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

  • Author Footnotes
    1 These authors contribute to this work equally.
    LEI ZHANG
    Footnotes
    1 These authors contribute to this work equally.
    Affiliations
    State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of Education), Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China
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  • Author Footnotes
    1 These authors contribute to this work equally.
    FEIFEI XIE
    Footnotes
    1 These authors contribute to this work equally.
    Affiliations
    State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of Education), Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China
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  • HAIE TANG
    Affiliations
    State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of Education), Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China
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  • XINRONG ZHANG
    Affiliations
    State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of Education), Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China
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  • JIANXIA HU
    Affiliations
    State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of Education), Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China
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  • XIAOHONG ZHONG
    Affiliations
    State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of Education), Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China
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  • NIRONG GONG
    Affiliations
    State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of Education), Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China
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  • YUNSHI LAI
    Affiliations
    State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of Education), Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China
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  • MIAOMIAO ZHOU
    Affiliations
    State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of Education), Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China
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  • JIANWEI TIAN
    Affiliations
    State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of Education), Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China
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  • ZHANMEI ZHOU
    Affiliations
    State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of Education), Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China
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  • LILING XIE
    Affiliations
    State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of Education), Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China
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  • ZHENG HU
    Affiliations
    State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of Education), Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China
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  • FENGXIN ZHU
    Affiliations
    State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of Education), Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China
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  • JIANPING JIANG
    Correspondence
    Jianping Jiang, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
    Affiliations
    State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of Education), Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China
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  • Jing Nie
    Correspondence
    Reprint requests: Jing Nie, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
    Affiliations
    State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of Education), Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China
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  • Author Footnotes
    1 These authors contribute to this work equally.
Published:October 18, 2021DOI:https://doi.org/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.

      Abbreviations:

      TMAO (trimethylamine-N-oxide), CKD (chronic kidney disease), PD (peritoneal dialysis), CRP (C-reactive protein), ESRD (end-stage renal disease), AGEs (advanced glycation end products), CVD (cardiovascular diseases), MCP-1/CCL2 (monocyte chemoattractant protein-1), IL-6 (interleukin 6), IL-1β (interleukin 1β), TMA (trimethylamine), FMO (flavin-containing monooxygenases), BMI (body mass index), nPCR (normalized protein catabolic rate), SCr (serum creatinine), β2-M (β2-microglobulin), lnTMAO (natural log transformed serum TMAO), AR (appearance rates), 5/6 Nx (five-sixths nephrectomy), TNF-α (tumor necrosis factor-α), CAPD (continuous ambulatory PD), ISPD (International Society for Peritoneal Dialysis), RPMCs (primary rat peritoneal mesothelial cells), HUVECs (Human umbilical vein endothelial cells), rGFR (residual glomerular filtration rate)
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