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

Nat Commun. 2019 Apr 23;10(1):1835. doi: 10.1038/s41467-019-09735-4.

Koichi Kikuchi ¹ ², Daisuke Saigusa ³, Yoshitomi Kanemitsu ⁴, Yotaro Matsumoto ⁴, Paxton Thanai ⁵, Naoto Suzuki ⁴, Koki Mise ⁶, Hiroaki Yamaguchi ⁷, Tomohiro Nakamura ⁸, Kei Asaji ⁴, Chikahisa Mukawa ⁴, Hiroki Tsukamoto ⁴, Toshihiro Sato ⁷, Yoshitsugu Oikawa ⁹, Tomoyuki Iwasaki ¹, Yuji Oe ¹⁰, Tomoya Tsukimi ¹¹, Noriko N Fukuda ¹¹, Hsin-Jung Ho ¹ ¹², Fumika Nanto-Hara ¹ ¹², Jiro Ogura ⁷, Ritsumi Saito ³, Shizuko Nagao ¹³, Yusuke Ohsaki ¹, Satoshi Shimada ¹, Takehiro Suzuki ¹ ¹², Takafumi Toyohara ¹, Eikan Mishima ¹, Hisato Shima ¹, Yasutoshi Akiyama ¹, Yukako Akiyama ¹, Mariko Ichijo ¹, Tetsuro Matsuhashi ⁹ ¹², Akihiro Matsuo ¹, Yoshiaki Ogata ², Ching-Chin Yang ¹ ¹², Chitose Suzuki ¹, Matthew C Breeggemann ¹⁴, Jurgen Heymann ¹⁴, Miho Shimizu ¹⁵, Susumu Ogawa ¹, Nobuyuki Takahashi ¹⁰, Takashi Suzuki ¹⁶, Yuji Owada ¹⁷, Shigeo Kure ⁹, Nariyasu Mano ⁷, Tomoyoshi Soga ¹¹, Takashi Wada ¹⁵, Jeffrey B Kopp ¹⁴, Shinji Fukuda ¹¹ ¹⁸ ¹⁹ ²⁰, Atsushi Hozawa ⁸, Masayuki Yamamoto ³, Sadayoshi Ito ¹, Jun Wada ⁶, Yoshihisa Tomioka ⁴, Takaaki Abe ²¹ ²² ²³

Affiliations

1 Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.
2 Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.
3 Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan.
4 Laboratory of Oncology, Pharmacy Practice and Sciences, Graduate School of Pharmaceutical Sciences, Sendai, 980-8578, Japan.
5 Waters Corporation, Tokyo, 140-0001, Japan.
6 Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.
7 Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, 980-8574, Japan.
8 Department of Preventive Medicine and Epidemiology, Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan.
9 Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.
10 Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, 980-8578, Japan.
11 Institute for Advanced Biosciences, Keio University, Tsuruoka, 997-0052, Japan.
12 Department of Medical Science, Tohoku University Graduate School of Biomedical Engineering, Sendai, 980-8574, Japan.
13 Education and Research Center of Animal Models for Human Diseases, Fujita Health University, Toyoake, Aichi, 470-1192, Japan.
14 Kidney Diseases Branch, NIDDK, NIH, Bethesda, MD, 20892-1268, USA.
15 Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, 920-8641, Japan.
16 Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.
17 Department of Organ Anatomy, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.
18 Intestinal Microbiota Project, Kanagawa Institute of Industrial Science and Technology, Kawasaki, 210-0821, Japan.
19 Transborder Medical Research Center, University of Tsukuba, Tsukuba, 305-8577, Japan.
20 PRESTO, Japan Science and Technology Agency, Kawaguchi, 332-0012, Japan.
21 Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan. [email protected].
22 Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan. [email protected].
23 Department of Medical Science, Tohoku University Graduate School of Biomedical Engineering, Sendai, 980-8574, Japan. [email protected].

PMID: 31015435 DOI: 10.1038/s41467-019-09735-4

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-128442

Phenyl sulfate

99.56%, Gut Microbiota-derived Metabolite

Endogenous Metabolite

Metabolic Disease

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