Table_2_m6A Modification Mediates Mucosal Immune Microenvironment and Therapeutic Response in Inflammatory Bowel Disease.DOC

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.

越来越多的研究证据表明，m6A修饰（m6A modification）与免疫浸润密切相关。然而，在炎症性肠病（inflammatory bowel disease, IBD）中，m6A修饰促进肠道免疫浸润的具体关联与调控机制仍未明确。本研究整合IBD组织的基因组信息，以评估疾病相关的m6A修饰特征，并探讨肠黏膜内m6A修饰模式与免疫微环境之间的相关性。随后，我们从m6A聚类（m6Acluster）的关键模块中筛选得到枢纽基因（hub genes），并分析了枢纽基因、免疫浸润与治疗响应三者间的关联。研究发现，与正常组织相比，克罗恩病（Crohn’s disease, CD）组织中IGF2BP1与IGF2BP2的表达水平显著下调，而溃疡性结肠炎（ulcerative colitis, UC）组织中IGF2BP2的表达水平同样显著降低（P < 0.05）。m6A聚类2（m6Acluster2）高表达IL15、IL16及IL18，显著富集于M0巨噬细胞、M1巨噬细胞、初始B细胞及记忆B细胞中；而高表达IL8的m6A聚类1（m6Acluster1）则显著富集于静息树突状细胞与浆细胞（P < 0.05）。此外，本研究揭示，在IBD患者中，与m6A表型相关的枢纽基因（即NUP37、SNRPG、H2AFZ）的表达水平，与M1巨噬细胞、M0巨噬细胞及初始B细胞的丰度呈正相关上调趋势（P < 0.01）。在枢纽基因高表达的基因聚类1中，免疫检查点（immune checkpoint）的表达水平显著升高。该基因聚类1中的患者对抗TNF治疗（anti-TNF therapy）的响应更为显著，且克罗恩病患者的治疗效果优于溃疡性结肠炎患者。上述研究结果表明，m6A修饰可能通过调控免疫浸润参与IBD的发病过程，并影响患者的治疗响应。评估与m6A表型相关的枢纽基因的表达水平，或可指导IBD的临床用药选择，并提升对抗TNF治疗响应的预测精度。