Attenuating ETEC virulence using a heat-labile enterotoxin–blocking binding protein

Bacterial enteric pathogens are major contributors to the global burden of diarrheal diseases and the associated consequences for human health including malnutrition, growth stunting, morbidity, and mortality. While mortality from diarrhea has decreased, incidence remains high, and better interventions for preventing disease are needed. Single-domain antibodies (i.e., V_HHs), functioning as target-binding proteins in the gastrointestinal tract, have been proposed as a potential approach to mitigate bacterial pathogenesis. Here, we describe a mitigation strategy where precision binding of a bivalent V_HH to the receptor-binding B-pentamer of heat-labile enterotoxin aggregates the AB₅ toxin and impairs enterotoxigenic <i>Escherichia coli</i> colonization in a flow chamber model simulating the human intestine. The V_HH construct also binds to the structurally similar cholera toxin and effectively abrogates its intestinal cell cytotoxicity in vitro. Based on these results, we believe that targeting virulence could emerge as a new strategy for the management of bacterial enteric pathogens, supporting gut health in at-risk populations alongside vaccination campaigns or in populations without access to vaccines.