{"database":"biostudies-literature","file_versions":[],"scores":{"citationCount":0,"reanalysisCount":0,"viewCount":55,"searchCount":0},"additional":{"submitter":["Arvans D"],"funding":["NIDDK NIH HHS"],"pagination":["876-887"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC5328155"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["28(3)"],"pubmed_abstract":["Hyperoxaluria is a major risk factor for kidney stones and has no specific therapy, although <i>Oxalobacter formigenes</i> colonization is associated with reduced stone risk. <i>O. formigenes</i> interacts with colonic epithelium and induces colonic oxalate secretion, thereby reducing urinary oxalate excretion, <i>via</i> an unknown secretagogue. The difficulties in sustaining <i>O. formigenes</i> colonization underscore the need to identify the derived factors inducing colonic oxalate secretion. We therefore evaluated the effects of <i>O. formigenes</i> culture conditioned medium (CM) on apical <sup>14</sup>C-oxalate uptake by human intestinal Caco-2-BBE cells. Compared with control medium, <i>O. formigenes</i> CM significantly stimulated oxalate uptake (>2.4-fold), whereas CM from <i>Lactobacillus acidophilus</i> did not. Treating the <i>O. formigenes</i> CM with heat or pepsin completely abolished this bioactivity, and selective ultrafiltration of the CM revealed that the <i>O. formigenes</i>-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 of <i>O. formigenes</i> CM significantly reduced (>32.5%) urinary oxalate excretion and stimulated (>42%) distal colonic oxalate secretion. We conclude that <i>O. formigenes</i>-derived bioactive factors stimulate oxalate transport in intestinal cells through mechanisms including PKA activation. The reduction in urinary oxalate excretion in hyperoxaluric mice treated with <i>O. formigenes</i> CM reflects the <i>in vivo</i> retention of biologic activity and the therapeutic potential of these factors."],"journal":["Journal of the American Society of Nephrology : JASN"],"pubmed_title":["<i>Oxalobacter formigenes-</i>Derived Bioactive Factors Stimulate Oxalate Transport by Intestinal Epithelial Cells."],"pmcid":["PMC5328155"],"funding_grant_id":["P30 DK041296","P30 DK042086","K08 DK067245"],"pubmed_authors":["Antonopoulos D","Roy-Chowdhury J","Musch M","Asplin J","Jung YC","Granja I","Bashir M","Chang E","Arvans D","Karrar E","Koval J","Hassan H"],"view_count":["55"],"additional_accession":[]},"is_claimable":false,"name":"<i>Oxalobacter formigenes-</i>Derived Bioactive Factors Stimulate Oxalate Transport by Intestinal Epithelial Cells.","description":"Hyperoxaluria is a major risk factor for kidney stones and has no specific therapy, although <i>Oxalobacter formigenes</i> colonization is associated with reduced stone risk. <i>O. formigenes</i> interacts with colonic epithelium and induces colonic oxalate secretion, thereby reducing urinary oxalate excretion, <i>via</i> an unknown secretagogue. The difficulties in sustaining <i>O. formigenes</i> colonization underscore the need to identify the derived factors inducing colonic oxalate secretion. We therefore evaluated the effects of <i>O. formigenes</i> culture conditioned medium (CM) on apical <sup>14</sup>C-oxalate uptake by human intestinal Caco-2-BBE cells. Compared with control medium, <i>O. formigenes</i> CM significantly stimulated oxalate uptake (>2.4-fold), whereas CM from <i>Lactobacillus acidophilus</i> did not. Treating the <i>O. formigenes</i> CM with heat or pepsin completely abolished this bioactivity, and selective ultrafiltration of the CM revealed that the <i>O. formigenes</i>-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 of <i>O. formigenes</i> CM significantly reduced (>32.5%) urinary oxalate excretion and stimulated (>42%) distal colonic oxalate secretion. We conclude that <i>O. formigenes</i>-derived bioactive factors stimulate oxalate transport in intestinal cells through mechanisms including PKA activation. The reduction in urinary oxalate excretion in hyperoxaluric mice treated with <i>O. formigenes</i> CM reflects the <i>in vivo</i> retention of biologic activity and the therapeutic potential of these factors.","dates":{"release":"2017-01-01T00:00:00Z","publication":"2017 Mar","modification":"2024-02-14T23:38:06.597Z","creation":"2019-03-26T23:04:09Z"},"accession":"S-EPMC5328155","cross_references":{"pubmed":["27738124"],"doi":["10.1681/asn.2016020132","10.1681/ASN.2016020132"]}}