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Intestinal microbiota control acute kidney injury severity by immune modulation

  • Jihyun Yang
    Affiliations
    Division of Nephrology, Department of Internal Medicine, Korea University Medical College, Seoul, Korea
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  • Chan Johng Kim
    Affiliations
    Division of Integrative Biosciences and Biotechnology & Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
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  • Yoon Sook Go
    Affiliations
    Division of Nephrology, Department of Internal Medicine, Korea University Medical College, Seoul, Korea
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  • Hee Young Lee
    Affiliations
    Division of Nephrology, Department of Internal Medicine, Korea University Medical College, Seoul, Korea
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  • Myung-Gyu Kim
    Affiliations
    Division of Nephrology, Department of Internal Medicine, Korea University Medical College, Seoul, Korea
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  • Se Won Oh
    Affiliations
    Division of Nephrology, Department of Internal Medicine, Korea University Medical College, Seoul, Korea
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  • Won Yong Cho
    Affiliations
    Division of Nephrology, Department of Internal Medicine, Korea University Medical College, Seoul, Korea
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  • Sin-Hyeog Im
    Correspondence
    Sin-Hyeog Im, Division of Integrative Biosciences and Biotechnology & Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Chungam-Ro 77, Nam-Gu, Pohang, Kyungsangbuk-Do, Republic of Korea 37673.
    Affiliations
    Division of Integrative Biosciences and Biotechnology & Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
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  • Sang Kyung Jo
    Correspondence
    Correspondence: Sang Kyung Jo, Department of Internal Medicine, Division of Nephrology, Korea University Medical College, Korea University Anam Hospital, Koreadae-Ro 73, Sungbuk-Gu, Seoul, Republic of Korea 02841.
    Affiliations
    Division of Nephrology, Department of Internal Medicine, Korea University Medical College, Seoul, Korea
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      Intestinal microbiota impacts the host immune system and influences the outcomes of chronic diseases. However, it remains uncertain whether acute kidney injury (AKI) impacts intestinal microbiota or vice versa. To determine this, we investigated the mechanistic link between AKI, microbiota, and immune response in ischemia/reperfusion injury. Microbiota alteration and its biological consequences after ischemia/reperfusion injury were examined and the effect of dysbiotic microbiota on the outcome of AKI was also assessed by colonizing germ-free mice with post-AKI microbiota. The role of Th17, Th1, Tregs cells and macrophage polarization in mediating the renoprotective effect of antibiotic induced microbiota depletion in ischemia/reperfusion injury was also determined. Increase of Enterobacteriacea, decrease of Lactobacilli, and Ruminococacceae were found to be the hallmarks of ischemia/reperfusion injury induced dysbiosis and were associated with a decreased levels of short-chain fatty acids, intestinal inflammation and leaky gut. Colonizing germ-free mice with post-AKI microbiota worsened ischemia/reperfusion injury severity with exaggerated inflammation in recipient mice compared to colonizing with microbiota from sham operated mice. Microbiota depletion by oral antibiotics protected against ischemia/reperfusion injury. This renoprotective effect was associated with reduced Th 17, Th 1 response along with expansion of regulatory T cells, and M2 macrophages. Our study demonstrated a unique bidirectional relationship between the kidney and the intestine during AKI. Intestinal dysbiosis, inflammation and leaky gut are consequences of AKI but they also represent an important modifier determining post-AKI severity. Thus, targeting the intestinal microbiota might provide a novel therapeutic strategy in AKI.

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