Osteopontin phosphopeptide mitigates calcium oxalate stone formation in a Drosophila melanogaster model.

Kidney stone disease affects nearly one in ten individuals and places a significant economic strain on global healthcare systems. Despite the high frequency of stones within the population, effective preventative strategies are lacking and disease prevalence continues to rise. Osteopontin (OPN) is a urinary protein that can inhibit the formation of renal calculi in vitro. However, the efficacy of OPN in vivo has yet to be determined. Using an established Drosophila melanogaster model of calcium oxalate urolithiasis, we demonstrated that a 16-residue synthetic OPN phosphopeptide effectively reduced stone burden in vivo. Oral supplementation with this peptide altered crystal morphology of calcium oxalate monohydrate (COM) in a similar manner to previous in vitro studies, and the presence of the OPN phosphopeptide during COM formation and adhesion significantly reduced crystal attachment to mammalian kidney cells. Altogether, this study is the first to show that an OPN phosphopeptide can directly mitigate calcium oxalate urolithiasis formation in vivo by modulating crystal morphology. These findings suggest that OPN supplementation is a promising therapeutic approach and may be clinically useful in the management of urolithiasis in humans.

Probiotic Bifidobacteria Mitigate the Deleterious Effects of para-Cresol in a Drosophila melanogaster Toxicity Model.

Renal impairment associated with chronic kidney disease (CKD) causes the buildup of uremic toxins that are deleterious to patient health. Current therapies that manage toxin accumulation in CKD offer an incomplete therapeutic effect against toxins such as para-cresol (p-cresol) and p-cresyl sulfate. Probiotic therapies can exploit the wealth of microbial diversity to reduce toxin accumulation. Using in vitro culture techniques, strains of lactobacilli and bifidobacteria from a 24-strain synbiotic were investigated for their ability to remove p-cresol. Four strains of bifidobacteria internalized p-cresol from the extracellular environment. The oral supplementation of these toxin-clearing probiotics was more protective than control strains in a Drosophila melanogaster toxicity model. Bifidobacterial supplementation was also associated with higher abundance of lactobacilli in the gut microbiota of p-cresol-exposed flies. The present findings suggest that these strains might reduce p-cresol in the gut in addition to increasing the prevalence of other beneficial bacteria, such as lactobacilli, and should be tested clinically to normalize the dysbiotic gut microbiota observed in CKD patients. IMPORTANCE Chronic kidney disease (CKD) affects approximately 10% of the global population and has limited treatment options. The accumulation of gut microbiota-derived uremic toxins, such as para-cresol (p-cresol) and p-cresyl sulfate, is associated with the onset of comorbidities (i.e., atherosclerosis and cognitive disorders) in CKD. Unfortunately, dialysis, the gold standard therapy is unable to remove these toxins from the bloodstream due to their highly protein-bound nature. Some strains of Bifidobacterium have metabolic properties that may be useful in managing uremic toxicity. Using a Drosophila model, the present work highlights why dosing with certain probiotic strains may be clinically useful in CKD management.

New perspectives on an old grouping: The genomic and phenotypic variability of Oxalobacter formigenes and the implications for calcium oxalate stone prevention.

Oxalobacter formigenes is a unique bacterium with the ability to metabolize oxalate as a primary carbon source. Most kidney stones in humans are composed of calcium and oxalate. Therefore, supplementation with an oxalate-degrading bacterium may reduce stone burden in patients suffering from recurrent calcium oxalate-based urolithiasis. Strains of O. formigenes are divided into two groups: group I and group II. However, the differences between strains from each group remain unclear and elucidating these distinctions will provide a better understanding of their physiology and potential clinical applications. Here, genomes from multiple O. formigenes strains underwent whole genome sequencing followed by phylogenetic and functional analyses. Genetic differences suggest that the O. formigenes taxon should be divided into an additional three species: Oxalobacter aliiformigenes sp. nov, Oxalobacter paeniformigenes sp. nov, and Oxalobacter paraformigenes sp. nov. Despite the similarities in the oxalyl-CoA gene (oxc), which is essential for oxalate degradation, these strains have multiple unique genetic features that may be potential exploited for clinical use. Further investigation into the growth of these strains in a simulated fecal environment revealed that O. aliiformigenes strains are capable of thriving within the human gut microbiota. O. aliiformigenes may be a better therapeutic candidate than current group I strains (retaining the name O. formigenes), which have been previously tested and shown to be ineffective as an oral supplement to mitigate stone disease. By performing genomic analyses and identifying these novel characteristics, Oxalobacter strains better suited to mitigation of calcium oxalate-based urolithiasis may be identified in the future.