PROJECT SUMMARY
Vibrio cholerae is a Gram-negative bacterium and the etiologic agent of cholera, a severe human diarrheal
disease characterized by voluminous watery diarrhea and vomiting and when left untreated, severe
dehydration, hypovolemic shock, and death. Several oral cholera vaccines (OCV) have been developed but
demonstrate variable efficacy in distinct geographical regions. Thus, defining the factors that modulate such
variation and developing strategies to minimize variability in prophylactic efficacy remains a significant global
health priority. One host-associated factor that has demonstrated differences in composition and functional
output between populations of high and low OCV efficacy is the commensal microbial community of the
gastrointestinal tract, the gut microbiota. Our central hypothesis is that interpersonal variation in the
microbial community of the gastrointestinal tract contributes to significant interpersonal variation in
OCV responses caused by microbe-specific modulation of the intestinal immune system. Our
preliminary data suggest that the gut microbiota may acts a personalized contributor to oral cholera vaccination
outcome, whereby (i) specific microbial taxa correlate with distinct immune responses to oral cholera
vaccination; (ii), inter-individual variation in microbiota structure and (iii) dysbiotic microbiotas, representative of
gut microbial communities found in cholera endemic areas, directly influence infection and vaccination
outcomes to V. cholerae; and (iv) modulation of host intestinal CD4+ T-cells regulate host immune responses
to V. cholerae challenge. Precision editing of the gut microbiota may represent an effective strategy to enhance
oral vaccine responsiveness, but such approaches will require a detailed understanding of the specific
microbe(s) involved and the particular mechanisms by which they enhance or inhibit human
immunophenotypes of interest, particularly in the context of oral vaccine responses. Our ultimate goal is to
identify specific microbial taxa that drive differential immune responses to V. cholerae, as such candidates may
better inform the development of gut microbiota-targeted prebiotic and probiotic strategies for cholerae
prophylaxis. We will address this problem with the following study aims: Aim 1 - Determine the effect of inter-
individual microbiota variation on OCV responsiveness; Aim 2 - Define immune cell populations that mediate
microbiota-driven effects on OCV responses.
