Gut microbial metabolite TMAO increases peritoneal inflammation and peritonitis risk in peritoneal dialysis patients

• Published in: Translational research : the journal of laboratory and clinical medicine 2022-02, Vol.240, p.50-63
• Main Authors: ZHANG, LEI, XIE, FEIFEI, TANG, HAIE, ZHANG, XINRONG, HU, JIANXIA, ZHONG, XIAOHONG, GONG, NIRONG, LAI, YUNSHI, ZHOU, MIAOMIAO, TIAN, JIANWEI, ZHOU, ZHANMEI, XIE, LILING, HU, ZHENG, ZHU, FENGXIN, JIANG, JIANPING, Nie, Jing
• Format: Article
• Language: English
• Subjects: Adult; Animals; Cell Death; Cytokines - metabolism; Epithelium - pathology; Female; Gastrointestinal Microbiome - drug effects; Glucose - toxicity; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Inflammation - pathology; Inflammation Mediators - metabolism; Male; Metabolome - drug effects; Methylamines - adverse effects; Middle Aged; P-Selectin - metabolism; Peritoneal Dialysis - adverse effects; Peritoneum - pathology; Peritonitis - epidemiology; Peritonitis - etiology; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic - complications; Risk Factors; Up-Regulation
• ISSN: 1931-5244; 1878-1810
• DOI: 10.1016/j.trsl.2021.10.001

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 μM) 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 β2-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, TNF-α, IL-6, and IL-1β. In addition, TMAO significantly increased TNF-α-induced P-selectin production in mesothelial cells, as well as high glucose-induced TNF-α 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.