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.
↵This article has supplemental material available at jpet.aspetjournals.org.
- Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics