Editorial Comment on: Calcium Oxalate Urolithiasis: A Case of Missing Microbes? by Batagello et al. (From: Batagello CA,Monga M,Miller AW. J Endourol 2018;32:995–1005;DOI: 10.1089/end.2018.0294)

Given the significant role of dietary oxalate in recurrent calcium oxalate kidney stone disease (KSD), it is not surprising that intestinal bacteria may help regulate overall oxalate homeostasis in the body. A link between a member of the intestinal microbiome and recurrent KSD was made with the identification of Oxalobacter formigenes, an oxalate-degrading specialist, colonizing the intestine of the majority of nonstone formers. Although there is no doubt that O. formigenes is important in maintaining overall oxalate homeostasis, several pieces of evidence suggest that it does not act alone. First, members of the intestinal microbiome form symbiotic networks that promote each other's survival and overall host health. Second, the absence of O. formigenes is not causative of stone disease, as some recurrent stone formers are still colonized while some nonstone formers are not. Finally, clinical trials using O. formigenes or other probiotics to regenerate an oxalate-degrading bacterial environment failed to reduce urinary oxalate excretion despite colonization. ^1,2 Collectively these point toward a role for multiple bacterial species in the maintenance of “healthy” oxalate homeostasis. Further studies to understand how members of the intestinal microbiome collaborate to maintain a nonstone forming oxalate balance are required.

Miller et al. performed the first meta-analysis of studies examining the association of the gut microbiota and KSD. ³ Given the complexity of the intestinal microbiome and significant intervariability between individuals, this analysis is key to identify trends that shape future microbiome-based therapies for recurrent KSD. Indeed, this study supports the notion that multiple bacterial species play a role in maintaining overall oxalate homeostasis, as comparison of available data indicates that O. formigenes colonization is neither necessary nor sufficient to maintain oxalate metabolism and protect against KSD. That said, the most striking evidence that microbiome composition as a whole dictates overall oxalate metabolism comes from the finding that O. formigenes colonization was prolonged and the abundance of members of the Oxalobacteriaceae was greater in patients undergoing fecal transplants. Unlike probiotic supplementation that introduces a few bacterial species into the preexisting “dysfunctional” intestinal microbiome of the recipient, fecal transplant introduces intact “healthy” microbial networks, including those associated with Oxalobacter, into recipients in whom the “dysfunctional” microbiome has been removed. The fact that O. formigenes colonization and Oxalobacteroaceae abundance are prolonged and increased after fecal transplant clearly indicates that O. formigenes requires the presence of other bacterial species to remain in the intestine. This complicates the use of microbiome-based therapies for stone disease, as maintenance of this new “fully functioning” microbiome is paramount to prevent KSD recurrence over the long term. This will likely involve significant changes for the recipient, including diet, lifestyle, and other factors known to affect intestinal microbiome composition, closely mimicking those of the recipient in whom the “healthy” microbiome is stable.

Despite significant progress in improving our understanding of the intestinal microbiome's role in KSD, research into specific bacterial networks and factors that influence their reintroduction and long-term survival in the host is required before microbiome-based therapies become part of everyday practice. That said, the study performed by Miller and colleagues ³ is a significant step toward meeting this goal.