title: Oxalobacter formigenes-Derived Bioactive Factors Stimulate Oxalate Transport by Intestinal Epithelial Cells.
abstract: Hyperoxaluria is a major risk factor for kidney stones and has no specific therapy, althoughOxalobacter formigenescolonization is associated with reduced stone risk.O. formigenesinteracts with colonic epithelium and induces colonic oxalate secretion, thereby reducing urinary oxalate excretion,viaan unknown secretagogue. The difficulties in sustainingO. formigenescolonization underscore the need to identify the derived factors inducing colonic oxalate secretion. We therefore evaluated the effects ofO. formigenesculture conditioned medium (CM) on apical14C-oxalate uptake by human intestinal Caco-2-BBE cells. Compared with control medium,O. formigenesCM significantly stimulated oxalate uptake (>2.4-fold), whereas CM fromLactobacillus acidophilusdid not. Treating theO. formigenesCM with heat or pepsin completely abolished this bioactivity, and selective ultrafiltration of the CM revealed that theO. formigenes-derived factors have molecular masses of 10-30 kDa. Treatment with the protein kinase A inhibitor H89 or the anion exchange inhibitor 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid completely blocked the CM-induced oxalate transport. Knockdown of the oxalate transporter SLC26A6 also significantly restricted the induction of oxalate transport by CM. In a mouse model of primary hyperoxaluria type 1, rectal administration ofO. formigenesCM significantly reduced (>32.5%) urinary oxalate excretion and stimulated (>42%) distal colonic oxalate secretion. We conclude thatO. formigenes-derived bioactive factors stimulate oxalate transport in intestinal cells through mechanisms including PKA activation. The reduction in urinary oxalate excretion in hyperoxaluric mice treated withO. formigenesCM reflects thein vivoretention of biologic activity and the therapeutic potential of these factors.
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Donna
authors.initials: D
authors.lastname: Arvans
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Yong-Chul
authors.initials: YC
authors.lastname: Jung
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois.|Biosciences Division, Argonne National Laboratory, Argonne, Illinois.
authors.forename: Dionysios
authors.initials: D
authors.lastname: Antonopoulos
authors.affiliation: Biosciences Division, Argonne National Laboratory, Argonne, Illinois.
authors.forename: Jason
authors.initials: J
authors.lastname: Koval
authors.affiliation: Litholink Corporation, Laboratory Corporation of America Holdings, Chicago, Illinois; and.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Granja
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Bashir
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Eltayeb
authors.initials: E
authors.lastname: Karrar
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, New York, New York.
authors.forename: Jayanta
authors.initials: J
authors.lastname: Roy-Chowdhury
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Mark
authors.initials: M
authors.lastname: Musch
authors.affiliation: Litholink Corporation, Laboratory Corporation of America Holdings, Chicago, Illinois; and.
authors.forename: John
authors.initials: J
authors.lastname: Asplin
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Eugene
authors.initials: E
authors.lastname: Chang
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois; hhassan@medicine.bsd.uchicago.edu.
authors.forename: Hatim
authors.initials: H
authors.lastname: Hassan
mesh_terms: D000818:Animals; D001685:Biological Factors / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D006959:Hyperoxaluria / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology* / Q000378:metabolism*; D017136:Ion Transport; D008297:Male; D051379:Mice; D010070:Oxalates / Q000378:metabolism*; D020624:Oxalobacter formigenes
chemical_list: D001685:Biological Factors; D010070:Oxalates
keywords: Oxalobacter formigenes; PKA; SLC26A6; intestinal oxalate transport; secreted bioactive factors