Decreased Kidney Function Is Associated with Enhanced Hepatic Flavin Monooxygenase Activity and Increased Circulating Trimethylamine N-Oxide Concentrations in Mice

Abstract

Circulating trimethylamine -oxide (TMAO) predicts poor cardiovascular outcomes in patients with chronic kidney disease (CKD). Accumulation of serum TMAO has been observed in CKD patients; however, the mechanisms contributing to this finding have been inadequately explored. The purpose of this study was to investigate the mechanisms responsible for TMAO accumulation in the setting of decreased kidney function using a CKD mouse model. Mice were fed a diet supplemented with 0.2% adenine to induce CKD, which resulted in increased serum TMAO concentrations (females: CKD 29.4 ± 32.1M vs. non-CKD 6.9 ± 6.1 M, < 0.05; males: CKD 18.5 ± 13.1 M vs. non-CKD 1.0 ± 0.5M, < 0.001). As anticipated, accumulation of circulating TMAO was accompanied by a decrease in renal clearance (females: CKD 5.2 ± 3.8 l/min vs. non-CKD 90.4 ± 78.1l/min, < 0.01; males: CKD 10.4 ± 8.1 l/min vs. non-CKD 260.4 ± 134.5l/min; < 0.001) and fractional excretion of TMAO. Additionally, CKD animals exhibited an increase in hepatic flavin monooxygenase (FMO)-mediated formation of TMAO (females: CKD 125920 ± 2181 pmol/mg per 60 minutes vs. non-CKD 110299 ± 4196 pmol/mg per 60 minutes, < 0.001; males: CKD 131286 ± 2776 pmol/mg per 60 minutes vs. non-CKD 74269 ± 1558 pmol/mg per 60 minutes, < 0.001), which likely resulted from increased FMO3 expression in CKD mice. The current study provides evidence that both decreased renal clearance and increased hepatic production of TMAO may contribute to increments in serum TMAO in the setting of CKD. Hepatic FMO activity may represent a novel therapeutic target for lowering circulating TMAO in CKD patients.

Dietary metabolism, the gut microbiome, and heart failure

“…In this latter study, the recruited patients also had impaired kidney function and thus clearance, which may have heightened the sensitivity for the detection of genetic variants associated with variations in circulating levels of TMAO, despite its smaller sample size. Furthermore, another recent study also observed increased FMO3 expression associated with decreased kidney function in mice, suggesting genetic impact on plasma TMAO variability in specific settings such as decreased renal function 205 .…”

Trimethylamine N-Oxide in Relation to Cardiometabolic Health—Cause or Effect?

“…These effects could be the results of activation in FMOs elicited by octylamine and uremic serum [122]. Lower clearance in TMAO coincided with increased FMO 3 expression in a CKD mouse model [123]. High plasma TMAO levels in CKD patients may contribute to the observed damage in blood vessels [122].…”

The Microbial Metabolite Trimethylamine N-Oxide Links Vascular Dysfunctions and the Autoimmune Disease Rheumatoid Arthritis

“…For example, TMAO promotes inflammation in adipose tissue of mice on a high-fat and high-sugar diet [2]. Excessively high levels of TMAO is an established risk factor for CVD [3,4,5,6], glucose intolerance [2], kidney damage [7,8,9], obesity, and diabetes [10,11,12]. High levels may also increase the risk of colorectal, hepatic, and prostate cancer in humans [13].…”