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Gut microbiome-derived phenyl sulfate contributes to albuminuria in diabetic kidney disease.

Koichi KikuchiDaisuke SaigusaYoshitomi KanemitsuYotaro MatsumotoPaxton ThanaiNaoto SuzukiKoki MiseHiroaki YamaguchiTomohiro NakamuraKei AsajiChikahisa MukawaHiroki TsukamotoToshihiro SatoYoshitsugu OikawaTomoyuki IwasakiYuji OeTomoya TsukimiNoriko N FukudaHsin-Jung HoFumika Nanto-HaraJiro OguraRitsumi SaitoShizuko NagaoYusuke OhsakiSatoshi ShimadaTakehiro SuzukiTakafumi ToyoharaEikan MishimaHisato ShimaYasutoshi AkiyamaYukako AkiyamaMariko IchijoTetsuro MatsuhashiAkihiro MatsuoYoshiaki OgataChing-Chin YangChitose SuzukiMatthew C BreeggemannJurgen HeymannMiho ShimizuSusumu OgawaNobuyuki TakahashiTakashi SuzukiYuji OwadaShigeo KureNariyasu ManoTomoyoshi SogaTakashi WadaJeffrey B KoppShinji FukudaAtsushi HozawaMasayuki YamamotoSadayoshi ItoJun WadaYoshihisa TomiokaTakaaki K Abe
Published in: Nature communications (2019)
Diabetic kidney disease is a major cause of renal failure that urgently necessitates a breakthrough in disease management. Here we show using untargeted metabolomics that levels of phenyl sulfate, a gut microbiota-derived metabolite, increase with the progression of diabetes in rats overexpressing human uremic toxin transporter SLCO4C1 in the kidney, and are decreased in rats with limited proteinuria. In experimental models of diabetes, phenyl sulfate administration induces albuminuria and podocyte damage. In a diabetic patient cohort, phenyl sulfate levels significantly correlate with basal and predicted 2-year progression of albuminuria in patients with microalbuminuria. Inhibition of tyrosine phenol-lyase, a bacterial enzyme responsible for the synthesis of phenol from dietary tyrosine before it is metabolized into phenyl sulfate in the liver, reduces albuminuria in diabetic mice. Together, our results suggest that phenyl sulfate contributes to albuminuria and could be used as a disease marker and future therapeutic target in diabetic kidney disease.
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