Interpersonal variation in microbiome structure modulates inter-individual immune responses to Vibrio cholerae

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.