Gut Microbial Metabolite TMAO Increases Peritoneal Inflammation and Peritonitis Risk in Peritoneal Dialysis Patients
Translational research(2022)
Abstract
Trimethylamine-N-oxide (TMAO), a gut microbiota-produced metabolite, is accumulated in chronic kidney disease (CKD) patients. It is well known to contribute to CKD-related cardiovascular complications. However, the effect of TMAO on peritoneal dialysis (PD)-related peritonitis remains largely unknown. Here, we demonstrate that serum concentrations of TMAO were positively correlated with C-reactive protein levels, and the appearance rate of dialysate IL-6 and PAI-1, in PD patients. During the follow-up period of 28.3 +/- 8.0 months, patients with higher TMAO levels (>= 50 mu M) had a higher risk of new-onset peritonitis (HR, 3.60; 95%CI, 1.18-10.99; P=0.025) after adjusting for sex, age, diabetes, PD duration, BUN, rGFR, C-reactive protein, BMI and beta 2-M. In CKD rat models, TMAO significantly promoted peritoneal dialysate-induced inflammatory cell infiltration, inflammatory cytokines production in the peritoneum. In vitro study revealed that TMAO directly induced primary peritoneal mesothelial cell necrosis, together with increased production of pro-inflammatory cytokines including CCL2, INF-alpha, IL-6, and IL-1 beta. In addition, TMAO significantly increased INF-alpha-induced P-selectin production in mesothelial cells, as well as high glucose-induced INF-alpha and CCL2 expression in endothelial cells. In conclusion, our data demonstrate that higher levels of TMAO exacerbate peritoneal inflammation and might be a risk factor of incidence of peritonitis in PD patients.
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Key words
TMAO,CKD,PD,CRP,ESRD,AGEs,CVD,MCP-1/CCL2,IL-6,IL-1β,TMA,FMO,BMI,nPCR,SCr,β2-M,lnTMAO,AR,5/6 Nx,TNF-α,CAPD,ISPD,RPMCs,HUVECs,rGFR
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