image: The “MDME Axis”: a new framework explaining how metabolites from gut microbiome epigenetically reprogram our genes, influencing host health and disease.
Credit: ©Science China Press
Gut microbiota play a critical role not only in maintaining host health but also profoundly influence the development and progression of various diseases. In recent years, studies have shown that microbiota-derived metabolites (MDMs) serve as key mediators of communication between microbes and the host, regulating the host’s epigenetic status through multiple mechanisms, thereby directly influencing gene expression and cellular function. However, a unified theoretical framework capable of moving beyond correlation to explain the precise mechanisms of this complex dialogue has remained elusive. This review, published in Science Bulletin, provides a comprehensive and systematic summary of how MDMs modulate epigenetic modifications and extensively participate in both physiological homeostasis and disease pathogenesis. It proposes the conceptual framework of the MDME axis.
The regulatory mechanisms of the MDME axis encompass DNA methylation, histone modifications, RNA modifications, and chromatin remodeling. Microorganisms transform dietary or host-derived metabolites—including short-chain fatty acids (SCFAs), tryptophan and other amino acid degradation products, various vitamins, and polyphenols—to influence the host's epigenetics through diverse molecular mechanisms. SCFAs are among the most extensively studied metabolites. Produced by microbial fermentation of dietary fibers, they act as effective inhibitors of histone deacetylases, enhance histone acetylation levels, open chromatin structure, and promote gene transcription. These metabolites can also serve as acyl donors, directly participating in novel histone modifications such as crotonylation, butyrylation, and propionylation. Tryptophan-derived metabolites regulate the activity of histone-modifying enzymes and influence chromatin accessibility. Microbially synthesized B vitamins function as cofactors involved in one-carbon metabolism and the S-adenosylmethionine cycle, providing essential substrates for methylation. Secondary bile acids and polyphenol-derived bioactive compounds also participate in gene expression regulation by modulating epigenetic enzyme activity. These mechanisms not only act locally within the gut but also exert systemic effects via the bloodstream, reaching distant organs such as the liver and brain, forming a whole-body regulatory network. It is noteworthy that the MDME axis is not a unidirectional pathway but a highly dynamic bidirectional regulatory system. On one hand, microbial metabolites produced from dietary components or de novo synthesis are absorbed by the host and influence epigenetic states. On the other hand, the host’s epigenetic status can reciprocally shape the composition and functionality of microbial communities.
It is noteworthy that the regulatory effects of MDMs exhibit system-wide penetrance. Their actions are not confined to the intestinal milieu but can travel through the circulation to reach distal organs such as the liver and brain, thereby establishing a cross-organ epigenetic regulatory network that orchestrates host physiology at the whole-body level. At the same time, the host’s own epigenetic status can reciprocally shape microbial composition and functionality, forming a bidirectional “microbial metabolites-epigenetics-host” loop that underscores the complex and dynamic nature of host-microbiome symbiosis.
Within the framework of the MDME axis, this review takes an integrative, cross-organ and cross-process perspective to systematically explain how MDMs drive multisystem diseases through epigenetic regulation. In doing so, it highlights the MDME axis as a critical nexus linking gastrointestinal disorders, cancer, metabolic diseases, neurological conditions, and aging.
Despite significant progress, a major challenge in this field remains establishing causality rather than just identifying correlation.. Most current evidence is derived from model systems, lacking functional validation in humans. Future research requires multi-omics integration, single-cell epigenetics technologies, and spatial transcriptomics to decipher the cell-type specificity and tissue-context dependency of MDMs’ actions, and to further explore the regulation of novel epigenetic modifications. From a translational perspective, epigenetic therapies based on dietary interventions, probiotics/prebiotics, and metabolite supplementation offer novel strategies for treating cancer, metabolic disorders, neurodegenerative diseases, and other conditions. Interdisciplinary collaboration integrating microbiology, metabolomics, epigenetics, and immunology will advance the goal of precisely modulating the MDME axis to improve human health.
In summary, the MDME axis proposed in this review not only deepens our understanding of microbiota-host interaction mechanisms but also reshapes our perspective on the symbiotic underpinnings of multisystem diseases, providing a critical theoretical foundation for the development of microbiota-derived metabolite–based intervention strategies.
Journal
Science Bulletin