Gut Microbial Translocation in the Pathogenesis of Systemic Inflammation in Patients with End-Stage Renal Disease

Role of Nrf2 Dysfunction in Uremia-Associated Intestinal Inflammation and Epithelial Barrier Disruption

“…McIntyre et al reported increasing levels of circulating bacterial endotoxin/lipopolysaccharide with progressive stages of CKD, with levels being highest in dialysis patients [43]. Given the accumulating evidence that gut bacterial translocation is associated with systemic inflammation in ESRD patients [15,16], and that the latter is an independent predictor of increased mortality in hemodialysis patients [17][18][19], studies that advance the understanding of gut inflammation are needed as interventions in this area may beneficially impact clinical outcomes. The phase 3 clinical trial of bardoxolone methyl (potent systemic Nrf2 activator) in diabetic CKD patients was terminated early due to unforeseen cardiovascular events in the treatment arm [44], highlighting the need to explore tissue-specific targets for restoration of Nrf2 activity.…”

“…Disruption of the epithelial barrier structure and function in turn amplifies local and systemic inflammation by allowing translocation of bacterial toxins and other noxious products into the intestinal wall and systemic circulation. Indeed, inflammation in the CKD population is frequently associated with endotoxemia without signs of clinical infection [13,14], and recent papers highlight bacterial translocation and its association with systemic inflammation in end-stage renal disease (ESRD) patients maintained on hemodialysis [15,16]. Serum pro-inflammatory cytokine levels (IL-1, TNF-a, IL-6, IL-13) and circulating endotoxin are significantly associated with increased mortality in hemodialysis patients [17][18][19], and systemic inflammation is strongly associated with comorbidities including cardiovascular disease, anemia, and malnutrition [20][21][22].…”

Effect of high amylose resistant starch (HAM‐RS2) supplementation on biomarkers of inflammation and oxidative stress in hemodialysis patients: a randomized clinical trial

“…Oxidative stress and inflammation are inseparably linked as each triggers and amplifies the other. Emerging evidence points to the gastrointestinal tract as one of the major sources of systemic inflammation in patients and animals with CKD . In this context, several studies have demonstrated disruption of the gastro‐intestinal epithelial barrier structure and function in CKD animals and profound changes in the composition and function of the intestinal microbiota in humans with end stage renal disease (ESRD) and in animals with advanced CKD .…”

“…Emerging evidence points to the gastrointestinal tract as one of the major sources of systemic inflammation in patients and animals with CKD. 12,13 In this context, several studies have demonstrated disruption of the gastro-intestinal epithelial barrier structure and function in CKD animals [14][15][16] and profound changes in the composition and function of the intestinal microbiota in humans with end stage renal disease (ESRD) and in animals with advanced CKD. 17 The CKD-induced microbial dysbiosis and disruption of the gut epithelial barrier contribute to systemic inflammation by: a-raising generation of microbial toxic and proinflammatory products and b-accommodating the entry of the noxious microbial byproducts and other harmful luminal contents into the intestinal wall and systemic circulation through disrupted epithelial barrier.…”

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

“…However, the benefits of probiotics and synbiotics in the reduction of PCS and IS appear to be associated with the sustained use of the therapy, since an increase in those toxins was observed when the supplementation was discontinued [134,141,145]. In addition, potential harmful effects of probiotic supplementation, such as bacterial translocation in conditions of increased intestinal permeability and immunodeficiency [146], generally found in advanced stages of CKD have not been investigated so far.…”