Serum metabolomic profiling uncovered metabolic shifts in individuals upon moderate-altitude exposure and identified the potentiality of beta-alanine to ameliorate hyperuricemia
Xuanfu Chen,
Guoxiang Zou,
Zhibo Yang,
Xin Qi,
Feier Song,
Long Peng,
Dingchen Wang,
Jingyan Zhou,
Jiahui Ma,
Haiwei He,
Yimei Hong,
Yu-E Wang,
Yanqun Fan,
Zhipeng Liu,
Xin Li
Affiliations
Xuanfu Chen
Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Guangzhou, China; Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
Guoxiang Zou
Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
Zhibo Yang
Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
Xin Qi
Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
Feier Song
Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
Long Peng
Department of Neurosurgery, Guangdong Provincial People's Hospital Ganzhou Hospital, China
Dingchen Wang
Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China; School of Medicine, South China University of Technology, Guangzhou, China
Jingyan Zhou
Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China; The Second Clinical School of Medicine, Southern Medical University, Guangzhou, China
Jiahui Ma
School of Medicine, South China University of Technology, Guangzhou, China
Haiwei He
Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
Yimei Hong
Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
Yu-E Wang
Nyingchi People's Hospital, Tibet, China
Yanqun Fan
Biotree Metabolomics Technology Research Center, Shanghai, China; Corresponding author. Biotree Metabolomics Technology Research Center, Shanghai, China.
Zhipeng Liu
Biotree Metabolomics Technology Research Center, Shanghai, China; Corresponding author. Biotree Metabolomics Technology Research Center, Shanghai, China.
Xin Li
Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China; Nyingchi People's Hospital, Tibet, China; Corresponding author. Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
Background: High-altitude exposure has been associated with an increased risk of hyperuricemia (HU) and gout, though the underlying mechanisms remain poorly understood. Methods: We conducted a comprehensive analysis of the serum metabolome and phenome in both discovery and validation cohorts of Han Chinese individuals who underwent long-term moderate-altitude exposure (∼12 months), as well as in an independent cohort consisting of local Han Chinese and Tibetans residing in Nyingchi (>5 years). Beta-Alanine intervention was applied in hypoxanthine and potassium oxonate-induced in vitro and in vivo experiments. Results: Individuals exposed to moderate altitude exhibited elevated serum urate and an increase in overall medium-chain fatty acids (MCFAs), coupled with a decrease in overall amino acids (AAs) and short-chain fatty acids (SCFAs). Rmcorr correlation analysis revealed a significant negative association between Beta-Alanine and serum urate, whereas nonanoic acid was in versa, potentially driving lower serum urate in long-term exposed residents. Both in vitro and in vivo experiments demonstrated that Beta-Alanine inhibited xanthine oxidase (XOD) and reversed the HU phenotype in human hepatocytes and mice induced by hypoxanthine (HX) and potassium oxonate (PO), with a urate-lowering effect in mice. Hepatic pathology and transcriptome analysis of HU mice treated with Beta-Alanine indicated that the mechanisms involved the inhibition of XOD, amelioration of the inflammation phenotype in hepatocytes, and promotion of renal urate excretion. Furthermore, the 10-fold cross-validation random forest classification (RFC) predictive modeling based on selected metabolites and phenotypes achieved an area under receiver operating characteristic (ROC) curve (AUC) value of 0.93 (95 % confidence interval (CI): 0.85–1.00) and 0.79 (95 % CI: 0.59–0.98) for distinguishing individuals with high risk of asymptomatic HU (AHU) in the training dataset and validation dataset, respectively. Conclusions: This study reveals serum urate and metabolome altered in moderate-altitude exposed individuals and Beta-Alanine intervention could ameliorate hyperuricemia. Our findings suggest that targeting the circulating metabolome may pave novel avenues to counter diseases associated with HU.
