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
N1 - Funding Information:
We thank the following people. Akinori Yuri and Tatsuki Tachikawa (Laboratory of Oncology, Pharmacy Practice and Sciences, Graduate School of Pharmaceutical Sciences) and Kiyoki Kitagawa and Tomoaki Funamoto (Department of Nephrology and Laboratory Medicine, Kanazawa University) for discussion. Masafumi Sugitani (Ono Pharmaceutical Co.) for technical support in the Tg rat experiments. Kazuhiro Tanabe (LSI Medience Co.) for the technical establishment of alternative measuring of PS and other uremic toxins. Fumiko Date and Miki Yoshizawa (Histological platform, Tohoku University School of Medicine) for histological assistance. Kazuyuki Hida (National Hospital Organization Okayama Medical Center, Okayama, Japan), Tatsuaki Nakato (Okayama Saiseikai General Hospital, Okayama, Japan), Takashi Matsuoka (Kurashiki Central Hospital), Ikki Shimizu (The Sakakibara Heart Institute of Okayama, Okayama, Japan), Tomokazu Nunoue (Tsuyama Chuo Hospital, Okayama, Japan), Katsuhiro Miyashita (Japanese Red Cross Okayama Hospital, Okayama, Japan), and Shinichiro Ando (Okayama City General Medical Center, Okayama, Japan) for the U-CARE study. We also appreciate Dr. Tania Bezak at Trinity College Dublin for English editing. This work was supported in part by the Japan Society for the Promotion of Science KAKENHI Grant Numbers 18H02822 (T.A.), 23790168 (H.Y.), 15H00485 (T.S.), 16H04901 (S.F.), 17H05654 (S.F.), and 18H04805 (S.F.), by the JST PRESTO JPMJPR1537 (S.F.) and from a grant of the Japan Kidney Foundation. This work was also supported in part by the Tohoku Medical Megabank Project through the Ministry of Education, Culture, Sports, Science and Technology, Japan; by the Reconstruction Agency, Japan; by the Japan Agency for Medical Research and Development (AMED; grant numbers JP18km0105001 and JP18km0105002) and also in part by the Intramural Research Program, NIDDK, NIH (J.B.K). T.S., F.N., and H.-J.H. were funded by a collaborative research grant of DSP.
Publisher Copyright:
© 2019, The Author(s).
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
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1835
ER -
