<abstract> <p><italic>Vibrio cholerae</italic> is a non-invasive enteric pathogen known to cause a major public health problem called cholera. The pathogen inhabits the aquatic environment while outside the human host, it is transmitted into the host easily through ingesting contaminated food and water containing the vibrios, thus causing diarrhoea and vomiting. <italic>V. cholerae</italic> must resist several layers of colonization resistance mechanisms derived from the host or the gut commensals to successfully survive, grow, and colonize the distal intestinal epithelium, thus causing an infection. The colonization resistance mechanisms derived from the host are not specific to <italic>V. cholerae</italic> but to all invading pathogens. However, some of the gut commensal-derived colonization resistance may be more specific to the pathogen, making it more challenging to overcome. Consequently, the pathogen has evolved well-coordinated mechanisms that sense and utilize the anti-colonization factors to modulate events that promote its survival and colonization in the gut. This review is aimed at discussing how <italic>V. cholerae</italic> interacts and resists both host- and microbe-specific colonization resistance mechanisms to cause infection.</p> </abstract>

About one-third of the countries in the world are on the verge of a cholera outbreak placing over a billion individuals at risk. Water sanitation and health (WASH) programs together with vaccination are preventive measures to eradicate cholera by 2030. While WASH takes a long time to successfully implement, vaccinations can reduce the cholera burden. 2030 is in less than a decade and yet the current WHO prequalified oral cholera vaccines (OCVs) failed to provide sufficient protective immunity to infants – the most affected age group in cholera outbreaks and cholera endemic regions, a shorter immunity in older children and adults, the requirement of multiple doses, and cold-chain for transport and storage are some of the limitations of OCVs and WHO recommends further research to provide better vaccines. DNA vaccine approach could be a potential approach in the future of cholera vaccines, providing ease of vaccine design and hence reducing production time, it is safer and cheaper, stable at room temperature, and can induce both humoral and cellular immune responses. Therefore, this can be a better alternative to the over-dependence on the first and second generations of vaccines.