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

Research output: Contribution to journalArticle

31 Citations (Scopus)

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

Fingerprint

Lactobacillus
Kidney
Caco-2 Cells
Indican
Tight Junction Proteins
Toll-Like Receptor 2
Bacteroides
Serum
Chronic Renal Insufficiency
Renal Insufficiency
Urea
Colon
Inflammation
Proteins
Sclerosis
Inbred SHR Rats
Nephrectomy
Proteinuria
C-Reactive Protein
Population

Keywords

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

ASJC Scopus subject areas

  • Nephrology
  • Transplantation

Cite this

@article{bfdea167c87342ae86a9134374089221,
title = "Gut Lactobacillus protects against the progression of renal damage by modulating the gut environment in rats",
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.",
keywords = "chronic kidney disease, gut microbiota, protein bound uremic retention solutes, tight junction, Toll-like receptor",
author = "Ayumi Yoshifuji and Shu Wakino and Junichiro Irie and Takaya Tajima and Kazuhiro Hasegawa and Takeshi Kanda and Hirobumi Tokuyama and Koichi Hayashi and Hiroshi Itoh",
year = "2016",
month = "3",
day = "1",
doi = "10.1093/ndt/gfv353",
language = "English",
volume = "31",
pages = "401--412",
journal = "Nephrology Dialysis Transplantation",
issn = "0931-0509",
publisher = "Oxford University Press",
number = "3",

}

TY - JOUR

T1 - Gut Lactobacillus protects against the progression of renal damage by modulating the gut environment in rats

AU - Yoshifuji, Ayumi

AU - Wakino, Shu

AU - Irie, Junichiro

AU - Tajima, Takaya

AU - Hasegawa, Kazuhiro

AU - Kanda, Takeshi

AU - Tokuyama, Hirobumi

AU - Hayashi, Koichi

AU - Itoh, Hiroshi

PY - 2016/3/1

Y1 - 2016/3/1

N2 - 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.

AB - 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.

KW - chronic kidney disease

KW - gut microbiota

KW - protein bound uremic retention solutes

KW - tight junction

KW - Toll-like receptor

UR - http://www.scopus.com/inward/record.url?scp=84960112689&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84960112689&partnerID=8YFLogxK

U2 - 10.1093/ndt/gfv353

DO - 10.1093/ndt/gfv353

M3 - Article

C2 - 26487672

AN - SCOPUS:84960112689

VL - 31

SP - 401

EP - 412

JO - Nephrology Dialysis Transplantation

JF - Nephrology Dialysis Transplantation

SN - 0931-0509

IS - 3

ER -