Abstract
Chronic kidney disease induces disruption of the intestinal epithelial barrier, leading to gut bacterial translocation. Here, we appreciated bacterial translocation by analyzing circulating lipopolysaccharides (LPS) using two methods, one measuring only active free LPS, and the other quantifying total LPS as well as LPS lipid A carbon chain length. This was done in end-stage renal disease (ESRD) patients and healthy volunteers (HV). We observed both higher LPS concentration in healthy volunteers and significant differences in composition of translocated LPS based on lipid A carbon chain length. Lower LPS activity to mass ratio and higher concentration of high-density lipoproteins were found in HV, suggesting a better plasma capacity to neutralize LPS activity. Higher serum concentrations of soluble CD14 and pro-inflammatory cytokines in ESRD patients confirmed this hypothesis. To further explore whether chronic inflammation in ESRD patients could be more related to LPS composition rather than its quantity, we tested the effect of HV and patient sera on cytokine secretion in monocyte cultures. Sera with predominance of 14-carbon chain lipid A-LPS induced higher secretion of pro-inflammatory cytokines than those with predominance of 18-carbon chain lipid A-LPS. TLR4 or LPS antagonists decreased LPS-induced cytokine production by monocytes, demonstrating an LPS-specific effect. Thereby, septic inflammation observed in ESRD patients may be not related to higher bacterial translocation, but to reduced LPS neutralization capacity and differences in translocated LPS subtypes.
Highlights
End-stage renal disease (ESRD) is associated with persistent elevated plasma concentrations of pro-inflammatory cytokines
LPS Is Detectable in ESRD and in Healthy Setting, but LPS Subtype Composition Differs Between ESRD Patients and healthy volunteers (HV)
Our results suggest that septic inflammation observed in ESRD is not related to increased gut permeability and subsequent LPS translocation, but to both a shift towards more inflammatory LPS subtypes and reduced capacity to neutralize LPS
Summary
End-stage renal disease (ESRD) is associated with persistent elevated plasma concentrations of pro-inflammatory cytokines. Exposure to bacterial structures, such as lipopolysaccharides (LPS) yields an inflammatory response mediated by innate immunity [4]. This inflammatory response to LPS in ESRD has been demonstrated to be potentialized by uremic toxins and contributes to altered immune response dysfunctions observed in chronic kidney disease (CKD) [5]. LPS is a major structural component of the outer membrane of Gram-negative bacterial cell wall. It is composed of three structural domains: an amphipathic lipid A, a core oligosaccharide and an Oantigen polysaccharide [6]. LPS is considered as a main pathogen-associated molecular pattern (PAMP) [9]
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