The upper intestinal environment and mediators of human cholera severity

About This Grant

PROJECT SUMMARY/ABSTRACT Cholera outbreaks have become larger and more frequent due to humanitarian disasters, rising antimicrobial resistance, and expanding Vibrio cholerae environmental reservoirs in warming oceans. The development of new, non-antibiotic interventions to treat cholera and prevent symptomatic disease is hindered by a lack of knowledge about why some people exposed to V. cholerae have mild symptoms and others develop severe dehydrating disease. The intestinal microbiota is a modifiable host factor that is known to impact clinical outcomes in enteric infections, yet the role of host microbes in the severity of human cholera is unknown. Our prior work established that host microbes (measured in stool) predict susceptibility to cholera, and our downstream studies found that this model successfully identified a gut bacterium that modifies host colonization with V. cholerae. Here, we propose to use these tools and methods to determine how intestinal microbes impact the severity of cholera in humans. We approach this question by studying emesis, which is generated in the upper intestine during cholera, rather than studying the stool microbiota. We propose using emesis because V. cholerae is a small intestinal pathogen that colonizes and expresses cholera toxin in the upper intestine. The microbiota of the upper intestine differs from that measured in stool, because there is a higher oxygen tension and distinct microbial communities in the upper intestine compared to the rectum, where stool is formed. The goal of this study is to characterize the upper intestinal microbiota during human cholera and define the mechanisms by which host microbes impact the severity of cholera. By comparing the upper intestinal microbiota of people with mild to moderate cholera to those with severe disease, we will test how host microbiota impacts V. cholerae in the upper intestinal environment. The overall objective of this study is to understand how the upper intestinal microbiota impacts the severity of human cholera. Our central hypothesis is that upper intestinal host microbes modulate V. cholerae virulence factor expression. The rationale is that cholera emesis reflects the upper intestinal environment; therefore, emesis is more likely to contain gut microbes that interact with V. cholerae during active infection. We will test our hypothesis using two specific aims: 1) Define the cholera-specific upper intestinal microbiota, and 2) use emesis- derived bacterial isolates to define gut microbe-V. cholerae interactions. The proposed work is innovative because we will use emesis rather than stool to study the relevant host microbiota. This study is significant because we will gain foundational knowledge about clinically relevant host microbiota-enteric pathogen interactions. These results may impact human health by establishing a foundation for using commensal microbes as probiotics to reduce V. cholerae virulence, and ultimately to prevent symptomatic cholera or shorten the duration of disease.