High-circulating gut microbiota-dependent metabolite trimethylamine N-oxide is associated with poor prognosis in pulmonary arterial hypertension

Yicheng Yang; Qixian Zeng; Jianing Gao; Beilan Yang; Jingjing Zhou; Ke Li; Li Li; Anxin Wang; Xin Li; Zhihong Liu; Qin Luo; Zhihui Zhao; Bingyang Liu; Jing Xue; Xue Jiang; Matthew C Konerman; Lemin Zheng; Changming Xiong

doi:10.1093/ehjopen/oeac021

High-circulating gut microbiota-dependent metabolite trimethylamine N-oxide is associated with poor prognosis in pulmonary arterial hypertension

Eur Heart J Open. 2022 Mar 29;2(5):oeac021. doi: 10.1093/ehjopen/oeac021. eCollection 2022 Sep.

Authors

Yicheng Yang¹, Qixian Zeng¹, Jianing Gao², Beilan Yang¹, Jingjing Zhou¹, Ke Li³, Li Li⁴, Anxin Wang³, Xin Li¹, Zhihong Liu¹, Qin Luo¹, Zhihui Zhao¹, Bingyang Liu¹, Jing Xue³, Xue Jiang³, Matthew C Konerman^{5

6}, Lemin Zheng^{2

3}, Changming Xiong¹

Affiliations

¹ Center of Pulmonary Vascular Disease, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
² The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Health Science Center, Peking University, Beijing, China.
³ China National Clinical Research Center for Neurological Diseases, Tiantan Hospital, Advanced Innovation Center for Human Brain Protection, The Capital Medical University, Beijing, China.
⁴ Department of Pathology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
⁵ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Institute for Health Care Policy and Innovation, University of Michigan, Ann Arbor, MI, USA.
⁶ VA Center for Clinical Management Research, Ann Arbor, MI, USA.

Abstract

Aims: We aimed to examine the hypothesis that circulating trimethylamine-N-oxide (TMAO) levels serve as a biomarker in pulmonary arterial hypertension (PAH), and to determine whether 3,3-dimethyl-1-butanol (DMB), a TMAO inhibitor, exerted a protective effect in monocrotaline (MCT)-induced PAH rats.

Methods and results: In-patients with PAH were prospectively recruited from the Fuwai Hospital. Fasting blood samples were obtained to assess the TMAO levels and other laboratory values during the initial and second hospitalization. In a MCT-induced PAH rat, a normal diet and water supplemented with or without 1% DMB were administered for 4 weeks. The TMAO levels, haemodynamic examinations, changes in organ-tissue, and molecular levels were evaluated. In total, 124 patients with PAH were enrolled in this study. High TMAO levels were correlated with increased disease severity and poor prognosis even after adjusting for confounders. The TMAO levels in the rats decreased in the MCT + DMB group, accompanied by improved haemodynamic parameters, decreased right ventricular hypertrophy, and amelioration of pulmonary vascular remodelling. The decrease in abnormal apoptosis, excessive cell proliferation, transforming growth factor-β expression, and restoration of endothelial nitric oxide synthase after DMB treatment further explained the amelioration of PAH.

Conclusion: Increased TMAO levels were associated with poor prognosis in patients with PAH, and DMB played a protective effect in MCT-induced PAH rat.

Keywords: Gut microbiota; Metabolite; Prognosis; Pulmonary arterial hypertension; Pulmonary vascular remodelling; TMAO.