Oral proton‐reprogrammed nanomedicine to break the inflammatory bowel disease‐ <i>Clostridium difficile</i> infection vicious cycle

Abstract Clostridium difficile infection (CDI) is a major complication of inflammatory bowel disease (IBD), but the complicated treatment strategy of antimicrobial drugs and immunosuppressive drugs cannot effectively control the syndrome of IBD and CDI. Glycolysis in intestinal epithelial cells (IECs) leads to excessive production of lactic acid, which is considered to be a key factor in the destruction of the intestinal barrier by toxin B of Clostridium difficile (TcdB). In this study, we revealed that uncoupling protein 2 (UCP2) was highly expressed in IECs, and disrupted mitochondrial function to reprogram metabolism toward glycolysis, thereby weakening the resistance of IECs to TcdB. We developed an oral proton‐reprogrammed nanomedicine (OPR) to convert the metabolism of IECs from glycolysis to oxidative phosphorylation, which can effectively alleviate IBD and CDI syndromes. OPR blocks the rapid delivery of protons to the mitochondrial matrix induced by UCP2, which restores mitochondrial membrane potential (MMP) and drives protons to reenter the matrix through ATP synthase, mediating the recovery of mitochondrial function. In mouse IBD and IBD complicated CDI (IBD‐CDI) models, OPR selectively targeted inflammatory colonic lesions, alleviated mitochondria‐dependent pyroptosis of IECs, inhibited macrophage STING pathway activation, and reduced lactic acid levels. Especially in the treatment of IBD‐CDI syndrome, the therapeutic effect of OPR is far better than the combination of antibiotics and immunosuppressive drugs. In summary, our study establishes UCP2‐mediated mitochondrial disability as a key mechanism for the functioning of TcdB and suggests that IEC metabolic reprogramming could be a therapeutic target.