Inflammation and Disintegration of Intestinal Villi in an Experimental Model for Vibrio parahaemolyticus-Induced Diarrhea

Abstract

Vibrio parahaemolyticus is a leading cause of seafood-borne gastroenteritis in many parts of the world, but there is limited knowledge of the pathogenesis of V. parahaemolyticus-induced diarrhea. The absence of an oral infection-based small animal model to study V. parahaemolyticus intestinal colonization and disease has constrained analyses of the course of infection and the factors that mediate it. Here, we demonstrate that infant rabbits oro-gastrically inoculated with V. parahaemolyticus develop severe diarrhea and enteritis, the main clinical and pathologic manifestations of disease in infected individuals. The pathogen principally colonizes the distal small intestine, and this colonization is dependent upon type III secretion system 2. The distal small intestine is also the major site of V. parahaemolyticus-induced tissue damage, reduced epithelial barrier function, and inflammation, suggesting that disease in this region of the gastrointestinal tract accounts for most of the diarrhea that accompanies V. parahaemolyticus infection. Infection appears to proceed through a characteristic sequence of steps that includes remarkable elongation of microvilli and the formation of V. parahaemolyticus-filled cavities within the epithelial surface, and culminates in villus disruption. Both depletion of epithelial cell cytoplasm and epithelial cell extrusion contribute to formation of the cavities in the epithelial surface. V. parahaemolyticus also induces proliferation of epithelial cells and recruitment of inflammatory cells, both of which occur before wide-spread damage to the epithelium is evident. Collectively, our findings suggest that V. parahaemolyticus damages the host intestine and elicits disease via previously undescribed processes and mechanisms.

Author Summary

The marine bacterium Vibrio parahaemolyticus is a leading cause worldwide of gastroenteritis linked to the consumption of contaminated seafood. Despite the prevalence of V. parahaemolyticus-induced gastroenteritis, there is limited understanding of how this pathogen causes disease in the intestine. In part, the paucity of knowledge results from the absence of an oral infection-based animal model of the human disease. We developed a simple oral infection-based infant rabbit model of V. parahaemolyticus-induced intestinal pathology and diarrhea. This experimental model enabled us to define several previously unknown but key features of the pathology elicited by this organism. We found that V. parahaemolyticus chiefly colonizes the distal small intestine and that the organism's second type III secretion system is essential for colonization. The epithelial surface of the distal small intestine is also the major site of V. parahaemolyticus-induced damage, which arises via a characteristic sequence of events culminating in the formation of V. parahaemolyticus-filled cavities in the epithelial surface. This experimental model will transform future studies aimed at deciphering the bacterial and host factors/processes that contribute to disease, as well as enable testing of new therapeutics to prevent and/or combat infection.