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World J Gastroenterol. Jul 21, 2026; 32(27): 120135
Published online Jul 21, 2026. doi: 10.3748/wjg.120135
Metabolic memory in the gut: The microbiota-epigenetic crosstalk orchestrating obesity onset and novel therapeutic landscapes
Tian-Cheng Xu, Bin Xu, Jing-Yan Pan, Xin-Yu Shen, En-He Zhao, Mo Zhou, Cong-Yi Xie, Shuai-Yan Wang, Yu-Jue Wang, Yun Liu
Yun Liu, Yu-Jue Wang, Shuai-Yan Wang, Cong-Yi Xie, Mo Zhou, Bin Xu, Tian-Cheng Xu, Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
En-He Zhao, School of Acupuncture and Tuina, School of Health and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
Xin-Yu Shen, School of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
Jing-Yan Pan, School of Acupuncture-Moxibustion and Tuina, School of Health Preservation and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
Co-first authors: Yun Liu and Yu-Jue Wang.
Co-corresponding authors: Bin Xu and Tian-Cheng Xu.
Author contributions: Liu Y and Wang YJ were responsible for the idea and conceptual framework, they contributed equally to this manuscript and are co-first authors; Liu Y, Wang YJ, Zhou M, Zhao EH, Shen XY, and Pan JY wrote the first draft of the manuscript; Wang SY and Xie CY responsible for drafting and organizing the forms; Xie CY was responsible for graphical abstract; Xu B and Xu TC reviewed the manuscript and critically revised it for important intellectual content, and they are co-corresponding authors; and all authors have reviewed and approved the final version of the manuscript.
AI contribution statement: We used Doubao to revise individual sentences and conduct native-level linguistic polishing. No AI-generated writing content was used throughout the entire writing and revision process.
Supported by National Natural Science Foundation of China, No. 82305376; the Youth Talent Support Project of the China Acupuncture and Moxibustion Association, No. 2024-2026ZGZJXH-QNRC005; 2024 Jiangsu Province Youth Science and Technology Talent Support Project, No. JSTJ-2024-380; and Talent Cultivation Program for Young Researchers, Key Laboratory of the Ministry of Education Project, No. zyqt202501 and No. zyqt202503.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Corresponding author: Tian-Cheng Xu, PhD, Academic Fellow, Principal Investigator, Professor, Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, No. 138 Xianlin Avenue, Qixia District, Nanjing 210023, Jiangsu Province, China.
xtc@njucm.edu.cn
Received: February 24, 2026
Revised: March 7, 2026
Accepted: April 3, 2026
Published online: July 21, 2026
Processing time: 148 Days and 21.4 Hours
Metabolic memory, defined as the persistent cellular and molecular alterations induced by transient metabolic perturbations (e.g., high-fat/high-fructose diets) even after metabolic normalization, has emerged as a critical driver of chronic metabolic diseases, including obesity. Recent evidence highlights the gut as a key mediator of metabolic memory, where gut microbiota dysbiosis and subsequent epigenetic modifications establish long-lasting functional changes that predispose individuals to obesity and hinder treatment responses. This review summarizes the intricate interplay between gut-related metabolic memory and obesity: Transient exposure to obesogenic diets triggers sustained shifts in gut microbiota composition - such as the enrichment of Odoribacter (a source of histone deacetylase inhibitor butyrate, whose dosage governs beneficial versus deleterious effects) - even after the restoration of a normal diet. Butyrate, as a key microbial metabolite, modulates epigenetic marks (e.g., DNA methylation and histone acetylation) in intestinal epithelial cells, immune cells, and hepatocytes, perpetuating pro-inflammatory signaling, dysregulated lipid metabolism, and impaired gut barrier function. These persistent alterations, rooted in metabolic memory, promote systemic insulin resistance, adiposity accumulation, and chronic low-grade inflammation, which are hallmarks of obesity. Additionally, maternal obesogenic diets transmit metabolic memory to offspring via gut microbiota-epigenetic crosstalk, increasing intergenerational obesity susceptibility. For obesity treatment, targeting gut-related metabolic memory offers promising strategies: Early dietary interventions to prevent the establishment of detrimental microbiota-epigenetic signatures, microbiota modulation (e.g., probiotics targeting Odoribacter homeostasis), and epigenetic modifiers (e.g., butyrate analogs or histone deacetylase inhibitors) to reverse persistent epigenetic alterations. Understanding the gut-metabolic memory axis provides new insights into obesity pathogenesis and underscores the need for time-sensitive, microbiota-epigenetic targeted therapies to break the cycle of metabolic memory-driven obesity.
Core Tip: The gut serves as a critical repository for metabolic memory, where transient exposure to obesogenic diets triggers persistent microbiota-epigenetic crosstalk. Specific microbial shifts, such as the enrichment of Odoribacter, lead to sustained epigenetic modifications like histone hyperacetylation via butyrate, driving chronic inflammation and obesity even after dietary normalization. This memory can be vertically transmitted to offspring, increasing intergenerational obesity susceptibility. Breaking this cycle requires time-sensitive interventions, including microbiota modulation and epigenetic therapies to restore metabolic homeostasis.
