TMAO is both a biomarker and a renal toxin.

1 made the seminal discovery that 3 metabolites of dietary phosphatidylcholine (choline, trimethylamine N-oxide [TMAO] and betaine) predicted risk for cardiovascular disease in an independent large clinical cohort. They also demonstrated that supplementing the diet with choline or TMAO promoted atherosclerosis in a mouse model. 1 The gut flora was shown to be required for the production of TMAO, and when the gut flora was suppressed, dietary choline–enhanced atherosclerosis was inhibited. The robustness of TMAO derived from choline in dietary phosphatidylcholine as a predictor of cardiovascular risk was subsequently confirmed in a larger cohort. It was also demonstrated that l-carnitine, a constituent of red meat, was another excellent substrate for gut flora to produce TMA, which was then converted to TMAO. 4 More recently, it was shown that after l-carnitine ingestion, γ-butyrobetaine is produced as an intermediary metabolite by gut bacteria at a rate ≈1000-fold higher than the formation of TMA and in mice is converted into TMA and TMAO and accelerates atherosclerosis. 5 Other studies demonstrated that TMAO predicted risk in patients with heart failure. 6 Patients with heart failure with high TMAO levels had increased long-term mortality independent of traditional risk factors and independent of cardiorenal indexes. 6 In these studies 6 it was noted that there was an inverse correlation between TMAO levels and the estimated glomeru-lar filtration rate (r=−0.55; P<0.001). An accompanying editorial 7 stated that " …the strong correlation between TMAO concentration and kidney function raises the following question: given the importance of the kidney in eliminating TMAO, is higher TMAO level just a marker of renal impairment (7)? " The reference 8 cited in the editorial 7 reported that TMA (which is produced in the intestine by gut bacteria and transported to the liver where it is acted on by flavin monooxygenase family members 9 to form TMAO) and TMAO itself were both elevated in the plasma from 10 patients with end-stage renal disease undergoing hemodialysis when compared with 10 healthy adults. 8 Moreover, the authors observed that the elevated levels in the patients with end-stage renal disease were efficiently reduced during a single hemodialysis treatment. 8 It has been recognized that chronic kidney disease (CKD) alters the intestinal microbial flora. 10–12 In a recent publication from the Framingham Heart Study, liquid chromatogra-phy/mass spectrometry–based metabolite profiling on plasma from 1434 participants demonstrated that 9 metabolites predicted the development of CKD. 13 Interestingly, choline was …