Clostridium perfringens Delta toxin targets CD9 to drive NEC and brain injury

, the microbial factors driving NEC and the following brain pathology remain unclear. Here we identify Clostridium perfringens pathobionts containing Delta toxin in the gut microbiome of individuals with severe and fatal NEC. Clinically, infected infants show worse outcomes, including aberrant systemic inflammation, severe neurological damage and coagulopathy. We establish a mouse model in which Delta-toxin-positive C. perfringens infection, or Delta toxin exposure alone, recapitulates clinical features of NEC, including intestinal necrosis and acute cerebral injury. Mechanistically, Delta toxin preferentially targets macrophages, potently activating inflammasome signalling and pyroptosis, triggering a rapid inflammatory cascade that compromises blood-brain barrier integrity and drives neuroinflammation. Through a genome-wide CRISPR screen, we identify the tetraspanin CD9 as the host receptor for Delta toxin. Using systemic, myeloid-specific and intestinal-epithelial-specific Cd9-knockout mice, we show that systemic and myeloid Cd9 ablation protects mice against toxin-induced lethality, blood-brain barrier dysfunction and multiorgan injury, whereas epithelial Cd9 deletion shows partial protection, implicating macrophage targeting as a primary driver of C. perfringens CD9-dependent pathogenesis. Furthermore, a neutralizing anti-Delta toxin monoclonal antibody confers protection against disease progression. These findings suggest that a subset of NEC is a specific-toxin-mediated disorder and validate the Delta toxin-CD9 axis as a therapeutic target for this subset.