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

Kôichi Kikuchi ,Shinji Fukuda,Atsushi Hozawa,Shigeo Kure,Fumika Nanto-Hara,Hsin Jung Ho ,Jun Wada,Nariyasu Mano,Hiroaki Yamaguchi,Toshihiro Sato,Matthew C Breeggemann,Chikahisa Mukawa,Yuji Oe,M Ichijo ,Takashi Wada,Yukako Akiyama,Sadayoshi Ito,Naoto Suzuki,Yuji Owada,Paxton Thanai,Jeffrey B Kopp,Hisato Shima,Hiroki Tsukamoto,Noriko Fukuda ,Masayuki Yamamoto,Ryosuke Saito ,Takehiro Suzuki,Ching Chin Yang ,Yoshiaki Ogata,Tomoyoshi Soga,Yoshitomi Kanemitsu,Chitose Suzuki,Takafumi Toyohara,Akihiro Matsuo,Kazuyuki Mise ,Yotaro Matsumoto,Kei Asaji,Daisuke Saigusa,Jürgen Heymann ,Susumu Ogawa,Takashi Suzuki,Yusuke Ohsaki,Yoshitsugu Oikawa,Tomoya Tsukimi,Y Tomioka ,Eikan Mishima,Jiro Ogura,Tomoyuki Iwasaki,Shizuko Nagao,Yasutoshi Akiyama,Tomohiro Nakamura,Satoshi Shimada,Miho Shimizu,Tomohiro Matsuhashi ,Nobuyuki Takahashi,Takaaki Abe

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.

Highlights

Diabetic kidney disease is a major cause of renal failure that urgently necessitates a breakthrough in disease management
To identify metabolites linked to diabetic conditions, streptozotocin (STZ)-induced diabetes was induced in SLCO4C1-Tg rats on day 0
Elastica Masson and F4/80 staining showed some perivascular fibrotic area in the phenyl sulfate (PS)-treated group (Fig. 2h, black arrow heads). These results further suggest that the manifested podocyte damage and perivascular inflammation were elicited by PS, which contributed to albuminuria in high-fat diet (HFD)-KKAy mice

Summary

Introduction

Diabetic kidney disease is a major cause of renal failure that urgently necessitates a breakthrough in disease management. 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. The diversity among the oatp family members makes it difficult to extrapolate from experimental studies on rodents to humans To overcome this issue, we generated transgenic rats overexpressing human SLCO4C1 in the proximal tubule[6]. We generated transgenic rats overexpressing human SLCO4C1 in the proximal tubule[6] These rats are an excellent model for evaluating the human kidney-specific elimination for metabolites and uremic toxins. We find that levels of phenyl sulfate (PS), a gut microbiota-derived metabolite, significantly correlate with basal and predicted 2-year progression of albuminuria in patients with microalbuminuria. Our results suggest that PS is an early diagnosis marker, and a modifiable cause and a target for the treatment of DKD

Methods

Results

Conclusion