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

被引：236

作者：

Kikuchi, Koichi ^{[1
,2
]}

Saigusa, Daisuke ^{[3
]}

Kanemitsu, Yoshitomi ^{[4
]}

Matsumoto, Yotaro ^{[4
]}

Thanai, Paxton ^{[5
]}

Suzuki, Naoto ^{[4
]}

Mise, Koki ^{[6
]}

Yamaguchi, Hiroaki ^{[7
]}

Nakamura, Tomohiro ^{[8
]}

Asaji, Kei ^{[4
]}

Mukawa, Chikahisa ^{[4
]}

Tsukamoto, Hiroki ^{[4
]}

Sato, Toshihiro ^{[7
]}

Oikawa, Yoshitsugu ^{[9
]}

Iwasaki, Tomoyuki ^{[1
]}

Oe, Yuji ^{[10
]}

Tsukimi, Tomoya ^{[11
]}

Fukuda, Noriko N. ^{[11
]}

HO, Hsin-Jung ^{[1
,12
]}

Nanto-Hara, Fumika ^{[1
,12
]}

Ogura, Jiro ^{[7
]}

Saito, Ritsumi ^{[3
]}

Nagao, Shizuko ^{[13
]}

Ohsaki, Yusuke ^{[1
]}

Shimada, Satoshi ^{[1
]}

Suzuki, Takehiro ^{[1
,12
]}

Toyohara, Takafumi ^{[1
]}

Mishima, Eikan ^{[1
]}

Shima, Hisato ^{[1
]}

Akiyama, Yasutoshi ^{[1
]}

Akiyama, Yukako ^{[1
]}

Ichijo, Mariko ^{[1
]}

Matsuhashi, Tetsuro ^{[9
,12
]}

Matsuo, Akihiro ^{[1
]}

Ogata, Yoshiaki ^{[2
]}

Yang, Ching-Chin ^{[1
,12
]}

Suzuki, Chitose ^{[1
]}

Breeggemann, Matthew C. ^{[14
]}

Heymann, Jurgen ^{[14
]}

Shimizu, Miho ^{[15
]}

Ogawa, Susumu ^{[1
]}

Takahashi, Nobuyuki ^{[10
]}

Suzuki, Takashi ^{[16
]}

Owada, Yuji ^{[17
]}

Kure, Shigeo ^{[9
]}

Mano, Nariyasu ^{[7
]}

Soga, Tomoyoshi ^{[11
]}

Wada, Takashi ^{[15
]}

Kopp, Jeffrey B. ^{[14
]}

Fukuda, Shinji ^{[11
,18
,19
,20
]}

机构：

[1] Tohoku Univ, Div Nephrol Endocrinol & Vasc Med, Grad Sch Med, Sendai, Miyagi 9808574, Japan

[2] Tohoku Univ, Dept Clin Biol & Hormonal Regulat, Grad Sch Med, Sendai, Miyagi 9808574, Japan

[3] Tohoku Univ, Dept Integrat Genom, Tohoku Med Megabank Org, Sendai, Miyagi 9808573, Japan

[4] Grad Sch Pharmaceut Sci, Lab Oncol Pharm Practice & Sci, Sendai, Miyagi 9808578, Japan

[5] Waters Corp, Tokyo 1400001, Japan

[6] Okayama Univ, Dept Nephrol Rheumatol Endocrinol & Metab, Grad Sch Med Dent & Pharmaceut Sci, Okayama 7008558, Japan

[7] Tohoku Univ Hosp, Dept Pharmaceut Sci, Sendai, Miyagi 9808574, Japan

[8] Tohoku Univ, Dept Prevent Med & Epidemiol, Tohoku Med Megabank Org, Sendai, Miyagi 9808573, Japan

[9] Tohoku Univ, Dept Pediat, Grad Sch Med, Sendai, Miyagi 9808574, Japan

[10] Tohoku Univ, Div Clin Pharmacol & Therapeut, Grad Sch Pharmaceut Sci, Sendai, Miyagi 9808578, Japan

[11] Keio Univ, Inst Adv Biosci, Tsuruoka, Yamagata 9970052, Japan

[12] Tohoku Univ, Dept Med Sci, Grad Sch Biomed Engn, Sendai, Miyagi 9808574, Japan

[13] Fujita Hlth Univ, Educ & Res Ctr Anim Models Human Dis, Toyoake, Aichi 4701192, Japan

[14] NIDDK, Kidney Dis Branch, NIH, Bethesda, MD 20892 USA

[15] Kanazawa Univ, Dept Nephrol & Lab Med, Kanazawa, Ishikawa 9208641, Japan

[16] Tohoku Univ, Dept Pathol & Histotechnol, Grad Sch Med, Sendai, Miyagi 9808574, Japan

[17] Tohoku Univ, Dept Organ Anat, Grad Sch Med, Sendai, Miyagi 9808574, Japan

[18] Kanagawa Inst Ind Sci & Technol, Intestinal Microbiota Project, Kawasaki, Kanagawa 2100821, Japan

[19] Univ Tsukuba, Transborder Med Res Ctr, Tsukuba, Ibaraki 3058577, Japan

[20] Japan Sci & Technol Agcy, PRESTO, Kawaguchi, Saitama 3320012, Japan

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

基金：

日本学术振兴会;

关键词：

SOLUBLE UROKINASE RECEPTOR; UREMIC TOXINS; RENAL-FUNCTION; RISK-FACTORS; PROGRESSION; PODOCYTE; TYROSINE; INDOLE; LYASE; MICROALBUMINURIA;

D O I：

10.1038/s41467-019-09735-4

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：17

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