title: Evaluation of the impact of gut microbiota on uremic solute accumulation by a CE-TOFMS-based metabolomics approach.
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.
authors.affiliation: Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; Tohoku Medical Megabank Organization, Sendai, Japan.
authors.forename: Eikan
authors.initials: E
authors.lastname: Mishima
authors.affiliation: Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan; Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Fukuda
authors.affiliation: Laboratory of Oncology, Pharmacy Practice and Sciences, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan.
authors.forename: Chikahisa
authors.initials: C
authors.lastname: Mukawa
authors.affiliation: Laboratory of Oncology, Pharmacy Practice and Sciences, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Yuri
authors.affiliation: Laboratory of Oncology, Pharmacy Practice and Sciences, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan.
authors.forename: Yoshitomi
authors.initials: Y
authors.lastname: Kanemitsu
authors.affiliation: Laboratory of Oncology, Pharmacy Practice and Sciences, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan.
authors.forename: Yotaro
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Yasutoshi
authors.initials: Y
authors.lastname: Akiyama
authors.affiliation: Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan.
authors.forename: Noriko N
authors.initials: NN
authors.lastname: Fukuda
authors.affiliation: Laboratory of Oncology, Pharmacy Practice and Sciences, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tsukamoto
authors.affiliation: Laboratory of Oncology, Pharmacy Practice and Sciences, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Asaji
authors.affiliation: Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Hisato
authors.initials: H
authors.lastname: Shima
authors.affiliation: Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kikuchi
authors.affiliation: Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Chitose
authors.initials: C
authors.lastname: Suzuki
authors.affiliation: Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Laboratory of Oncology, Pharmacy Practice and Sciences, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Tomioka
authors.affiliation: Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan.
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Soga
authors.affiliation: Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Sadayoshi
authors.initials: S
authors.lastname: Ito
authors.affiliation: Department of Medical Science, Tohoku University Graduate School of Biomedical Engineering, Sendai, Japan; Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine, Sendai, Japan. Electronic address: takaabe@med.tohoku.ac.jp.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Abe
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood / Q000139:chemically induced / Q000378:metabolism* / Q000652:urine; D000225:Adenine / Q000633:toxicity; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D019075:Electrophoresis, Capillary; D005232:Fatty Acids, Volatile / Q000032:analysis / Q000378:metabolism; D000069196:Gastrointestinal Microbiome / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000473:pathology; D013058:Mass Spectrometry; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D051379:Mice; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000378:metabolism* / Q000473:pathology / Q000652:urine; D013047:Specific Pathogen-Free Organisms; D014118:Toxins, Biological / Q000097:blood* / Q000652:urine; D014511:Uremia / Q000097:blood / Q000378:metabolism* / Q000652:urine
chemical_list: D005232:Fatty Acids, Volatile; D014118:Toxins, Biological; D000225:Adenine
keywords: amino acids; chronic kidney disease; gut microbiota; metabolome; short-chain fatty acids; uremic toxins