MiR-146a Alleviates Inflammatory Bowel Disease in Mice Through Systematic Regulation of Multiple Genetic Networks

Introduction: Inflammatory bowel disease (IBD) is a chronic disease involving multiple genes, and the current available targeted drugs for IBD only deliver moderate efficacy. Whether there is a single gene that systematically regulates IBD is not yet known. plays a pivotal role in repression of innate immunity, but its function in the intestinal inflammation is sort of controversy, and the genetic regulatory networks regulated by miR-146a in IBD has not been revealed.

Methods: RT-qPCR was employed to detect the expression of in IBD patients and in a mouse IBD model induced by dextran sulfate sodium (DSS), and then we generated a knock-out mouse line with C57/Bl6N background. The disease activity index was scored in DSS-treated miR-146a deficiency mice and their wild type () littermates. Bulk RNA-sequencing, RT-qPCR and immunostaining were done to illustrate the downstream genetic regulatory networks of in flamed colon. Finally, the modified mimics were used to treat DSS-induced IBD in knock-out and IBD mice.

Results: We showed that the expression of in the colon was elevated in dextran sulfate sodium (DSS)-induced IBD mice and patients with IBD. DSS induced dramatic body weight loss and more significant rectal bleeding, shorter colon length, and colitis in knock-out mice than mice. The miR-146a mimics alleviated DSS-induced symptoms in both and mice. Further RNA sequencing illustrated that the deficiency of de-repressed majority of DSS-induced IBD-related genes that cover multiple genetic regulatory networks in IBD, and supplementation with mimics inhibited the expression of many IBD-related genes. Quantitative RT-PCR or immunostaining confirmed that , MMP3, MMP8, MMP10, IL1A, IL1B, IL6, CXCL2, CXCL3, S100A8, S100A9, TRAF6, P65, p-P65, and IRAK1 were regulated by miR-146a in DSS induced IBD. Among them, , and were involved in the active stage of IBD in humans.

Discussion: Our date demonstrated that miR-146a acts as a top regulator in C57/BL6N mice to systematically repress multiple genetic regulatory networks involved in immune response of intestine to environment factors, and combinatory treatment with and mimics attenuates DSS-induced IBD in mice through down-regulating multiple genetic regulatory networks which were increased in colon tissue from IBD patients. Our findings suggests that is a top inhibitor of IBD, and that and mimics might be potential drug for IBD.