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Abstract: PO2485

The Role of Abnormal Expression of Clock Gene DBP Mediated by Gut Microbiota Dysbiosis in Cognitive Dysfunction in ESRD and the Underlying Mechanism

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Chen, Lei, Dialysis Department of Nephrology Hospital, the First Affiliated Hospital of Xi‘an Jiaotong University., Xi‘an, Shaanxi, China
  • Luo, Yulong, Dialysis Department of Nephrology Hospital, the First Affiliated Hospital of Xi‘an Jiaotong University., Xi‘an, Shaanxi, China
Background

The objective of this study is to explore whether gut microbiota dysbiosis is one of the main cause of cognitive dysfunction (CD) in CKD and to reveal its specific mechanism, bringing a new insight for its pathogenesis.

Methods

The fecal microbiota of normal rats was transplanted into CKD rats by intragastric gavage for 4 weeks. The gut microbiota was analyzed by 16S rRNA sequencing. The cognitive function (CF) was evaluated by Morris Water Maze. The level of microinflammatory biomarkers were detected by ELISA, and their correlation with CF was analyzed. The expression of DBP in rat macrophages was detected by qPCR. Further, the level of DBP in macrophages was verified in CKD patients, and the serum of CKD patients was used to stimulate the differentiation of THP-1 cells into macrophages. The proportion of M1 and M2 macrophages was detected by flow cytometry. The expression of DBP and cytokines in THP-1 was detected by qPCR. Finally, DBP in THP-1 cells was knocked down and overexpressed before treating with PMA, respectively, to measure the expression of cytokines.

Results

The ability to search the target quadrant decreased significantly in CKD rats, which were partially reversed by FMT. FMT improved the β-diversity of CKD microbiota, and increased the abundance of Prevotella_9, Prevotella_1 and Roseburia. Compared with sham rats, serum levels of IL-6, TNF-α and hsCRP were significantly increased in CKD rats, while they were decreased after FMT. The levels of above markers were negatively correlated with CF. DBP expression was higher in CKD rats macrophages, which was reversed by FMT. The percentage of M1 macrophages was increased in CKD patients, and DBP expression in macrophages was increased. Moreover, the serum of CKD patients induced the differentiation of THP-1 cells into M1 macrophages, during which the expression of DBP and cytokines was increased. Furthermore, DBP knockdown decrease the expression of proinflammatory cytokines, while DBP overexpression induced the expression of these cytokines significantly.

Conclusion

The microinflammation mediated by gut microbiota dysbiosis is an important cause of CD in CKD. DBP, induced by dysbiosis, positively regulates the expression of inflammatory factors in macrophages differentiation, leading to microinflammation, which may be involved in the pathogenesis of CD in CKD.

Funding

  • Government Support – Non-U.S.