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

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.

SUBMITTER: Kikuchi K 

PROVIDER: S-EPMC6478834 | biostudies-other | 2019 Apr

REPOSITORIES: biostudies-other

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

Kikuchi Koichi K   Saigusa Daisuke D   Kanemitsu Yoshitomi Y   Matsumoto Yotaro Y   Thanai Paxton P   Suzuki Naoto N   Mise Koki K   Yamaguchi Hiroaki H   Nakamura Tomohiro T   Asaji Kei K   Mukawa Chikahisa C   Tsukamoto Hiroki H   Sato Toshihiro T   Oikawa Yoshitsugu Y   Iwasaki Tomoyuki T   Oe Yuji Y   Tsukimi Tomoya T   Fukuda Noriko N NN   Ho Hsin-Jung HJ   Nanto-Hara Fumika F   Ogura Jiro J   Saito Ritsumi R   Nagao Shizuko S   Ohsaki Yusuke Y   Shimada Satoshi S   Suzuki Takehiro T   Toyohara Takafumi T   Mishima Eikan E   Shima Hisato H   Akiyama Yasutoshi Y   Akiyama Yukako Y   Ichijo Mariko M   Matsuhashi Tetsuro T   Matsuo Akihiro A   Ogata Yoshiaki Y   Yang Ching-Chin CC   Suzuki Chitose C   Breeggemann Matthew C MC   Heymann Jurgen J   Shimizu Miho M   Ogawa Susumu S   Takahashi Nobuyuki N   Suzuki Takashi T   Owada Yuji Y   Kure Shigeo S   Mano Nariyasu N   Soga Tomoyoshi T   Wada Takashi T   Kopp Jeffrey B JB   Fukuda Shinji S   Hozawa Atsushi A   Yamamoto Masayuki M   Ito Sadayoshi S   Wada Jun J   Tomioka Yoshihisa Y   Abe Takaaki T  

Nature communications 20190423 1

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 podoc  ...[more]