High plasma levels of betaine, a trimethylamine N-Oxide-related metabolite, are associated with the severity of cirrhosis

Eline H van den Berg; Jose L Flores-Guerrero; Erwin Garcia; Margery A Connelly; Vincent E de Meijer; TransplantLines Investigators; Stephan J L Bakker; Hans Blokzijl; Robin P F Dullaart

doi:10.1111/liv.15310

High plasma levels of betaine, a trimethylamine N-Oxide-related metabolite, are associated with the severity of cirrhosis

Liver Int. 2023 Feb;43(2):424-433. doi: 10.1111/liv.15310. Epub 2022 May 27.

Authors

Eline H van den Berg¹, Jose L Flores-Guerrero², Erwin Garcia³, Margery A Connelly³, Vincent E de Meijer⁴; TransplantLines Investigators; Stephan J L Bakker², Hans Blokzijl¹, Robin P F Dullaart⁵

Affiliations

¹ Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
² Department of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
³ Laboratory Corporation of America Holdings (Labcorp), Morrisville, North Carolina, USA.
⁴ Department of Hepatopancreatobiliary Surgery and Liver Transplantation, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
⁵ Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Abstract

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 because of impaired hepatic betaine homocysteine methyltransferase activity, whereas TMAO generation from trimethylamine may be altered because of 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 4837 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 < .001), whereas TMAO was not significantly lower in cirrhotic patients vs. PREVEND population (p = .44). After liver transplantation (n = 13), betaine decreased (p = .017; p = .36 vs. PREVEND population), whereas TMAO levels tended to increase (p = .085) to higher levels than in the PREVEND population (p = .003). Betaine levels were positively associated with the CPT stage and MELD score (both p < .001). The association with the MELD score remained in the fully adjusted analysis (p < .001). The association of TMAO with the MELD score did not reach significance (p = .11). Neither betaine nor TMAO levels were associated with mortality on the waiting list for liver transplantation (adjusted p = .78 and p = .44, respectively).

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

Keywords: CPT classification; MELD score; NMR spectroscopy; TMAO; betaine; liver cirrhosis; orthotopic liver transplantation.

Publication types

Clinical Study

MeSH terms

Betaine* / metabolism
Biomarkers
Cohort Studies
End Stage Liver Disease*
Humans
Liver Cirrhosis
Severity of Illness Index

Substances

Betaine
Biomarkers
trimethyloxamine