Shiga toxin-centered pathophysiology defines the therapeutic limits of enterohemorrhagic Escherichia coli infection.

EHEC infection is a toxin-driven systemic disease primarily mediated by the production of Shiga toxin (Stx). Stx is encoded by lysogenic bacteriophages, and SOS-linked prophage induction can increase toxin production in response to environmental or therapeutic stimuli. Once expressed, the toxin rapidly disseminates systemically and binds to cells expressing the globotriaosylceramide (Gb3) receptor. The toxin is then internalized via retrograde intracellular trafficking pathways, ultimately causing inhibition of protein synthesis. These characteristics impose a limited therapeutic window for effective intervention. As a consequence of this pathophysiological framework, current clinical management strategies for EHEC infection remain confined to supportive care. This includes fluid and electrolyte management and organ support, including dialysis and transfusion, in cases complicated by hemolytic uremic syndrome. Antimicrobial therapies that induce the SOS response are mismatched with EHEC pathophysiology and may worsen disease severity by triggering phage activation and toxin expression. The inability to use certain antibiotics in EHEC infection reflects the unique pathophysiological characteristics of the disease. This review considers EHEC infection as a systemic toxigenic disorder and examines Stx-centered pathophysiological constraints. Furthermore, it evaluates the limitations of current therapeutic strategies and examines experimental therapeutic approaches based on the unique pathophysiology of EHEC.