J Rheum Dis 2019; 26(1): 46-56  
Distinct Urinary Metabolic Profile in Rheumatoid Arthritis Patients: A Possible Link between Diet and Arthritis Phenotype
Jung Hee Koh1,*, Yune-Jung Park2,*, Saseong Lee3, Young-Shick Hong4, Kwan Soo Hong5, Seung-Ah Yoo3, Chul-Soo Cho2,3, Wan-Uk Kim2,3
1Division of Rheumatology, Department of Internal Medicine, Pusan National University Hospital, Busan,2Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, 3Center for Integrative Rheumatoid Transcriptomics and Dynamics, The Catholic University of Korea, Seoul, 4Division of Food and Nutrition, Chonnam National University, Gwangju, 5Bioimaging Research Team, Korea Basic Science Institute, Cheongju, Korea
Correspondence to: Wan-Uk Kim http://orcid.org/0000-0001-8224-8496 Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea. E-mail:wan725@catholic.ac.kr
*These authors contributed equally to this work.
Received: September 11, 2018; Revised: October 30, 2018; Accepted: November 4, 2018; Published online: January 1, 2019.
© Korean College of Rheumatology. All rights reserved.

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Objective. We undertook this study to investigate the discriminant metabolites in urine from patients with established rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and from healthy individuals. Methods. Urine samples were collected from 148 RA patients, 41 SLE patients and 104 healthy participants. The urinary metabolomic profiles were assessed using 1H nuclear magnetic resonance spectroscopy. The relationships between discriminant metabolites and clinical variables were assessed. Collagen-induced arthritis was induced in mice to determine if a choline-rich diet reduces arthritis progression. Results. The urinary metabolic fingerprint of patients with established RA differs from that of healthy controls and SLE patients. Markers of altered gut microbiota (trimethylamine-N-oxide, TMAO), and oxidative stress (dimethylamine) were upregulated in patients with RA. In contrast, markers of mitochondrial dysfunction (citrate and succinate) and metabolic waste products (p-cresol sulfate, p-CS) were downregulated in patients with RA. TMAO and dimethylamine were negatively associated with serum inflammatory markers in RA patients. In particular, patients with lower p-CS levels exhibited a more rapid radiographic progression over two years than did those with higher p-CS levels. The in vivo functional study demonstrated that mice fed with 1% choline, a source of TMAO experienced a less severe form of collagen-induced arthritis than did those fed a control diet. Conclusion. Patients with RA showed a distinct urinary metabolomics pattern. Urinary metabolites can reflect a pattern indicative of inflammation and accelerated radiographic progression of RA. A choline-rich diet reduces experimentally-induced arthritis. This finding suggests that the interaction between diet and the intestinal microbiota contributes to the RA phenotype.
Keywords: Rheumatoid arthritis, Urine, Metabolomics, Trimethylamine-N-oxide, Diet

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