High Plasma Levels of Betaine, a Trimethylamine N-Oxide Related Metabolite, are Associated with Severity of Cirrhosis

BACKGROUND AND AIMS: The gut microbiome-related metabolites betaine and trimethylamine N-oxide (TMAO) affect major health issues. In cirrhosis, betaine metabolism may be diminished due to impaired hepatic betaine homocysteine methyltransferase activity, whereas TMAO generation from trimethylamine may be altered due to impaired hepatic flavin monooxygenase expression. Here we determined plasma betaine and TMAO levels in patients with end-stage liver disease and assessed their relationships with liver disease severity.

METHODS: Plasma betaine and TMAO concentrations were measured by nuclear magnetic resonance spectroscopy in 129 cirrhotic patients (TransplantLines cohort study; NCT03272841) and compared with levels from 4,837 participants of the PREVEND cohort study. Disease severity was assessed by Child-Pugh-Turcotte (CPT) classification and Model for End-stage Liver Disease (MELD) score.

RESULTS: Plasma betaine was on average 60% higher (P<0.001), whereas TMAO was not significantly lower in cirrhotic patients vs. PREVEND population (P=0.44). After liver transplantation (n=13), betaine decreased (P=0.017; P=0.36 vs. PREVEND population), whereas TMAO levels tended to increase (P=0.085) to higher levels than in the PREVEND population (P=0.003). Betaine levels were positively associated with CPT stage and MELD score (both P<0.001). The association with MELD score remained in fully adjusted analysis (P<0.001). The association of TMAO with MELD score did not reach significance (P=0.11). Neither betaine, nor TMAO levels were associated with mortality on the waiting list for liver transplantation (adjusted P=0.78 and P=0.44, respectively).

CONCLUSION: Plasma betaine levels are elevated in cirrhotic patients in parallel with disease severity, and decrease after liver transplantation.