Age-related gut microbiome profile and reversal of microbial imbalance by trimetazidine intervention

doi:10.3748/wjg.v32.i16.115969

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Apr 28, 2026 (publication date) through Apr 17, 2026

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World Journal of Gastroenterology

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1007-9327

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Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.

World J Gastroenterol. Apr 28, 2026; 32(16): 115969
Published online Apr 28, 2026. doi: 10.3748/wjg.v32.i16.115969

Age-related gut microbiome profile and reversal of microbial imbalance by trimetazidine intervention

Xue-Mei Wang, Ben-Chen Rao, Guan-Yue Su, Hai-Yu Wang, Gui-Zhen Zhang, Fei-Lin Ge, Zu-Jiang Yu, Zhi-Gang Ren, Hong-Xia Liang

Xue-Mei Wang, Guan-Yue Su, Hai-Yu Wang, Gui-Zhen Zhang, Zu-Jiang Yu, Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China

Ben-Chen Rao, Zhi-Gang Ren, Department of Infectious Diseases, State Key Laboratory of Antiviral Drugs, Pingyuan Laboratory, Zhengzhou 450052, Henan Province, China

Fei-Lin Ge, Department of Chinese Medicine, State Key Laboratory of Antiviral Drugs, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China

Hong-Xia Liang, Department of Infectious Disease and Hepatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China

Co-corresponding authors: Zhi-Gang Ren and Hong-Xia Liang.

Author contributions: Ren ZG and Liang HX made substantial contributions to the conception or design of the study; Ren ZG, Wang XM, Rao BC, Zhang GZ, and Wang HY collected clinical samples and clinical data; Wang XM and Rao BC performed the animal experiments and collected animal samples, and were in charge of the acquisition, analysis and interpretation of data, and wrote the manuscript; Ren ZG, Yu ZJ and Liang HX were responsible for revision of the manuscript; Wang XM, Rao BC, Su GY, Wang HY, Zhang GZ, Ge FL, Yu ZJ, Ren ZG, and Liang HX finally read and approved the version to be published; Wang XM, Su GY and Rao BC extracted bacterial DNA and performed MiSeq sequencing; Wang XM and Rao BC analyzed the data; Ren ZG and Liang HX contributed equally to this work as co-corresponding authors; the reasons are the following: They played a key role in coordinating the research team; second, they made a great contribution to the original innovation of the article; in summary, we believe that designating Ren ZG and Liang HX as co-corresponding authors is fitting for our manuscript as it accurately reflects our team’s collaborative spirit, equal contributions, and diversity.

Supported by the National Natural Science Foundation of China, No. 82470654; the Natural Science Foundation Key Project of Henan Province, No. 232300421124; and the Henan Zhongyuan Medical Science and Technology Innovation and Development Foundation, No. ZYYC202301ZD.

Institutional review board statement: The study was reviewed and approved by the Research and Clinical Trial Ethics Review Committee of the First Affiliated Hospital of Zhengzhou University Institutional Review Board (Approval No. 2021-KY-0716-003).

Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Animal Welfare and Ethics Committee of the Laboratory Animal Center of Zhengzhou University, No. ZZU-LAC20201013[04].

Conflict-of-interest statement: The authors declare that they have no conflict of interest.

ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.

Data sharing statement: The 16S rRNA gene sequencing and metagenomic sequencing datasets generated during this study have been deposited in the NCBI Sequence Read Archive under BioProject accession number PRJNA1285086. All data are publicly accessible and can be accessed at the NCBI BioProject database. Raw sequencing data, processed data, and metadata are available for immediate access without restrictions (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA1285086).

Corresponding author: Hong-Xia Liang, MD, PhD, Doctor, Department of Infectious Disease and Hepatology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou 450052, Henan Province, China. hxliang@zzu.edu.cn

Received: November 3, 2025
Revised: December 15, 2025
Accepted: January 26, 2026
Published online: April 28, 2026
Processing time: 169 Days and 11.1 Hours

Abstract

BACKGROUND

Aging is the primary risk factor for numerous chronic diseases, cognitive deterioration, and mortality. The gut microbiota is increasingly implicated in the aging process, yet a comprehensive understanding of its dynamic compositional and functional shifts throughout the human lifespan and its mechanistic contributions to aging remains unclear.

AIM

To study the gut microbiota profiles of age-related changes during aging in both human and rat cohorts, with particular focus on microbiota involved in lipid metabolism. Subsequently, to intervene fatty acid oxidation inhibitor trimetazidine (TMZ) was used in the aging process.

METHODS

The metagenomic sequencing and 16S rRNA sequencing were performed to detect gut microbiota in 300 individuals of different age groups and rats of different weeks, mapping the evolutionary profiles of microbiota during aging across all age groups and focusing on analyzing significantly changed gut microbiota and their biological functions. Based on clues obtained from the above analysis that microbiota with fatty acid oxidation function was closely related to aging, and validation was conducted using fatty acid oxidation inhibitor TMZ in aging animal models.

RESULTS

Multicohort analysis revealed that gut microbial diversity follows a nonlinear trajectory, initially increasing until age 10, remaining relatively stable until approximately 70 years and declining thereafter. Functional enrichment analysis demonstrated a significant, age-associated increase in lipid metabolism pathways in both human and animal models, which was consistent with marked changes in abundance in the gut microbiota involved in lipid metabolism such as Luteipulveratus (P < 0.05). TMZ, a fatty acid oxidation inhibitor, reshaped the gut microbiota structure and suppressed the abundance of lipid metabolism-associated gut microbiota in aging rats. Further molecular validation confirmed that the TMZ inhibited fatty acid β-oxidation and significantly downregulated the expression levels of key senescence marker proteins and genes.

CONCLUSION

In conclusion, gut microbiota undergoes age-dependent remodeling, with significant enrichment of the fatty acid oxidation-related microbiome. The fatty acid oxidation inhibitor TMZ may attenuate aging phenotype through the dual modulation of gut microbial composition and lipid metabolism and may provide an antiaging strategy.

Keywords: Intestinal microbiota; Dysbiosis; Lipid metabolism; Trimetazidine; Senescence

Core Tip: This study reveals that gut microbiota alterations during aging follow a nonlinear trajectory across human and rat cohorts. The key finding demonstrates increased fatty acid oxidation-related microbiota in aged individuals. Functional enrichment analysis revealed a possible association between the gut microbiota and lipid metabolism. Trimetazidine (TMZ), a fatty acid oxidation inhibitor, successfully modulated aging-associated gut microbiota and suppressed senescence markers P21 in rats. These findings establish fatty acid oxidation maybe as a crucial mechanistic link between gut microbiota and aging, positioning TMZ as a potential therapeutic intervention for healthy aging through microbiome regulation.