavanshi MfalseComplex 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, and <i>in vitro</i> experimental models, we found that microbiome composition influenced multiple oxalate-microbe-host interfaces. Importantly, administration of the oxalate-degrading specialist, <i>Oxalobacter formigenes,</i> 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 2025-01-01T00:00:00Z2025 Feb2025-07-10T03:08:50.898Z2025-04-06T03:20:55.457ZS-EPMC115657793955396110.1101/2024.10.28.620613