Epithelial C150RF48/miR-147 is an essential regulator of gut inflammation and microbiome homeostasis

Abstract Aberrant inflammation plays an important role in the pathogenesis of several gastrointestinal diseases, including inflammatory bowel disease (IBD) and colorectal cancer (CRC). Insufficient understanding of the molecular mechanisms that control gut inflammation is one of the critical barriers to effective IBD and CRC therapies. To this end, we have uncovered C15ORF48/miR-147 as a novel negative regulator of gut inflammation. The C15ORF48/miR-147 gene encodes a small protein (C15ORF48) and a microRNA (miR-147-3p). Both molecular products are expressed predominantly in the large intestine, and their genetic ablation significantly exacerbates dextran sodium sulfate (DSS)-induced colitis in mice. The fulminant DSS-induced colitis phenotype in C15ORF48/miR-147−/− mice is driven by a cell-autonomous defect in gut epithelial cells and is mediated by gut dysbiosis. miR-147-3p and C15ORF48 synergize to silence the expression of NDUFA4, an accessory subunit of complex IV (CIV) in the mitochondrial electron transport chain. Our findings suggest that NDUFA4 plays an essential role in the activation of NF-kB signaling and the downstream inflammatory responses. Furthermore, C15ORF48, being an NDUFA4 structural paralog, can replace NDUFA4 in CIV and thus attenuate CIV activity and mitochondrial respiration, which may subsequently impact gut microbiome homeostasis. Collectively, our findings have established the C15ORF48/miR-147-NDUFA4 molecular axis as a novel, indispensable regulator of gut inflammation and a critical mediator between gut epithelial cells and microbiota.