M6A Modification Mediates Mucosal Immune Microenvironment and Therapeutic Response in Inflammatory Bowel Disease.

Yongyu Chen,Song He,Jing Lei

doi:10.3389/fcell.2021.692160

Abstract

Accumulating evidence links m6A modification with immune infiltration. However, the correlation and mechanism by which m6A modification promotes intestinal immune infiltration in inflammatory bowel disease (IBD) is unknown. Here, genomic information from IBD tissues was integrated to evaluate disease-related m6A modification, and the correlation between the m6A modification pattern and the immune microenvironment in the intestinal mucosa was explored. Next, we identified hub genes from the key modules of the m6Acluster and analyzed the correlation among the hub genes, immune infiltration, and therapy. We found that IGF2BP1 and IGF2BP2 expression was decreased in Crohn’s disease (CD) tissues and that IGF2BP2 was decreased in ulcerative colitis (UC) tissues compared with normal tissues (P < 0.05). m6Acluster2, containing higher expressions of IL15, IL16, and IL18, was enriched in M0 macrophage, M1 macrophage, native B cells, memory B cells, and m6Acluster1 with high expression of IL8 and was enriched in resting dendritic and plasma cells (P < 0.05). Furthermore, we reveal that expression of m6A phenotype-related hub genes (i.e., NUP37, SNRPG, H2AFZ) was increased with a high abundance of M1 macrophages, M0 macrophages, and naive B cells in IBD (P < 0.01). Immune checkpoint expression in the genecluster1 with higher expression of hub genes was increased. The anti-TNF therapeutic response of patients in genecluster1 was more significant, and the therapeutic effect of CD was better than that of UC. These findings indicate that m6A modification may affect immune infiltration and therapeutic response in IBD. Assessing the expression of m6A phenotype-related hub genes might guide the choice of IBD drugs and improve the prediction of therapeutic response to anti-TNF therapy.

Highlights

Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic intestinal inflammatory disease (Torres et al, 2017; Ungaro et al, 2017)
To ascertain whether the above m6A regulators influenced the disease progression of inflammatory bowel disease (IBD), we evaluated the mRNA expression of m6A regulators in UC, CD, and normal tissues and found that expression of “readers” (i.e., IGF2BP1 and IGF2BP2) was dramatically decreased in CD tissues compared with normal tissues (P < 0.01) (Figure 1D)
We explored differences in the expression of 29 disease-related genes between normal, CD, and UC tissues and found that the expression of NUP37, SNRPG, H2AFZ, MAGOHB, NUP107, ALYREF, CDK2, F3, SNRPD1, SNRPF, and UBE2N was significantly upregulated in the IBD tissues compared with normal tissues (Figure 4E; P < 0.05) there was no significant difference in the other 18 genes (Figure 4E; P > 0.05)

Summary

Introduction

Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic intestinal inflammatory disease (Torres et al, 2017; Ungaro et al, 2017). The immune system is implicated as a major contributor to IBD progression, predominantly through an imbalance between the anti-inflammatory responses of regulatory T cells and M2 macrophages versus the pro-inflammatory responses of M1 macrophages, m6A Modification Mediates IBD Development. Current treatments are aimed at relieving inflammation through the use of steroids, biological agents (primarily anti-TNF), and immunosuppressive drugs (Torres et al, 2017; Ungaro et al, 2017). Approximately 30% of patients using antiTNF agents do not respond to treatment (Belarif et al, 2019). The potential mechanism of the progression of IBD needs to be elucidated

Methods

Results

Conclusion