Gut Lactobacillus protects against the progression of renal damage by modulating the gut environment in rats

Ayumi Yoshifuji, Shu Wakino, Junichiro Irie, Takaya Tajima, Kazuhiro Hasegawa, Takeshi Kanda, Hirobumi Tokuyama, Koichi Hayashi, Hiroshi Itoh

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Abstract

Background The role of gut microbiota in the progression of chronic kidney disease (CKD) has not been fully elucidated. Methods Renal failure was induced in 6-week-old spontaneously hypertensive rats by 5/6 nephrectomy (Nx). We analyzed the gut microbiota population to identify the relevant species potentially involved in inducing renal damage. Human colon Caco-2 cells were used to delineate the mechanism involved in the molecular changes in the gut of Nx rats. Results Nx rats showed an increase in Bacteroides (Bact) and a decrease in Lactobacillus (Lact) species compared with sham-operated rats. Lact, but not Bact, populations were significantly associated with urinary protein excretion. Treatment of Nx rats with 1 × 1010 CFU/kg/day Lact ameliorated increased urinary protein excretion and higher serum levels of the uremic toxins, indoxyl sulfate and p-cresyl sulfate, and serum urea nitrogen levels. Lact also attenuated systemic inflammation in Nx rats, as evaluated by serum lipopolysaccharide, interleukin-6 and C-reactive protein levels. Histologically, renal sclerosis in Nx rats was restored by Lact treatment. A reduction in the expression of tight junction proteins and the Toll-like receptor 2 (TLR2), a putative Lact receptor, in the colons of Nx rats were mitigated by Lact. Treatment of Caco-2 cells with indole downregulated tight junction protein expression, which was abolished by exposure to Lact. The effects of Lact were reversed by treatment with OxPAPC, a TLR inhibitor. Similarly, the increase in the permeability of the Caco-2 cell monolayer was reversed by the administration of Lact. Lact upregulated TLR2 expression in Caco-2 cells. Lact also attenuated the increase in serum indoxyl sulfate and urea levels and urinary protein excretion in Nx rats even in the pseudogerm-free environment. Conclusions Lact supplementation mitigated the systemic inflammation and proteinuria associated with renal failure, suggesting that in the gut microbiota, Lact plays a protective role against the progression of CKD.

Original languageEnglish
Pages (from-to)401-412
Number of pages12
JournalNephrology Dialysis Transplantation
Volume31
Issue number3
DOIs
Publication statusPublished - 2016 Mar 1

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Keywords

  • chronic kidney disease
  • gut microbiota
  • protein bound uremic retention solutes
  • tight junction
  • Toll-like receptor

ASJC Scopus subject areas

  • Nephrology
  • Transplantation

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