Intestinal inflammation induced by heat-labile toxin-producing enterotoxigenic E: Coli infection and impact on immune responses in an experimental human challenge model

Enterotoxigenic Escherichia coli (ETEC) causes significant morbidity, mortality, and growth faltering among children, particularly in low- and middle-income countries. While gut inflammation contributes to growth faltering, the role of ETEC in inflammation remains poorly understood. We previously demonstrated that ETEC-producing heat-labile toxin (LT) and heat-stable toxins (ST) induced significant inflammation in humans, but LT-ETEC strains are understudied. In this study, we evaluated the intestinal inflammation induced by the LT-ETEC strain LSN03-016011/A in a human challenge model. Stool samples were analyzed for pre- and post-challenge myeloperoxidase (MPO) and pro and anti-inflammatory cytokines, ETEC shedding, and ETEC-specific antibody responses. MPO, IL-1β, and CXCL-8 levels significantly increased post-ETEC challenge, but there was no significant difference between symptomatic and asymptomatic participants. Participants protected from severe diarrhea had higher levels of pre-challenge IL-10, IL-13, and IFN-γ compared to those not protected. The MPO and specific cytokine levels were significantly correlated with the seroconversion status to LT and the colonization factor antigen CS17. This study provides evidence that LT-ETEC strain can induce significant intestinal inflammation even in the absence of symptoms, highlighting the need for a vaccine and a better understanding of the impact of ETEC-attributable inflammation on child health in endemic areas.