ISAC Award Program Application Concept

Effect of oxalic acid on microbial oxalate oxidizing genes
Aaron Miller   (Cleveland, OH)
Oxalate, a simple dicarboxylic acid, is found in many foods and produced as a terminal metabolite in the liver. It contributes significantly to urologic diseases such as kidney stones, chronic kidney disease, and end-stage renal disease. Although oxalate degradation is solely provided by the microbiome, this compound inhibits the growth of many oxalate-degrading bacteria. Our recent research has shown that a large proportion of microbial species in the gut are capable of oxalate metabolism and that diverse oxalate-degrading bacteria can prevent hyperoxaluria in the absence of Oxalobacter formigenes, which is the most well-studied oxalate-degrading species. We also recently discovered that oxalate exposure induces the duplication of oxalate-degrading genes at the level of the whole gut microbiota. The proposed study aims to investigate the redundancy of oxalate metabolism in the human gut microbiota and how oxalate exposure promotes oxalate-degrading gene duplication events through phylogenetic analyses, knock-in mutant models, in vitro bioreactor studies, and culturomic/molecular analyses. The expected breakthrough is a comprehensive understanding of oxalate-mediated gut microbiome modulation through oxalate-degrading gene enrichment and duplication events. The study's findings will build on our previous research showing that oxalate metabolism is provided by a metabolically cooperative and redundant community of microorganisms in the gut, rather than a single species. The proposed investigation is expected to lead to ground-breaking discoveries, including the identification of specific genetic changes that occur in response to oxalate exposure, how oxalate exposure leads to oxalate-degrading gene enrichment and duplication, and the potential role of horizontal gene transfer. These data will be critical for developing dietary and therapeutic interventions to improve human health by targeting the gut microbiome. The proposed study combines genetic engineering, molecular, culturomic, and bioreactor studies, to provide ground-breaking results that will have implications for accelerating innovation in the field and for the development of novel dietary and therapeutic interventions.
Data for this report has not yet been released.

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