Evaluation of the impact of gut microbiota on uremic solute accumulation by a CE-TOFMS-based metabolomics approach

Eikan Mishima, Shinji Fukuda, Chikahisa Mukawa, Akinori Yuri, Yoshitomi Kanemitsu, Yotaro Matsumoto, Yasutoshi Akiyama, Noriko N. Fukuda, Hiroki Tsukamoto, Kei Asaji, Hisato Shima, Koichi Kikuchi, Chitose Suzuki, Takehiro Suzuki, Yoshihisa Tomioka, Tomoyoshi Soga, Sadayoshi Ito, Takaaki Abe

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Gut microbiota is involved in the metabolism of uremic solutes. However, the precise influence of microbiota to the retention of uremic solutes in CKD is obscure. To clarify this, we compared adenine-induced renal failure and control mice under germ-free or specific pathogen-free (SPF) conditions, examining the metabolite profiles of plasma, feces, and urine using a capillary electrophoresis time-of-flight mass spectrometry-based approach. Mice with renal failure under germ-free conditions demonstrated significant changes in plasma metabolites. Among 183 detected solutes, plasma levels of 11 solutes, including major uremic toxins, were significantly lower in germ-free mice than in SPF mice with renal failure. These 11 solutes were considered microbiota-derived uremic solutes and included indoxyl sulfate, p-cresyl sulfate, phenyl sulfate, cholate, hippurate, dimethylglycine, γ-guanidinobutyrate, glutarate, 2-hydroxypentanoate, trimethylamine N-oxide, and phenaceturate. Metabolome profiling showed that these solutes were classified into three groups depending on their origins: completely derived from microbiota (indoxyl sulfate, p-cresyl sulfate), derived from both host and microbiota (dimethylglycine), and derived from both microbiota and dietary components (trimethylamine N-oxide). Additionally, germ-free renal failure conditions resulted in the disappearance of colonic short-chain fatty acids, decreased utilization of intestinal amino acids, and more severe renal damage compared with SPF mice with renal failure. Microbiota-derived short-chain fatty acids and efficient amino acid utilization may have a renoprotective effect, and loss of these factors may exacerbate renal damage in germ-free mice with renal failure. Thus, microbiota contributes substantially to the production of harmful uremic solutes, but conversely, growth without microbiota has harmful effects on CKD progression.

Original languageEnglish
JournalKidney International
DOIs
Publication statusAccepted/In press - 2016 Oct 5

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Metabolomics
Microbiota
Renal Insufficiency
Specific Pathogen-Free Organisms
Indican
Sulfates
Volatile Fatty Acids
Glutarates
Cholates
Kidney
Amino Acids
Metabolome
Gastrointestinal Microbiome
Capillary Electrophoresis
Adenine
Feces
Mass Spectrometry
Urine
Growth

Keywords

  • Amino acids
  • Chronic kidney disease
  • Gut microbiota
  • Metabolome
  • Short-chain fatty acids
  • Uremic toxins

ASJC Scopus subject areas

  • Medicine(all)
  • Nephrology

Cite this

Evaluation of the impact of gut microbiota on uremic solute accumulation by a CE-TOFMS-based metabolomics approach. / Mishima, Eikan; Fukuda, Shinji; Mukawa, Chikahisa; Yuri, Akinori; Kanemitsu, Yoshitomi; Matsumoto, Yotaro; Akiyama, Yasutoshi; Fukuda, Noriko N.; Tsukamoto, Hiroki; Asaji, Kei; Shima, Hisato; Kikuchi, Koichi; Suzuki, Chitose; Suzuki, Takehiro; Tomioka, Yoshihisa; Soga, Tomoyoshi; Ito, Sadayoshi; Abe, Takaaki.

In: Kidney International, 05.10.2016.

Research output: Contribution to journalArticle

Mishima, E, Fukuda, S, Mukawa, C, Yuri, A, Kanemitsu, Y, Matsumoto, Y, Akiyama, Y, Fukuda, NN, Tsukamoto, H, Asaji, K, Shima, H, Kikuchi, K, Suzuki, C, Suzuki, T, Tomioka, Y, Soga, T, Ito, S & Abe, T 2016, 'Evaluation of the impact of gut microbiota on uremic solute accumulation by a CE-TOFMS-based metabolomics approach', Kidney International. https://doi.org/10.1016/j.kint.2017.02.011
Mishima, Eikan ; Fukuda, Shinji ; Mukawa, Chikahisa ; Yuri, Akinori ; Kanemitsu, Yoshitomi ; Matsumoto, Yotaro ; Akiyama, Yasutoshi ; Fukuda, Noriko N. ; Tsukamoto, Hiroki ; Asaji, Kei ; Shima, Hisato ; Kikuchi, Koichi ; Suzuki, Chitose ; Suzuki, Takehiro ; Tomioka, Yoshihisa ; Soga, Tomoyoshi ; Ito, Sadayoshi ; Abe, Takaaki. / Evaluation of the impact of gut microbiota on uremic solute accumulation by a CE-TOFMS-based metabolomics approach. In: Kidney International. 2016.
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abstract = "Gut microbiota is involved in the metabolism of uremic solutes. However, the precise influence of microbiota to the retention of uremic solutes in CKD is obscure. To clarify this, we compared adenine-induced renal failure and control mice under germ-free or specific pathogen-free (SPF) conditions, examining the metabolite profiles of plasma, feces, and urine using a capillary electrophoresis time-of-flight mass spectrometry-based approach. Mice with renal failure under germ-free conditions demonstrated significant changes in plasma metabolites. Among 183 detected solutes, plasma levels of 11 solutes, including major uremic toxins, were significantly lower in germ-free mice than in SPF mice with renal failure. These 11 solutes were considered microbiota-derived uremic solutes and included indoxyl sulfate, p-cresyl sulfate, phenyl sulfate, cholate, hippurate, dimethylglycine, γ-guanidinobutyrate, glutarate, 2-hydroxypentanoate, trimethylamine N-oxide, and phenaceturate. Metabolome profiling showed that these solutes were classified into three groups depending on their origins: completely derived from microbiota (indoxyl sulfate, p-cresyl sulfate), derived from both host and microbiota (dimethylglycine), and derived from both microbiota and dietary components (trimethylamine N-oxide). Additionally, germ-free renal failure conditions resulted in the disappearance of colonic short-chain fatty acids, decreased utilization of intestinal amino acids, and more severe renal damage compared with SPF mice with renal failure. Microbiota-derived short-chain fatty acids and efficient amino acid utilization may have a renoprotective effect, and loss of these factors may exacerbate renal damage in germ-free mice with renal failure. Thus, microbiota contributes substantially to the production of harmful uremic solutes, but conversely, growth without microbiota has harmful effects on CKD progression.",
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