Intestinal Dysbiosis, Barrier Dysfunction, and Bacterial Translocation Account for CKD–Related Systemic Inflammation

Abstract

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 α3-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 IFNγ-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 translocation, 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.

Inflammation: A Key Contributor to the Genesis and Progression of Chronic Kidney Disease

“…Once in circulation, in addition to inducing a general systemic inflammation [56] , these toxins are capable of mediating renal tubulointerstitial fibrosis via upregulation and activation of tumor necrosis factor-β1 and the renin-angiotensin-aldosterone system, contributing to epithelial-mesangial transformation and CKD progression [57][58][59] . This concept was nicely demonstrated recently by Andersen et al [60] . Using an Alport syndrome ( Col4α3 deficient)-CKD mouse model, the authors have demonstrated gut dysbiosis as a dominant source of systemic inflammation, including activation of innate and adaptive immune cells.…”

Linking gut microbiota to cardiovascular disease and hypertension: Lessons from chronic kidney disease

“…Noteworthy and opposite to findings in the Chinese patient cohort, they observed a higher amount of colony forming units per gram of feces. Again, they observed differentially structured communities, with changes in the class of Bacteroidales, Burholderiales (family of Alcaligenaceae), Enterobacteriales, and Verrucomicrobiales [9]. In aggregate, these studies show that ESRD promotes alterations in the composition of the gut microbiota.…”

“…Whether CKD, similar to dietary changes [29] may cause alterations of the inner colonic mucus layer, thereby compromising the gut barrier function, remains to be studied. Uremic serum and plasma increased intestinal permeability in vitro, suggesting the involvement of a humoral component [30,9]. Both direct toxicity by uremic retention molecules (especially ammoniumhydroxide) and butyrate depletion may be involved.…”

“…Vaziri et al observed intense infiltrates of lymphocytes into the lamina propria of animals with 5/6th nephrectomy induced CKD [28]. Tight junction disintegration in intestinal epithelial cells has been demonstrated by some [28], but not all investigators [9]. Whether CKD, similar to dietary changes [29] may cause alterations of the inner colonic mucus layer, thereby compromising the gut barrier function, remains to be studied.…”

The cross-talk between the kidney and the gut: implications for chronic kidney disease

“…The eradication of facultative anaerobic microbiota with antibiotics in uremic rats prevented bacterial translocation and reduced serum endotoxin levels and markers of systemic inflammation [121]. Thus, the gut seems to be a source of inflammation in CKD.…”