Vibrio cholerae is a human pathogen which colonizes small intestines of host, resulting in the onset of a severe diarrheal disease known as cholera. In order for V. cholerae to successfully colonize the host, it must not only express a series of virulence factors but also adapt their metabolism to intestinal niches during infection. However, how V. cholerae maneuver intestinal nutrients over gut microbiome to grow during colonization is far less clear. We and others have found that found that toxigenic V. cholerae strains ferment mannitol significantly slower than nontoxigenic strains. To understand the molecular mechanisms of this distinct between these isolates, we examined the expression patterns of genes related to mannitol utilization. We discovered that the expression of mannitol-specific phosphoenolpyruvate-dependent phosphotransferase systems (PTS) (mtl operon) in nontoxigenic strains was higher than in toxigenic strains. By analyzing promoter sequences of ~100 V. cholerae O1 El Tor strains isolated from different places globally at different time, we found that one SNP (single-nucleotide polymorphism) change that contributed to differential mtl operon expression. More interestingly, by swapping mtl promoter of toxigenic strains with that of nontoxigenic strains, the resulting mutants displayed significant reduction in colonization of a mouse model. These mutants also displayed increased levels of mannitol fermentation products such as formate and lactate. Based on our preliminary studies, we propose that a single SNP mutation in the mannitol PTS promoter of toxigenic V. cholerae strains slow down their mannitol fermentation rate, which results in preventing certain species of gut microbiota from utilization of fermentation products. This allow V. cholerae compete over gut microbiome during initial phase of infection and establish colonization. To test these hypotheses, we will infect mice with either wild type toxigenic strains or toxigenic strains with the mtl promoter ?corrected? (lacking the SNP). We will then do a comparative metagenomic analysis of the gut microbiome composition to determine any shifts upon infection with these two types of strains. Moreover, we have found that gut E. coli population was increased upon colonization of fast mannitol fermentation V. cholerae mutants. We will use genetic and genomic approaches to examine whether mannitol fermentation products promote the growth E. coli and possibly other gut microbiota by providing excessive electron donors and rendering colonization resistance against V. cholerae. We will investigate the relationship between V. cholerae mannitol fermentation and gut microbiome composition shifts during V. cholerae infection.

Public Health Relevance

Cholera is a devastating diarrheal illness currently taking lives in poverty-stricken countries around the world. This study proposed will shed light on importance of V. cholerae-gut microbiome interactions, with the goal of better understanding V. cholerae in vivo metabolisms and, potentially, discovering novel treatment options for the cholera disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Hall, Robert H
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University of Pennsylvania
Schools of Medicine
United States
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Wang, Jipeng; Xing, Xiaolin; Yang, Xiaoman et al. (2018) Gluconeogenic growth of Vibrio cholerae is important for competing with host gut microbiota. J Med Microbiol 67:1628-1637
Lembke, Mareike; Pennetzdorfer, Nina; Tutz, Sarah et al. (2018) Proteolysis of ToxR is controlled by cysteine-thiol redox state and bile salts in Vibrio cholerae. Mol Microbiol 110:796-810