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

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.

Differences in the Microbial Composition of Hemodialysis Patients Treated With and Without β-Blockers

“…In the present study, hemodialysis patients treated with β-blockers had increased α-diversity and a distinct β-diversity compared to non-users. The microbial communities contained higher levels of Bacteroidetes and lower levels of Firmicutes in all hemodialysis patients, which is similar to CKD rat microbial communities [35] and in a human CKD microbiota study. [36] Co-occurrence analysis revealed no difference in keystone taxa Bacteroides between β-blocker users and non-users.…”

Constipation in chronic kidney disease: it is time to reconsider

“…Ironcontaining phosphate binders, such as sucroferric oxyhydroxide and ferric citrate, may induce diarrhea instead of constipation [57,58]. It is important to note that iron supplementation may have a favorable or unfavorable influence on the gut microbiota [59][60][61].…”

Differences in Gut Microbiota Profiles and Functions Between End-stage Renal Disease and Healthy Populations 

“…In addition to the impact of protein intake and uremic toxins on α-diversity in ESRD patients, reduced consumption of fruits, vegetables, and dietary ber to avoid potassium overload causes gut dysbiosis [56]. Other contributing factors include the rise in gastrointestinal luminal pH rise due to uremic milieu (ammonia and ammonium hydroxide) [7,13,57,58] and complex drug exposure (e.g., antibiotics, phosphate binders, and iron) [59][60][61]. As expected, we found higher MDI in ESRD patients than in controls, which may help to differentiate ESRD patients from subjects without kidney disease.…”