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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

The Phosphate Binder Ferric Citrate Alters the Gut Microbiome in Rats with Chronic Kidney Disease

Wei Ling Lau, Nosratola D. Vaziri, Ane C. F. Nunes, André M. Comeau, Morgan G. I. Langille, Whitney England, Mahyar Khazaeli, Yasunori Suematsu, Joann Phan and Katrine Whiteson
Journal of Pharmacology and Experimental Therapeutics December 2018, 367 (3) 452-460; DOI: https://doi.org/10.1124/jpet.118.251389
Wei Ling Lau
Division of Nephrology and Hypertension, Departments of Medicine (W.L.L., N.D.V., A.C.F.N., M.K.) and Molecular Biology and Biochemistry (W.E., J.P., K.W.), University of California, Irvine, California; Centre for Comparative Genomics and Evolutionary Bioinformatics Integrated Microbiome Resource, Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada (A.M.C., M.G.I.L.); and Department of Cardiology, Fukuoka University, Fukuoka, Japan (Y.S.)
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Nosratola D. Vaziri
Division of Nephrology and Hypertension, Departments of Medicine (W.L.L., N.D.V., A.C.F.N., M.K.) and Molecular Biology and Biochemistry (W.E., J.P., K.W.), University of California, Irvine, California; Centre for Comparative Genomics and Evolutionary Bioinformatics Integrated Microbiome Resource, Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada (A.M.C., M.G.I.L.); and Department of Cardiology, Fukuoka University, Fukuoka, Japan (Y.S.)
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Ane C. F. Nunes
Division of Nephrology and Hypertension, Departments of Medicine (W.L.L., N.D.V., A.C.F.N., M.K.) and Molecular Biology and Biochemistry (W.E., J.P., K.W.), University of California, Irvine, California; Centre for Comparative Genomics and Evolutionary Bioinformatics Integrated Microbiome Resource, Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada (A.M.C., M.G.I.L.); and Department of Cardiology, Fukuoka University, Fukuoka, Japan (Y.S.)
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André M. Comeau
Division of Nephrology and Hypertension, Departments of Medicine (W.L.L., N.D.V., A.C.F.N., M.K.) and Molecular Biology and Biochemistry (W.E., J.P., K.W.), University of California, Irvine, California; Centre for Comparative Genomics and Evolutionary Bioinformatics Integrated Microbiome Resource, Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada (A.M.C., M.G.I.L.); and Department of Cardiology, Fukuoka University, Fukuoka, Japan (Y.S.)
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Morgan G. I. Langille
Division of Nephrology and Hypertension, Departments of Medicine (W.L.L., N.D.V., A.C.F.N., M.K.) and Molecular Biology and Biochemistry (W.E., J.P., K.W.), University of California, Irvine, California; Centre for Comparative Genomics and Evolutionary Bioinformatics Integrated Microbiome Resource, Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada (A.M.C., M.G.I.L.); and Department of Cardiology, Fukuoka University, Fukuoka, Japan (Y.S.)
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Whitney England
Division of Nephrology and Hypertension, Departments of Medicine (W.L.L., N.D.V., A.C.F.N., M.K.) and Molecular Biology and Biochemistry (W.E., J.P., K.W.), University of California, Irvine, California; Centre for Comparative Genomics and Evolutionary Bioinformatics Integrated Microbiome Resource, Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada (A.M.C., M.G.I.L.); and Department of Cardiology, Fukuoka University, Fukuoka, Japan (Y.S.)
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Mahyar Khazaeli
Division of Nephrology and Hypertension, Departments of Medicine (W.L.L., N.D.V., A.C.F.N., M.K.) and Molecular Biology and Biochemistry (W.E., J.P., K.W.), University of California, Irvine, California; Centre for Comparative Genomics and Evolutionary Bioinformatics Integrated Microbiome Resource, Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada (A.M.C., M.G.I.L.); and Department of Cardiology, Fukuoka University, Fukuoka, Japan (Y.S.)
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Yasunori Suematsu
Division of Nephrology and Hypertension, Departments of Medicine (W.L.L., N.D.V., A.C.F.N., M.K.) and Molecular Biology and Biochemistry (W.E., J.P., K.W.), University of California, Irvine, California; Centre for Comparative Genomics and Evolutionary Bioinformatics Integrated Microbiome Resource, Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada (A.M.C., M.G.I.L.); and Department of Cardiology, Fukuoka University, Fukuoka, Japan (Y.S.)
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Joann Phan
Division of Nephrology and Hypertension, Departments of Medicine (W.L.L., N.D.V., A.C.F.N., M.K.) and Molecular Biology and Biochemistry (W.E., J.P., K.W.), University of California, Irvine, California; Centre for Comparative Genomics and Evolutionary Bioinformatics Integrated Microbiome Resource, Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada (A.M.C., M.G.I.L.); and Department of Cardiology, Fukuoka University, Fukuoka, Japan (Y.S.)
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Katrine Whiteson
Division of Nephrology and Hypertension, Departments of Medicine (W.L.L., N.D.V., A.C.F.N., M.K.) and Molecular Biology and Biochemistry (W.E., J.P., K.W.), University of California, Irvine, California; Centre for Comparative Genomics and Evolutionary Bioinformatics Integrated Microbiome Resource, Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada (A.M.C., M.G.I.L.); and Department of Cardiology, Fukuoka University, Fukuoka, Japan (Y.S.)
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Abstract

