[en] Frailty is a complicated syndrome that occurs at various ages, with highest incidence in aged populations, suggesting associations between the pathogenesis of frailty and age-related changes. Gut microbiota (GM) diversity and abundance change with age, accompanied by increased levels of trimethylamine oxide (TMAO), a systemic inflammation-inducing GM metabolite. Thus, we hypothesized that TMAO may be involved in the development of frailty. We successfully established and verified a novel model of frailty in adult mice based on a 4-week intraperitoneal injection regime of TMAO followed by LPS challenge. The frailty index significantly increased in TMAO-treated mice after LPS challenge. TMAO also decreased claudin-1 immunofluorescent staining intensity in the jejunum, ileum, and colon, indicating that the destruction of intestinal wall integrity may increase vulnerability to exogenous pathogens and invoke frailty. 16S sequencing showed that TMAO significantly reduced the GM Firmicutes/Bacteroidetes (F/B) ratio, but not α-diversity. Interestingly, after LPS challenge, more genera of bacterial taxa were differently altered in the control mice than in the TMAO-treated mice. We infer that a variety of GM participate in the maintenance of homeostasis, whereas TMAO could blunt the GM and impair the ability to recover from pathogens, which may explain the continuous increase in the frailty index in TMAO-treated mice after LPS challenge. TMAO also significantly increased serum imidazole metabolites, and led to different patterns of change in serum peptide and phenylpropanoid metabolites after LPS stimulation. These changes indicate that glucose metabolism may be one mechanism by which GM inactivation causes frailty. In conclusion, TMAO leads to frailty by destroying intestinal barrier integrity and blunting the GM response.
Chen, Si-Yue; Graduate School, Shanghai University of Traditional Chinese Medicine, Shanghai, China ; Laboratory of Neuropsychopharmacology, College of Fundamental Medicine, Shanghai University of Medicine & Health Science, Shanghai, China
Rong, Xing-Yu; Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China
Sun, Xinyi ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique ; Laboratory of Neuropsychopharmacology, College of Fundamental Medicine, Shanghai University of Medicine & Health Science, Shanghai, China
Zou, Yi-Rong; Laboratory of Neuropsychopharmacology, College of Fundamental Medicine, Shanghai University of Medicine & Health Science, Shanghai, China
Zhao, Chao; Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China ; Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Shanghai, China
Wang, Hui-Jing; Graduate School, Shanghai University of Traditional Chinese Medicine, Shanghai, China ; Laboratory of Neuropsychopharmacology, College of Fundamental Medicine, Shanghai University of Medicine & Health Science, Shanghai, China
Language :
English
Title :
A Novel Trimethylamine Oxide-Induced Model Implicates Gut Microbiota-Related Mechanisms in Frailty.
This work was supported by the National Key Research and Development Program of China (2018YFC2000500/03, 2018YFC2002000). CZ was supported by the original exploration program of Fudan University (2021).Reviewed by: Prabhanshu Tripathi, Indian Institute of Toxicology Research Council of Scientific and Industrial Research (CSIR), India; Rajesh Pandey, CSIR-Institute of Genomics and Integrative Biology (CSIR-IGIB), India
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