Metabolomics analysis of human plasma reveals decreased production of trimethylamine N-oxide retards the progression of chronic kidney disease.

Background And Purpose: Chronic kidney disease (CKD) is a global public health problem and one of the leading causes of all-cause mortality. However, the pathogenic mechanisms and intervention methods for CKD progression are not fully understood.

Experimental Approach: Plasma from patients with uraemia and from healthy controls (n = 30 per group) was analysed with LC-MS/MS-based non-targeted metabolomics to identify potential markers of uraemia. These potential markers were validated in the same cohort and a second cohort (n = 195) by quantitative analysis of the markers, using LC-MS/MS. The most promising marker was identified by correlation analysis and further validated using HK-2 cells and mouse models.

Key Results: Trimethylamine N-oxide (TMAO) was identified as a promising marker among the 18 potential markers found in the first cohort, and it was optimally correlated with renal function of CKD patients in the second cohort. Treatment of HK-2 cells with TMAO decreased cell viability and up-regulated expression of α-smooth muscle actin. In mice, a TMAO-containing diet decreased kidney mass and increased protein expression of α-smooth muscle actin. Also, control of TMAO production by inhibiting its biosynthetic pathway with 3,3-dimethyl-1-butanol or disrupting gut microbiota function with an antibiotic cocktail, attenuated renal injury in a murine model of CKD.

Conclusion And Implications: Our data show that decreased TMAO production could be a new strategy to attenuate the progression of renal injury in CKD.