In chronic kidney disease (CKD), the gut microbiome is altered and bacterial-derived uremic toxins promote systemic inflammation and cardiovascular disease. Ferric citrate complex is a dietary phosphate binder prescribed for patients with end-stage kidney disease to treat hyperphosphatemia and secondary hyperparathyroidism. Iron is an essential nutrient in both microbes and mammals. This study was undertaken to test the hypothesis that the large iron load administered with ferric citrate in CKD may significantly change the gut microbiome. Male Sprague-Dawley rats underwent 5/6 nephrectomy to induce CKD. Normal control and CKD rats were randomized to regular chow or a 4% ferric citrate diet for 6 weeks. Fecal and cecal microbial DNA was analyzed via 16S ribosomal RNA gene sequencing on the Illumina MiSeq system. CKD rats had lower abundances of Firmicutes and Lactobacillus compared with normal rats and had lower overall gut microbial diversity. CKD rats treated with ferric citrate had improved hemoglobin and creatinine clearance and amelioration of hyperphosphatemia and hypertension. Ferric citrate treatment increased bacterial diversity in CKD rats almost to levels observed in control rats. The tryptophanase-possessing families Verrucomicrobia, Clostridiaceae, and Enterobacteriaceae were increased by ferric citrate treatment. The uremic toxins indoxyl sulfate and p-cresyl sulfate were not increased with ferric citrate treatment. Verrucomicrobia was largely represented by Akkermansia muciniphila, which has important roles in mucin degradation and gut barrier integrity. In summary, ferric citrate therapy in CKD rats was associated with significant changes in the gut microbiome and beneficial kidney and blood pressure parameters.

Footnotes

    • Received June 12, 2018.
    • Accepted September 28, 2018.
  • This work was supported by an unrestricted research grant from Keryx Biopharmaceuticals Inc. W.L.L. has received funding from the American Heart Association, Hub Therapeutics, Sanofi, and the Division of Nephrology at University of California, Irvine. N.D.V. has received funding from Reata, Keryx Biopharmaceuticals, and Novartis. A.C.F.N. received support from a Brazil Science Without Borders grant. Y.S. received support from a Sumitomo Life Welfare and Culture Foundation and Overseas Research Scholarship and a Fukuoka University School of Medicine Alumni Overseas Research Scholarship.

  • https://doi.org/10.1124/jpet.118.251389.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 367 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 367, Issue 3
1 Dec 2018
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Ferric Citrate and the Gut Microbiome in CKD Rats

Wei Ling Lau, Nosratola D. Vaziri, Ane C. F. Nunes, André M. Comeau, Morgan G. I. Langille, Whitney England, Mahyar Khazaeli, Yasunori Suematsu, Joann Phan and Katrine Whiteson
Journal of Pharmacology and Experimental Therapeutics December 1, 2018, 367 (3) 452-460; DOI: https://doi.org/10.1124/jpet.118.251389

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Ferric Citrate and the Gut Microbiome in CKD Rats

Wei Ling Lau, Nosratola D. Vaziri, Ane C. F. Nunes, André M. Comeau, Morgan G. I. Langille, Whitney England, Mahyar Khazaeli, Yasunori Suematsu, Joann Phan and Katrine Whiteson
Journal of Pharmacology and Experimental Therapeutics December 1, 2018, 367 (3) 452-460; DOI: https://doi.org/10.1124/jpet.118.251389
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