N6-methyladenosine in inflammatory bowel disease: An emerging regulator of pathogenesis and a novel therapeutic frontier.

Inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic, immune-mediated intestinal disorder. Recent studies have identified N6-methyladenosine (m6A)—the most abundant internal mRNA modification in mammals—as a critical epitranscriptomic regulator in IBD pathogenesis. The m6A machinery comprises “writers” (methyltransferases such as METTL3, METTL14, and WTAP), “erasers” (demethylases FTO and ALKBH5), and “readers” (binding proteins including YTH domain family, IGF2BPs, and hnRNPs). These components dynamically control mRNA stability, splicing, nuclear export, and translation, thereby influencing cellular homeostasis, immune responses, and inflammation. The impact of m6A on IBD is primarily exerted through its regulation of the four components of the intestinal barrier: mechanical, chemical, immunological, and biological barriers.

·Intestinal Mechanical barrier: m6A influences epithelial integrity by modulating tight junction proteins, epithelial cell survival (e.g., apoptosis and ferroptosis), and the self-renewal and differentiation of intestinal stem cells. For example, METTL3 deficiency compromises tight junction expression and impairs stem cell function, while IGF2BP2 protects against ferroptosis by stabilizing GPX4 mRNA.

·Intestinal Chemical barrier: m6A affects the secretion of antimicrobial peptides (such as β-defensins) and the abundance of goblet cells, thereby maintaining the mucus layer and luminal defense.

·Intestinal Immunological barrier: This is the most extensively studied aspect. m6A regulates both innate and adaptive immune cells. In innate immunity, it modulates dendritic cell activation and macrophage polarization; in adaptive immunity, it primarily regulates T cell differentiation and function. For instance, METTL3-mediated m6A modification sustains Treg suppressive capacity via SOCS regulation, while YTHDF1 suppresses inflammatory signaling through TRAF6 translation inhibition. The regulatory mechanisms of m6A on other immune cells remain to be explored.

·Intestinal Biological barrier: The gut microbiota modulates the m6A machinery via metabolites, ROS/LPS pathways, and host immunity, whereas m6A in turn shapes the gut microbiota through direct actions, effects on other barriers, and regulation of host gene expression.

Beyond pathogenesis, m6A machinery shows promise as biomarkers for IBD diagnosis, therapeutic target, predictors of treatment response and adverse effects (e.g., thiopurine-induced leukopenia), and indicators of prognosis. Although most evidence remains preclinical, targeting the m6A pathway offers a novel therapeutic frontier for IBD.

In summary, m6A modification exerts multi-layered, cell-type-specific, and phase-dependent regulation of the intestinal mechanical, chemical, immunological, and biological barriers in IBD. Despite most evidence being preclinical, targeting the m6A pathway offers a promising avenue for precision diagnosis, individualized therapy, and prognosis prediction, warranting urgent translational efforts to benefit IBD patients.