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

Zhang, Lei; Xie, Feifei; Tang, Haie; Zhang, Xinrong; Hu, Jianxia; Zhong, Xiaohong; Gong, Nirong; Lai, Yunshi; Zhou, Miaomiao; Tian, Jianwei; Zhou, Zicong; Xie, Liling; Hu, Zheng; Zhu, Feiqi; Jiang, Jianping; Nie, Jing

doi:10.1016/j.trsl.2021.10.001

Cited by 33 publications

(34 citation statements)

References 63 publications

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“…The modulation of IL-12 by this cluster is mediated by PTEN and, consequently, by the PI3K-Akt-GSK3 pathway [ 49 ]. However, higher levels of plasma TMAO were correlated with higher levels of plasma pro-inflammatory markers in peritonitis, including SERPINE1 [ 50 ]. Similarly, plasma TMAO levels were positively correlated with plasma IL-12 levels in patients with common variable immunodeficiency [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

TMAO Upregulates Members of the miR-17/92 Cluster and Impacts Targets Associated with Atherosclerosis

Díez-Ricote

Ruiz-Valderrey

Micó

et al. 2022

IJMS

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Atherosclerosis is a hallmark of cardiovascular disease, and lifestyle strongly impacts its onset and progression. Nutrients have been shown to regulate the miR-17/92 cluster, with a role in endothelial function and atherosclerosis. Choline, betaine, and L-carnitine, found in animal foods, are metabolized into trimethylamine (TMA) by the gut microbiota. TMA is then oxidized to TMAO, which has been associated with atherosclerosis. Our aim was to investigate whether TMAO modulates the expression of the miR-17/92 cluster, along with the impact of this modulation on the expression of target genes related to atherosclerosis and inflammation. We treated HepG-2 cells, THP-1 cells, murine liver organoids, and human peripheral mononuclear cells with 6 µM of TMAO at different timepoints. TMAO increased the expression of all analyzed members of the cluster, except for miR-20a-5p in murine liver organoids and primary human macrophages. Genes and protein levels of SERPINE1 and IL-12A increased. Both have been associated with atherosclerosis and cardiovascular disease (CDVD) and are indirectly modulated by the miR-17-92 cluster. We concluded that TMAO modulates the expression of the miR-17/92 cluster and that such modulation could promote inflammation through IL-12A and blood clotting through SERPINE1 expression, which could ultimately promote atherosclerosis and CVD.

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Section: Discussionmentioning

confidence: 99%

TMAO Upregulates Members of the miR-17/92 Cluster and Impacts Targets Associated with Atherosclerosis

Díez-Ricote

Ruiz-Valderrey

Micó

et al. 2022

IJMS

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“…Long-term PDF stimulation would further lead to intestinal barrier injury and increases intestinal permeability, which then increases the possibility of pathogen invasion, a risk factor for peritonitis and abdominal infection ( Shu et al, 2009 ). Studies have also confirmed that most pathogenic organisms are of intestinal origin in patients with continuous PD ( Zhang et al, 2022 ). However, there are no specific drugs available for PD-related intestinal complications.…”

Section: Introductionmentioning

confidence: 90%

Astragaloside IV Alleviates Intestinal Barrier Dysfunction via the AKT-GSK3β-β-Catenin Pathway in Peritoneal Dialysis

Wang

Yang

et al. 2022

Front. Pharmacol.

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Background and aims: Long-term peritoneal dialysis (PD) causes intestinal dysfunction, including constipation, diarrhea, or enteric peritonitis. However, the etiology and pathogenesis of these complications are still unclear and there are no specific drugs available in the clinic. This study aims to determine whether Astragaloside IV (AS IV) has therapeutic value on PD-induced intestinal epithelial barrier dysfunction in vivo and in vitro.Methods: We established two different long-term PD treatment mice models by intraperitoneally injecting 4.25% dextrose-containing peritoneal dialysis fluid (PDF) in uremia mice and normal mice, which were served as controls. In addition, PDF was applied to T84 cells in vitro. The therapeutic effects of AS IV on PD-induced intestinal dysfunction were then examined by histopathological staining, transmission electron microscopy, western blotting, and reverse transcription polymerase chain reaction. The protein levels of protein kinase B (AKT), glycogen synthase kinase 3β (GSK-3β) and β-catenin were examined after administration of AS IV.Results: In the present study, AS IV maintained the intestinal crypt, microvilli and desmosome structures in an orderly arrangement and improved intestinal epithelial permeability with the up-regulation of tight junction proteins in vivo. Furthermore, AS IV protected T84 cells from PD-induced damage by improving cell viability, promoting wound healing, and increasing the expression of tight junction proteins. Additionally, AS IV treatment significantly increased the levels of phosphorylation of AKT, inhibited the activity GSK-3β, and ultimately resulted in the nuclear translocation and accumulation of β-catenin.Conclusion: These findings provide novel insight into the AS IV-mediated protection of the intestinal epithelial barrier from damage via the AKT-GSK3β-β-catenin signal axis during peritoneal dialysis.

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“…Elevated serum TMAO was identified as positively related to mortality in 521 patients with CKD studies over a 5-year follow-up [89]. Furthermore, an observational prospective cohort study of peritoneal dialysis (PD) patients (n = 105) demonstrated that elevated plasma TMAO induces peritoneal inflammation and increases the risk of peritonitis in patients undergoing PD [92].…”

Section: Gut Microbial Metabolites and Ckdmentioning

confidence: 99%

Faecal Microbiota Transplantation and Chronic Kidney Disease

et al. 2022

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Faecal microbiota transplantation (FMT) has attracted increasing attention as an intervention in many clinical conditions, including autoimmune, enteroendocrine, gastroenterological, and neurological diseases. For years, FMT has been an effective second-line treatment for Clostridium difficile infection (CDI) with beneficial outcomes. FMT is also promising in improving bowel diseases, such as ulcerative colitis (UC). Pre-clinical and clinical studies suggest that this microbiota-based intervention may influence the development and progression of chronic kidney disease (CKD) via modifying a dysregulated gut–kidney axis. Despite the high morbidity and mortality due to CKD, there are limited options for treatment until end-stage kidney disease occurs, which results in death, dialysis, or kidney transplantation. This imposes a significant financial and health burden on the individual, their families and careers, and the health system. Recent studies have suggested that strategies to reverse gut dysbiosis using FMT are a promising therapy in CKD. This review summarises the preclinical and clinical evidence and postulates the potential therapeutic effect of FMT in the management of CKD.

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

Cited by 33 publications

References 63 publications

TMAO Upregulates Members of the miR-17/92 Cluster and Impacts Targets Associated with Atherosclerosis

TMAO Upregulates Members of the miR-17/92 Cluster and Impacts Targets Associated with Atherosclerosis

Astragaloside IV Alleviates Intestinal Barrier Dysfunction via the AKT-GSK3β-β-Catenin Pathway in Peritoneal Dialysis

Faecal Microbiota Transplantation and Chronic Kidney Disease

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