Sel1-like Proteins and Peptides are the Major Oxalobacter formigenes-derived Factors Stimulating Oxalate Transport by Human Intestinal Epithelial Cells

Kidney stones (KS) are very common, excruciating, and associated with tremendous healthcare cost, chronic kidney disease (CKD), and kidney failure (KF). Most KS are composed of calcium oxalate and small increases in urinary oxalate concentration significantly enhance the stone risk. Oxalate also potentially contributes to CKD progression, kidney disease-associated cardiovascular diseases, and poor renal allograft survival. This emphasizes the urgent need for plasma and urinary oxalate lowering therapies, which can be achieved by enhancing enteric oxalate secretion. We previously identified Oxalobacter formigenes (O. formigenes)-derived factors secreted in its culture conditioned medium (CM) which stimulate oxalate transport by human intestinal Caco2-BBE (C2) cells and reduce urinary oxalate excretion in hyperoxaluric mice by enhancing colonic oxalate secretion. Given their remarkable therapeutic potential, we now identified Sel1-like proteins as the major O. formigenes-derived secreted factors using Mass Spectrometry and functional assays. Crystal structures for six proteins were determined to confirm structures and better understand functions. OxBSel1-14-derived small Peptides P8 & P9 were identified as the major factors, with P8+9 closely recapitulating the CM's effects, acting through the oxalate transporters SLC26A2 & SLC26A6 and PKA activation. Besides C2 cells, P8+9 also stimulate oxalate transport by human ileal and colonic organoids, confirming that they work in human tissues. In conclusion, P8 & P9 Peptides are identified as the major O. formigenes-derived secreted factors and they have significant therapeutic potential for hyperoxalemia, hyperoxaluria, and related disorders, impacting the outcomes of patients suffering from KS, enteric hyperoxaluria, primary hyperoxaluria, CKD, KF, and renal transplant recipients.

Hyperoxalemia; Hyperoxaluria; Oxalobacter formigenes-derived Sel1 proteins and peptides; PKA; intestinal oxalate transport.