Renal lithiasis, or kidney stones, and associated complications are a major burden on our health care system affecting 8.8% of the population in the United States. Oxalate is a simple organic acid widely consumed by humans and is also a constituent in 80% of all kidney stones. Many adults host intestinal oxalate-degrading bacteria, which can degrade oxalate and significantly reduce the amount circulating in the blood. Individuals who do not host oxalate-degrading bacteria can acquire them and the benefits they confer, as probiotic supplements. However, these probiotics are often lost in the intestines over time, and a high oxalate diet is required for their maintenance. The mechanisms driving the loss of probiotic oxalate-degrading bacteria on a low oxalate diet represents a considerable gap in our understanding of the gut microbiome and is a challenge for the successful treatment of hyperoxaluria. My long-term goal is to understand the mechanisms that facilitate the persistent colonization of bacteria in the gut and develop effective probiotics to treat oxalate-related illnes. The overall objectives of this application are to use molecular techniques such as metagenomics and qPCR to identify the mechanisms behind the loss of oxalate-degrading bacteria inoculated into a host. We hypothesize that the oxalate-degrading function is supported by the metabolic activity of the non- degrading proportion of the gut microbiota.
Three specific aims are proposed to test this hypothesis: (1) Determine the persistence of the oxalate-degrading community on variable oxalate loads; (2) Identify the unique metabolic pathways and microbial taxa that are present in persistent oxalate-degrading microbiota; and (3) Quantify the differences in the relative expression of genes encoding for oxalate-sensitive anion-transport proteins in animals with or without natural communities of oxalate-degrading bacteria. Completion of the specific aims will identify the mechanisms facilitating the persistence and loss of oxalate-degrading communities in the gut. Outcomes will have a positive impact by identifying the molecular mechanisms that lead to the persistence and loss of oxalate-degrading bacteria, which is an important step in making oxalate-degrading bacteria a viable treatment for hyperoxaluria.

Public Health Relevance

The prevalence of kidney stones has tripled in the United States over the last fifty years, costing billions of dollars to the health care system annually. Approximately 80% of kidney stones contain oxalate, and oxalate-degrading bacteria in the gastrointestinal tract are an effective preventative measure to guard against oxalate-related ailments such as kidney stones. The goals of this project are to determine the mechanisms behind the loss of oxalate-degrading bacteria in mammals and how to sustainably transfer oxalate-degrading bacteria between different mammalian species, to maintain a stable and functional equilibrium.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZDK1)
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Rankin, Tracy L
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Cleveland Clinic Lerner
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Miller, Aaron W; Dale, Colin; Dearing, M Denise (2017) Microbiota Diversification and Crash Induced by Dietary Oxalate in the Mammalian Herbivore Neotoma albigula. mSphere 2:
Oakeson, Kelly F; Miller, Aaron; Dale, Colin et al. (2016) Draft Genome Sequence of an Oxalate-Degrading Strain of Clostridium sporogenes from the Gastrointestinal Tract of the White-Throated Woodrat (Neotoma albigula). Genome Announc 4:
Miller, Aaron W; Oakeson, Kelly F; Dale, Colin et al. (2016) Effect of Dietary Oxalate on the Gut Microbiota of the Mammalian Herbivore Neotoma albigula. Appl Environ Microbiol 82:2669-2675
Miller, Aaron W; Oakeson, Kelly F; Dale, Colin et al. (2016) Microbial Community Transplant Results in Increased and Long-Term Oxalate Degradation. Microb Ecol 72:470-8