miR147 promotes mucosal integrity and intestinal inflammation

miR147 plays a crucial role in promoting mucosal integrity and regulating intestinal inflammation. As a protective microRNA, miR147 is specifically enriched in intestinal epithelial cells (IECs), particularly in differentiated enterocytes at the luminal surface of the colon. Its expression is intrinsic to epithelial differentiation and not dependent on microbial exposure, as demonstrated in germ-free mice. During inflammation, miR147 expression is upregulated in response to cytokine-driven signals, as observed in dextran sodium sulfate (DSS)-induced colitis models and inflammatory conditioned media experiments.

Functionally, miR147 is vital for maintaining epithelial barrier integrity and promoting mucosal healing during inflammation. Global and epithelial-specific miR147 knockout mice exhibit severe colitis characterized by significant body weight loss, shortened colons, epithelial destruction, and increased intestinal permeability. Transcriptomic analysis revealed that miR147 suppresses proinflammatory and mitochondrial metabolism genes, particularly Ndufa4, a mitochondrial complex IV-associated gene. Ndufa4 was identified as a direct target of miR147, and its dysregulation in miR147-deficient tissues leads to disrupted metabolism and weakened barrier function. Mechanistic studies confirmed that the miR147–Ndufa4 axis is essential for epithelial homeostasis, as mice engineered to lack the miR147 binding site in Ndufa4 mirrored the severe inflammation seen in miR147 knockouts.

Furthermore, miR147 supports robust type I interferon signaling in colonocytes, enhancing antiviral and anti-inflammatory defense while sustaining metabolic balance. The study suggests that miR147 mimics or Ndufa4-targeted therapies could restore mucosal healing and reduce inflammation, highlighting miR147 as a potential therapeutic target for inflammatory bowel disease (IBD) and colorectal cancer.