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ETEC remains a major cause of diarrhea worldwide, particularly in vulnerable populations. Despite extensive research, no broadly protective licensed vaccines are available largely because of antigenic heterogeneity and the limited understanding of immune correlates of protection. We identified critical knowledge gaps in antigen prioritization and host\u2013pathogen interactions and translational limitations that have hindered vaccine success. We critically evaluated emerging platforms (including mRNA vaccines, nanoparticles, multiepitope strategies, and reverse vaccinology) for their potential to overcome variability and increase immunogenicity. We examined the roles of ecological environmental reservoirs associated with human and animal systems, in addition to antimicrobial pressure, in shaping ETEC evolution and vaccine effectiveness within a One Health framework; moreover, we propose an integrated approach that links genomic surveillance-based vaccine ecology and next-generation vaccine technologies to support adaptive immunogen design. This review provides actionable recommendations for the development of broadly protective and translationally viable ETEC vaccines from the One Health perspective.<\/jats:p>","DOI":"10.3390\/microorganisms14061171","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T13:12:08Z","timestamp":1779455528000},"page":"1171","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["One Health Perspective on the Enterotoxigenic Escherichia coli Diversity"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-0186-4024","authenticated-orcid":false,"given":"Ricardo","family":"Rodr\u00edguez-Mart\u00ednez","sequence":"first","affiliation":[{"name":"Departamento de Microbiolog\u00eda, Escuela Nacional de Ciencias Biol\u00f3gicas, Instituto Polit\u00e9cnico Nacional Carpio y Plan de Ayala, Col. Casco de Santo Tom\u00e1s, Mexico City 11340, Mexico"},{"name":"Laboratorio de Investigaci\u00f3n en Bacteriolog\u00eda Intestinal, Hospital Infantil de M\u00e9xico Federico G\u00f3mez, Mexico City 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jetsi","family":"Mancilla-Rojano","sequence":"additional","affiliation":[{"name":"Laboratorio de Investigaci\u00f3n en Inmunoqu\u00edmica, Hospital Infantil de M\u00e9xico Federico G\u00f3mez, Mexico City 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5299-759X","authenticated-orcid":false,"given":"Sara A.","family":"Ochoa","sequence":"additional","affiliation":[{"name":"Laboratorio de Investigaci\u00f3n en Bacteriolog\u00eda Intestinal, Hospital Infantil de M\u00e9xico Federico G\u00f3mez, Mexico City 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7496-8247","authenticated-orcid":false,"given":"Graciela","family":"Castro-Escarpulli","sequence":"additional","affiliation":[{"name":"Departamento de Microbiolog\u00eda, Escuela Nacional de Ciencias Biol\u00f3gicas, Instituto Polit\u00e9cnico Nacional Carpio y Plan de Ayala, Col. Casco de Santo Tom\u00e1s, Mexico City 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8018-1275","authenticated-orcid":false,"given":"Ariadnna","family":"Cruz-C\u00f3rdova","sequence":"additional","affiliation":[{"name":"Laboratorio de Investigaci\u00f3n en Inmunoqu\u00edmica, Hospital Infantil de M\u00e9xico Federico G\u00f3mez, Mexico City 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Xicohtencatl-Cortes","sequence":"additional","affiliation":[{"name":"Laboratorio de Investigaci\u00f3n en Bacteriolog\u00eda Intestinal, Hospital Infantil de M\u00e9xico Federico G\u00f3mez, Mexico City 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1016\/S1473-3099(18)30475-4","article-title":"Morbidity and mortality due to shigella and enterotoxigenic Escherichia coli diarrhoea: The Global Burden of Disease Study 1990\u20132016","volume":"18","author":"Khalil","year":"2018","journal-title":"Lancet Infect. 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