Elevated trimethylamine- N-oxide (TMAO) is associated with poor prognosis in primary sclerosing cholangitis patients with normal liver function

Martin Kummen; Mette Vesterhus; Marius Trøseid; Bjørn Moum; Asbjørn Svardal; Kirsten Muri Boberg; Pål Aukrust; Tom Hemming Karlsen; Rolf Kristian Berge; Johannes Roksund Hov

doi:10.1177/2050640616663453

Elevated trimethylamine- N-oxide (TMAO) is associated with poor prognosis in primary sclerosing cholangitis patients with normal liver function

United European Gastroenterol J. 2017 Jun;5(4):532-541. doi: 10.1177/2050640616663453. Epub 2016 Aug 2.

Authors

Martin Kummen^{1

2

3

4}, Mette Vesterhus^{1

5}, Marius Trøseid^{2

4

6}, Bjørn Moum^{3

7}, Asbjørn Svardal⁸, Kirsten Muri Boberg^{1

3

9}, Pål Aukrust^{2

3

4

6}, Tom Hemming Karlsen^{1

2

3

4

9

10}, Rolf Kristian Berge^{8

11}, Johannes Roksund Hov^{1

2

3

4

9}

Affiliations

¹ Norwegian PSC Research Center, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.
² K.G. Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway.
³ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁴ Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
⁵ Department of Medicine, National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway.
⁶ Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.
⁷ Division of Medicine, Department of Gastroenterology, Oslo University Hospital Ullevål, Oslo, Norway.
⁸ Department of Clinical Science, University of Bergen, Bergen, Norway.
⁹ Section of Gastroenterology, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.
¹⁰ Department of Clinical Medicine, University of Bergen, Bergen, Norway.
¹¹ Department of Heart Disease, Haukeland University Hospital, Bergen, Norway.

Abstract

Background: Trimethylamine-N-oxide (TMAO) is produced in the liver from trimethylamine, which is exclusively generated by gut bacteria.

Objective: The objective of this article is to investigate the relationship between TMAO and primary sclerosing cholangitis (PSC) and its clinical characteristics.

Methods: Serum TMAO was measured in 305 PSC patients, 90 ulcerative colitis patients and 99 healthy controls.

Results: In PSC patients with normal liver function (n = 197), TMAO was higher in patients reaching liver transplantation or death during follow-up than those who did not, with an optimal TMAO cut-off of 4.1 µM (AUC = 0.64, p < 0.001). PSC patients with high TMAO (>4.1 µM, n = 77) exhibited shorter transplantation-free survival than patients with low TMAO (n = 120, log-rank test: p < 0.0001). High TMAO (>4.1 µM) was associated with reduced transplantation-free survival (HR 1.87, p = 0.011), independently of the Mayo risk score (HR 1.74, p < 0.001). Overall, PSC patients demonstrated reduced TMAO values compared with ulcerative colitis and healthy controls, mainly caused by PSC patients with reduced liver function (INR > 1.2), suggesting impaired oxidation of trimethylamine to TMAO. PSC patients with and without inflammatory bowel disease had similar TMAO levels.

Conclusion: In PSC patients with normal liver function, elevated TMAO was associated with shorter transplantation-free survival, potentially reflecting clinically relevant metabolic changes resulting from dietary interactions with the gut microbiota.

Keywords: Primary sclerosing cholangitis; gastrointestinal microbiome; trimethylamine-N-oxide.