Cultivated Enterococcus faecium B6 from children with obesity promotes nonalcoholic fatty liver disease by the bioactive metabolite tyramine

ABSTRACT

Gut microbiota plays an essential role in nonalcoholic fatty liver disease (NAFLD). However, the contribution of individual bacterial strains and their metabolites to childhood NAFLD pathogenesis remains poorly understood. Herein, the critical bacteria in children with obesity accompanied by NAFLD were identified by microbiome analysis. Bacteria abundant in the NAFLD group were systematically assessed for their lipogenic effects. The underlying mechanisms and microbial-derived metabolites in NAFLD pathogenesis were investigated using multi-omics and LC-MS/MS analysis. The roles of the crucial metabolite in NAFLD were validated in vitro and in vivo as well as in an additional cohort. The results showed that Enterococcus spp. was enriched in children with obesity and NAFLD. The patient-derived Enterococcus faecium B6 (E. faecium B6) significantly contributed to NAFLD symptoms in mice. E. faecium B6 produced a crucial bioactive metabolite, tyramine, which probably activated PPAR-γ, leading to lipid accumulation, inflammation, and fibrosis in the liver. Moreover, these findings were successfully validated in an additional cohort. This pioneering study elucidated the important functions of cultivated E. faecium B6 and its bioactive metabolite (tyramine) in exacerbating NAFLD. These findings advance the comprehensive understanding of NAFLD pathogenesis and provide new insights for the development of microbe/metabolite-based therapeutic strategies.

Graphical abstract

KEYWORDS:

• Gut microbiota
• Enterococcus
• non-alcoholic fatty liver disease
• metabolites
• tyramine

Acknowledgments

We thank the Novogene Bioinformatics Technology Co., Ltd. (Beijing, China) for excellent technical assistance in the sequencing of the 16S rRNA gene, Applied Protein Technology Co. Ltd. (Shanghai, China) for excellent technical assistance in transcriptomic and untargeted metabolomics detection, and Personalbio Technology Co., Ltd. (Shanghai, China) for excellent technical assistance in the whole genome sequencing.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

The research was designed by Jia Wei and Miyang Luo; The clinical information and samples from patients were collected by Jia Wei, Wen Dai, Xiongfeng Pan, Yamei Li, Yamei Duan, Xiang Xiao, Ping Ye, Yan Zhong, and Ningan Xu. The animal and cell experiments were performed by Jia Wei, Wen Dai, Yue Yang, Zhenzhen Yao, Yixu Liu, Zhihang Huang, and Jiajia Zhang. The multi-omics analysis was performed by Jia Wei, Wen Dai, and Xiongfeng Pan. The bacterial experiments were performed by Jia Wei and Zhihang Huang. Jiayou Luo, Fei Yang, Xiangling Feng, Ming Zeng, and Miyang Luo provided critical reagents and technical support, and assisted in revising the manuscript. Jia Wei and Miyang Luo wrote and revised the manuscript. All authors reviewed and approved the manuscript.

Data availability statement

All of the sequencing data that support the findings of the study are openly available in the National Center for Biotechnology Information (NCBI) BioProjects (https://www.ncbi.nlm.nih.gov/bioproject/) with the accession numbers PRJNA838778 and PRJNA1032872. Additional data that support the findings of this study are available on request from the corresponding author.

Ethics statement

The studies were approved by the Xiangya School of Public Health Central South University Ethics Research Committee (XYGW-2018-04, XYGW-2021-19) and the Hunan Children’s Hospital Ethics Research Committee (HCHLL-2019-12). Written informed consent was obtained from all participants or their legal guardians/next of kin. The animal experiments were approved by the Laboratory Animal Welfare and Ethics Committee and adhered to the Animal Ethics Statement of Central South University (XMSB-2022–0027).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2024.2351620

Additional information

Funding

This work was supported by grants from the National Natural Science Foundation of China (82304171), the Hunan Province Natural Science Foundation (2022JJ40668, 2021JJ30901), and the Fundamental Research Funds for the Central Universities of Central South University (2022ZZTS0846).