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

Koichi Kikuchi, Daisuke Saigusa, Yoshitomi Kanemitsu, Yotaro Matsumoto, Paxton Thanai, Naoto Suzuki, Koki Mise, Hiroaki Yamaguchi, Tomohiro Nakamura, Kei Asaji, Chikahisa Mukawa, Hiroki Tsukamoto, Toshihiro Sato, Yoshitsugu Oikawa, Tomoyuki Iwasaki, Yuji Oe, Tomoya Tsukimi, Noriko N. Fukuda, Hsin-Jung Ho, Fumika Nanto-Hara, Jiro Ogura, Ritsumi Saito, Shizuko Nagao, Yusuke Ohsaki, Satoshi Shimada, Takehiro Suzuki, Takafumi Toyohara, Eikan Mishima, Hisato Shima, Yasutoshi Akiyama, Yukako Akiyama, Mariko Ichijo, Tetsuro Matsuhashi, Akihiro Matsuo, Yoshiaki Ogata, Ching-Chin Yang, Chitose Suzuki, Matthew C. Breeggemann, Jurgen Heymann, Miho Shimizu, Susumu Ogawa, Nobuyuki Takahashi, Takashi Suzuki, Yuji Owada, Shigeo Kure, Nariyasu Mano, Tomoyoshi Soga, Takashi Wada, Jeffrey B. Kopp, Shinji Fukuda, Atsushi Hozawa, Masayuki Yamamoto, Sadayoshi Ito, Jun Wada, Yoshihisa Tomioka and Takaaki Abe ()
Additional contact information
Koichi Kikuchi: Tohoku University Graduate School of Medicine
Daisuke Saigusa: Tohoku University
Yoshitomi Kanemitsu: Graduate School of Pharmaceutical Sciences
Yotaro Matsumoto: Graduate School of Pharmaceutical Sciences
Paxton Thanai: Waters Corporation
Naoto Suzuki: Graduate School of Pharmaceutical Sciences
Koki Mise: Dentistry and Pharmaceutical Sciences
Hiroaki Yamaguchi: Tohoku University Hospital
Tomohiro Nakamura: Tohoku University
Kei Asaji: Graduate School of Pharmaceutical Sciences
Chikahisa Mukawa: Graduate School of Pharmaceutical Sciences
Hiroki Tsukamoto: Graduate School of Pharmaceutical Sciences
Toshihiro Sato: Tohoku University Hospital
Yoshitsugu Oikawa: Tohoku University Graduate School of Medicine
Tomoyuki Iwasaki: Tohoku University Graduate School of Medicine
Yuji Oe: Tohoku University Graduate School of Pharmaceutical Sciences
Tomoya Tsukimi: Keio University
Noriko N. Fukuda: Keio University
Hsin-Jung Ho: Tohoku University Graduate School of Medicine
Fumika Nanto-Hara: Tohoku University Graduate School of Medicine
Jiro Ogura: Tohoku University Hospital
Ritsumi Saito: Tohoku University
Shizuko Nagao: Fujita Health University
Yusuke Ohsaki: Tohoku University Graduate School of Medicine
Satoshi Shimada: Tohoku University Graduate School of Medicine
Takehiro Suzuki: Tohoku University Graduate School of Medicine
Takafumi Toyohara: Tohoku University Graduate School of Medicine
Eikan Mishima: Tohoku University Graduate School of Medicine
Hisato Shima: Tohoku University Graduate School of Medicine
Yasutoshi Akiyama: Tohoku University Graduate School of Medicine
Yukako Akiyama: Tohoku University Graduate School of Medicine
Mariko Ichijo: Tohoku University Graduate School of Medicine
Tetsuro Matsuhashi: Tohoku University Graduate School of Medicine
Akihiro Matsuo: Tohoku University Graduate School of Medicine
Yoshiaki Ogata: Tohoku University Graduate School of Medicine
Ching-Chin Yang: Tohoku University Graduate School of Medicine
Chitose Suzuki: Tohoku University Graduate School of Medicine
Matthew C. Breeggemann: Kidney Diseases Branch, NIDDK, NIH
Jurgen Heymann: Kidney Diseases Branch, NIDDK, NIH
Miho Shimizu: Kanazawa University
Susumu Ogawa: Tohoku University Graduate School of Medicine
Nobuyuki Takahashi: Tohoku University Graduate School of Pharmaceutical Sciences
Takashi Suzuki: Tohoku University Graduate School of Medicine
Yuji Owada: Tohoku University Graduate School of Medicine
Shigeo Kure: Tohoku University Graduate School of Medicine
Nariyasu Mano: Tohoku University Hospital
Tomoyoshi Soga: Keio University
Takashi Wada: Kanazawa University
Jeffrey B. Kopp: Kidney Diseases Branch, NIDDK, NIH
Shinji Fukuda: Keio University
Atsushi Hozawa: Tohoku University
Masayuki Yamamoto: Tohoku University
Sadayoshi Ito: Tohoku University Graduate School of Medicine
Jun Wada: Dentistry and Pharmaceutical Sciences
Yoshihisa Tomioka: Graduate School of Pharmaceutical Sciences
Takaaki Abe: Tohoku University Graduate School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-09735-4

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