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Andersen, Kirstin; Kesper, Marie Sophie; Marschner, Julian A.; Konrad, Lukas; Ryu, Mi; Kumar, Santhosh V. R.; Kulkarni, Onkar P.; Mulay, Shrikant R.; Romoli, Simone; Demleitner, Jana; Schiller, Patrick; Dietrich, Alexander; Müller, Susanna; Gross, Oliver; Ruscheweyh, Hans-Joachim; Huson, Daniel H.; Stecher, Bärbel; Anders, Hans-Joachim (2017): Intestinal Dysbiosis, Barrier Dysfunction, and Bacterial Translocation Account for CKD-Related Systemic Inflammation. In: Journal of the American Society of Nephrology, Vol. 28, No. 1: pp. 76-83
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CKD associates with systemic inflammation, but the underlying cause is unknown. Here, we investigated the involvement of intestinal microbiota. We report that collagen type 4 alpha 3-deficient mice with Alport syndrome related progressive CKD displayed systemic inflammation, including increased plasma levels of pentraxin-2 and activated antigen presenting cells, CD4 and CD8 T cells, and Th17 or IFN gamma-producing T cells in the spleen as well as regulatory T cell suppression. CKD related systemic inflammation in these mice associated with intestinal dysbiosis of proteobacterial blooms, translocation of living bacteria across the intestinal barrier into the liver, and increased serum levels of bacterial endotoxin. Uremia did not affect secretory IgA release into the ileum lumen or mucosal leukocyte subsets. To test for causation between dysbiosis and systemic inflammation in CKD, we eradicated facultative anaerobic microbiota with antibiotics. This eradication prevented bacterial translocation, significantly reduced serum endotoxin levels, and fully reversed all markers of systemic inflammation to the level of nonuremic controls. Therefore, we conclude that uremia associates with intestinal dysbiosis, intestinal barrier dysfunction, and bacterial trans location, which trigger the state of persistent systemic inflammation in CKD. Uremic dysbiosis and intestinal barrier dysfunction may be novel therapeutic targets for intervention to suppress CKD related systemic inflammation and its consequences.