Loratadine as an Anti-inflammatory Agent Against Clostridium difficile Toxin B

Abstract Background Clostridium difficile infection (CDI) is a debilitating nosocomial infection. C. difficile produces toxins A and B, which cause inflammation. Existing therapies have issues with recurrence, cost, and safety. We aim to discover a safe, effective, and economical nonmicrobiological therapeutic approach against CDI. Methods We included human primary peripheral blood mononuclear cells (PBMCs), fresh human colonic explants, and humanized HuCD34-NCG mice. Toxin A+B+ VPI 10463 and A−B+ ribotype 017 C. difficile strains were used. We used single-cell RNA profiling and high-throughput screening to find actionable toxin B–dependent pathways in PBMCs. Results Histamine 1 receptor–related drugs were found among the hit compounds that reversed toxin-mediated macrophage inflammatory protein (MIP) 1α expression in PBMCs. We identified loratadine as the safest representative antihistamine for therapeutic development. Loratadine inhibited toxin B–induced MIP-1α secretion in fresh human colonic tissues. Oral loratadine (10 mg/kg/d) maintained survival, inhibited intestinal CCl3 messenger RNA expression, and prevented vancomycin-associated recurrence in the VPI 10463–infected mice and ribotype 017-infected hamsters. Splenocytes from loratadine-treated mice conferred anti-inflammatory effects to the VPI 10463–infected T/B-cell­–deficient Rag−/− mice. Oral loratadine suppressed human MIP-1α expression in monocytes/macrophages in toxin B–expressing ribotype 017-infected humanized HuCD34-NCG mice. Conclusions Loratadine may be repurposed to optimize existing therapies against CDI. Lay Summary Loratadine, a Food and Drug Administration–approved antihistamine, inhibits toxin B–mediated proinflammatory macrophage inflammatory protein 1α secretion from immune cells. Its anti-inflammatory effect ameliorates intestinal inflammation in Clostridium difficile–infected animals. Loratadine may be repurposed to optimize existing therapies. Graphical Abstract Graphical Abstract