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.