Intestinal barrier disruption and dysregulated mucosal immunity contribute to kidney fibrosis in chronic kidney disease

Jihyun Yang, Sung Yoon Lim, Yoon Sook Ko, Hee Young Lee, Se Won Oh, Myung-Gyu Kim, Won Yong Cho, Sang Kyung Jo

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Background. Emerging evidence suggests that intestinal dysbiosis is associated with diverse pathological processes. In this study we demonstrated intestinal barrier disruption and aberrant mucosal immunity in 5/6 nephrectomized mice and the effect of probiotics on chronic kidney disease (CKD). Methods. CKD was induced in 6-week-old mice by 5/6 nephrectomy. They were fed a lactobacilli mixture for 8 weeks. Serum, urine and stool samples were collected for renal function assessments and gut microbiome analyses. Gut permeability, colon heat shock protein 70 (HSP70) and colon epithelial integrity were evaluated and cytokine levels in colon and kidney were measured. Colon leukocytes were analyzed by flow cytometry and bone marrow-derived cells were cocultured with lactobacilli mixture. Results. In CKD mice, 'leaky gut' was accompanied by decreased colon HSP70 and claudin-1 expression, whereas it increased pore-forming claudin-2 expression and apoptosis. Although the percentage of regulatory T cells did not differ between CKD and control mice, cytokine expression and the ratio of CX3CR1intermediate:CX3CR1high pro-inflammatory/resident macrophages increased in the colon of CKD mice. Orally administered lactobacilli partially mitigated the CKD-induced 'leaky gut'; restored colon epithelial HSP70, claudin-1 and claudin-2 expression and decreased apoptosis. Probiotic treatment also restored the CX3CR1intermediate:CX3CR1high macrophage ratio and increased circular dichroism (CD)103+ CD11c+ regulatory dendritic cells in the colon. These changes suppressed systemic inflammation and kidney fibrosis. Conclusions Our results suggest that intestinal dysbiosis-associated gut barrier disruption and aberrant mucosal immunity are important for the systemic inflammation and progressive fibrosis of CKD. Targeting the intestine might provide novel therapeutic opportunities for CKD.

Original languageEnglish
Pages (from-to)419-428
Number of pages10
JournalNephrology Dialysis Transplantation
Volume34
Issue number3
DOIs
Publication statusPublished - 2019 Mar 1

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Mucosal Immunity
Chronic Renal Insufficiency
Colon
Fibrosis
Kidney
HSP70 Heat-Shock Proteins
Claudin-2
Lactobacillus
Claudin-1
Dysbiosis
Probiotics
Macrophages
Apoptosis
Cytokines
Inflammation
Regulatory T-Lymphocytes
Pathologic Processes
Circular Dichroism
Nephrectomy
Bone Marrow Cells

Keywords

  • chronic kidney disease
  • dysbiosis
  • inflammation
  • macrophages
  • probiotics

ASJC Scopus subject areas

  • Nephrology
  • Transplantation

Cite this

Intestinal barrier disruption and dysregulated mucosal immunity contribute to kidney fibrosis in chronic kidney disease. / Yang, Jihyun; Lim, Sung Yoon; Ko, Yoon Sook; Lee, Hee Young; Oh, Se Won; Kim, Myung-Gyu; Cho, Won Yong; Jo, Sang Kyung.

In: Nephrology Dialysis Transplantation, Vol. 34, No. 3, 01.03.2019, p. 419-428.

Research output: Contribution to journalArticle

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abstract = "Background. Emerging evidence suggests that intestinal dysbiosis is associated with diverse pathological processes. In this study we demonstrated intestinal barrier disruption and aberrant mucosal immunity in 5/6 nephrectomized mice and the effect of probiotics on chronic kidney disease (CKD). Methods. CKD was induced in 6-week-old mice by 5/6 nephrectomy. They were fed a lactobacilli mixture for 8 weeks. Serum, urine and stool samples were collected for renal function assessments and gut microbiome analyses. Gut permeability, colon heat shock protein 70 (HSP70) and colon epithelial integrity were evaluated and cytokine levels in colon and kidney were measured. Colon leukocytes were analyzed by flow cytometry and bone marrow-derived cells were cocultured with lactobacilli mixture. Results. In CKD mice, 'leaky gut' was accompanied by decreased colon HSP70 and claudin-1 expression, whereas it increased pore-forming claudin-2 expression and apoptosis. Although the percentage of regulatory T cells did not differ between CKD and control mice, cytokine expression and the ratio of CX3CR1intermediate:CX3CR1high pro-inflammatory/resident macrophages increased in the colon of CKD mice. Orally administered lactobacilli partially mitigated the CKD-induced 'leaky gut'; restored colon epithelial HSP70, claudin-1 and claudin-2 expression and decreased apoptosis. Probiotic treatment also restored the CX3CR1intermediate:CX3CR1high macrophage ratio and increased circular dichroism (CD)103+ CD11c+ regulatory dendritic cells in the colon. These changes suppressed systemic inflammation and kidney fibrosis. Conclusions Our results suggest that intestinal dysbiosis-associated gut barrier disruption and aberrant mucosal immunity are important for the systemic inflammation and progressive fibrosis of CKD. Targeting the intestine might provide novel therapeutic opportunities for CKD.",
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AU - Yang, Jihyun

AU - Lim, Sung Yoon

AU - Ko, Yoon Sook

AU - Lee, Hee Young

AU - Oh, Se Won

AU - Kim, Myung-Gyu

AU - Cho, Won Yong

AU - Jo, Sang Kyung

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AB - Background. Emerging evidence suggests that intestinal dysbiosis is associated with diverse pathological processes. In this study we demonstrated intestinal barrier disruption and aberrant mucosal immunity in 5/6 nephrectomized mice and the effect of probiotics on chronic kidney disease (CKD). Methods. CKD was induced in 6-week-old mice by 5/6 nephrectomy. They were fed a lactobacilli mixture for 8 weeks. Serum, urine and stool samples were collected for renal function assessments and gut microbiome analyses. Gut permeability, colon heat shock protein 70 (HSP70) and colon epithelial integrity were evaluated and cytokine levels in colon and kidney were measured. Colon leukocytes were analyzed by flow cytometry and bone marrow-derived cells were cocultured with lactobacilli mixture. Results. In CKD mice, 'leaky gut' was accompanied by decreased colon HSP70 and claudin-1 expression, whereas it increased pore-forming claudin-2 expression and apoptosis. Although the percentage of regulatory T cells did not differ between CKD and control mice, cytokine expression and the ratio of CX3CR1intermediate:CX3CR1high pro-inflammatory/resident macrophages increased in the colon of CKD mice. Orally administered lactobacilli partially mitigated the CKD-induced 'leaky gut'; restored colon epithelial HSP70, claudin-1 and claudin-2 expression and decreased apoptosis. Probiotic treatment also restored the CX3CR1intermediate:CX3CR1high macrophage ratio and increased circular dichroism (CD)103+ CD11c+ regulatory dendritic cells in the colon. These changes suppressed systemic inflammation and kidney fibrosis. Conclusions Our results suggest that intestinal dysbiosis-associated gut barrier disruption and aberrant mucosal immunity are important for the systemic inflammation and progressive fibrosis of CKD. Targeting the intestine might provide novel therapeutic opportunities for CKD.

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KW - inflammation

KW - macrophages

KW - probiotics

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