PD38-10\u2003QUANTIFYING THE FUNCTION OF THE OXALATE-DEGRADING MICROBIAL NETWORK AND ITS RELEVANCE FOR URINARY STONE DISEASE

Abstract

INTRODUCTION AND OBJECTIVES: Oxalate homeostasis is maintained in part by a diverse consortium of bacteria in the gut that includes oxalate-degrading bacteria and other functional groups that benefit indirectly from oxalate exposure. Individuals with an active episode of urinary stone disease (USD) harbor a reduced diversity of bacteria from this oxalate-degrading microbial network (ODMN). The objective of this study was to elucidate the metabolic function of the ODMN and its relevance to USD. METHODS: The metabolic potential of the ODMN was determined for the gut microbiota of Neotoma albigula, a wild rodent that consumes a high oxalate diet in the wild, through comparative shotgun metagenomics. The resulting metabolic structure of the ODMN was validated through both in vitro and in vivo systems that involved the substrates and bacteria hypothesized to be a part of the ODMN. Finally, the relevance of the ODMN function to USD was determined by comparing the urinary metabolic profile of USD patients to individuals with no history of USD. RESULTS: Metagenomics produced a three-step model of the ODMN: 1) Oxalate metabolism; 2) Acetogenesis, methanogenesis, and sulfate-reduction; and 3) Gluconeogenesis, fatty acid synthesis, and the citric acid cycle. Addition of substrates or bacteria hypothesized to be a part of the ODMN in vitro resulted in a 7-fold or 2.5-fold increase oxalate metabolism than if they were omitted, respectively. In mice inoculated by the N. albigula microbiota, 85% of fecal metabolites that were more abundant after exposure to dietary oxalate could be attributed to the 3rd step of the hypothesized ODMN, compared to 50% for mice with their native microbiota. In clinical urine samples, of the metabolites that differentiated healthy individuals from those with USD, 88% mapped to the 3rd step of the hypothesized ODMN metabolic network. CONCLUSIONS: Animal and clinical studies reveal that oxalate metabolism is associated with a diverse consortium of bacteria and that individuals with USD harbor a reduced consortium of bacteria associated with oxalate metabolism compared to individuals with no history of USD. Results of the current study elucidates the extended function of the ODMN, validates the structure through in vitro and in vivo models, and shows that the urinary metabolic profile of individuals with USD reflects reduced activity of the ODMN, corroborating microbial metagenomic results. Source of Funding: Lerner Research Institute