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 journalArticlepeer-review

    77 Citations (Scopus)


    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
    Issue number3
    Publication statusPublished - 2019 Mar 1

    Bibliographical note

    Funding Information:
    This study was supported by the Basic Science Research Program through the National Research Foundation (NRF) of Korea funded by the Ministry of Education (2017R1A 2B1002734).

    Publisher Copyright:
    © 2018 The Author(s).


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

    ASJC Scopus subject areas

    • Nephrology
    • Transplantation


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