Nurturing gut health: role of m6A RNA methylation in upholding the intestinal barrier

Abstract

The intestinal lumen acts as a critical interface connecting the external environment with the body's internal state. It's essential to prevent the passage of harmful antigens and bacteria while facilitating nutrient and water absorption. The intestinal barriers encompass microbial, mechanical, immunological, and chemical elements, working together to maintain intestinal balance. Numerous studies have associated m6A modification with intestinal homeostasis. This review comprehensively outlines potential mechanisms through which m6A modification could initiate, exacerbate, or sustain barrier damage from an intestinal perspective. The pivotal role of m6A modification in preserving intestinal equilibrium provides new insights, guiding the exploration of m6A modification as a target for optimizing preventive and therapeutic strategies for intestinal homeostasis.

Fig. 1. The molecular mechanisms of m6A modification.

m6A modification is a dynamic and reversible chemical modification. The methyltransferase complex, primarily composed of METTL3, METTL14, and WTAP, acts as the “Writers” responsible for catalyzing the formation of m6A. Demethylases, including FTO and ALKBH5, function as “Erasers” by catalyzing m6A demethylation. RNA-binding proteins, such as YTHDF1-3, YTHDC1-2, and IGF2BPs, serve as “Readers” that recognize and bind to m6A-modified mRNA transcripts. They play crucial roles in regulating RNA processing, stability, translation, and splicing in an m6A-dependent manner (Created with BioRender.com).

Fig. 2. The gut microbiota regulates m6A modification.

The gut microbiota plays a role in m6A modification levels by influencing SAM through the production of folate and cycloleucine, which participate in the folate and methionine cycles. SCFAs, secondary bile acids, and CPB2 mediate the m6A modification of CCNE1, ZNF333, GCNT2, and TLR2, leading to the regulation of intestinal epithelial cell proliferation, metaplasia, anti-infection mechanisms, and their ability to modulate inflammatory responses. LPS produced by the microbiota regulates the homeostasis of the intestinal barrier through an m6A-dependent manner, affecting macrophage production of inflammatory factors (Created with BioRender.com).

Fig. 3. The effect of m6A modification on the intestinal mechanical barrier.

m6A modification regulates intestinal epithelial integrity by affecting tight junction protein expression, and it influences intestinal epithelial cell survival by impacting apoptosis, autophagy, stem cell proliferation, as well as differentiation, eventually maintaining intestinal mechanical barrier homeostasis (Created with BioRender.com).

Fig. 4. The effect of m6A modification on the intestinal immune barrier.

Microbial and parasitic infections mediate the production of inflammatory factors and damage to intestinal epithelial cells through the m6A modification pathway. The m6A modification is essential for dendritic cell maturation, antigen presentation, and cell transfer processes. It also plays a significant role in macrophage polarization and innate immune responses. m6A modification also influences T cell proliferation, differentiation, and apoptosis to regulate adaptive immune responses (Created with BioRender.com).