Intestinal inflammation induced by heat-labile toxin-producing EnterotoxigenicE. Coliinfection and impact on immune responses in an experimental human challenge model

  1. Xueyan Zhang
  2. Jessica Brubaker
  3. Kawsar R. Talaat
  4. Chad K. Porter
  5. Brittany L Feijoo
  6. Brittany M Adjoodani
  7. Barbara DeNearing
  8. Michael G Prouty
  9. A Louis Bourgeois
  10. David A Sack
  11. Susanne Eder-Lingelbach
  12. Christian Taucher
  13. Subhra Chakraborty
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Abstract

EnterotoxigenicEscherichia coli(ETEC) causes significant morbidity, mortality, and growthth 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-only strains are understudied. In this study, we evaluated the intestinal inflammation induced by the LT-only 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 IL-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.

Author summary

EnterotoxigenicEscherichia coli(ETEC) is one of the leading causes of enteric infections, resulting in diarrhea, malnutrition, and other long-term health effects. However, how ETEC - particularly strains that produce only the heat-labile toxin (LT) - can contribute to gut inflammation is not fully understood. In this study, we examined the impact of an LT-ETEC infection on gut inflammation and its relations to ETEC-specific immune responses using samples from participants in a controlled human infection study. We found that LT-ETEC induces a significant level of gut inflammation marker myeloperoxidase (MPO) and pro-inflammatory cytokines IL-8 and IL-1β, when the patients had moderate to severe diarrhea and even when diarrheal symptoms were mild or absent. Gut inflammation level correlated with immune responses to ETEC. These findings suggest that LT-ETEC infection causes significant gut inflammation, which plays a role in immune responses. Our results highlight the need for preventive strategies to reduce the burden of ETEC-related illness, particularly in regions where these infections are common, to prevent broader adverse consequences for gut health and child development.

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