TY - JOUR
T1 - Gut microbiome-derived phenyl sulfate contributes to albuminuria in diabetic kidney disease
AU - Kikuchi, Koichi
AU - Saigusa, Daisuke
AU - Kanemitsu, Yoshitomi
AU - Matsumoto, Yotaro
AU - Thanai, Paxton
AU - Suzuki, Naoto
AU - Mise, Koki
AU - Yamaguchi, Hiroaki
AU - Nakamura, Tomohiro
AU - Asaji, Kei
AU - Mukawa, Chikahisa
AU - Tsukamoto, Hiroki
AU - Sato, Toshihiro
AU - Oikawa, Yoshitsugu
AU - Iwasaki, Tomoyuki
AU - Oe, Yuji
AU - Tsukimi, Tomoya
AU - Fukuda, Noriko N.
AU - Ho, Hsin Jung
AU - Nanto-Hara, Fumika
AU - Ogura, Jiro
AU - Saito, Ritsumi
AU - Nagao, Shizuko
AU - Ohsaki, Yusuke
AU - Shimada, Satoshi
AU - Suzuki, Takehiro
AU - Toyohara, Takafumi
AU - Mishima, Eikan
AU - Shima, Hisato
AU - Akiyama, Yasutoshi
AU - Akiyama, Yukako
AU - Ichijo, Mariko
AU - Matsuhashi, Tetsuro
AU - Matsuo, Akihiro
AU - Ogata, Yoshiaki
AU - Yang, Ching Chin
AU - Suzuki, Chitose
AU - Breeggemann, Matthew C.
AU - Heymann, Jurgen
AU - Shimizu, Miho
AU - Ogawa, Susumu
AU - Takahashi, Nobuyuki
AU - Suzuki, Takashi
AU - Owada, Yuji
AU - Kure, Shigeo
AU - Mano, Nariyasu
AU - Soga, Tomoyoshi
AU - Wada, Takashi
AU - Kopp, Jeffrey B.
AU - Fukuda, Shinji
AU - Hozawa, Atsushi
AU - Yamamoto, Masayuki
AU - Ito, Sadayoshi
AU - Wada, Jun
AU - Tomioka, Yoshihisa
AU - Abe, Takaaki
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41467-019-09735-4
DO - 10.1038/s41467-019-09735-4
M3 - Article
C2 - 31015435
AN - SCOPUS:85064911992
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1835
ER -