{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T10:10:11Z","timestamp":1788948611240,"version":"build-2803163510"},"reference-count":270,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Vaccine responses differ substantially among individuals and across populations. Although factors such as age, genetics, and vaccine type are recognized contributors, they do not fully explain this heterogeneity. Emerging evidence suggests that the human microbiota, particularly the gut microbiota, may modulate immune responses to vaccination and represents a potentially modifiable component of immunity. This review integrates data from human studies, microbiota-targeted clinical trials, and experiments using germ-free and humanized models to clarify the mechanisms underlying microbiota\u2013immune system interactions during vaccination. Identified mechanisms include pattern-recognition receptor signaling, modulation of innate immune activation, regulation of germinal-center responses, maintenance of mucosal barrier integrity, and the influence of microbial metabolites on T and B lymphocytes. The relevance of these pathways varies by age, developmental stage, and vaccine platform, including live-attenuated, inactivated, subunit, viral-vector, and mRNA vaccines. Additional factors such as diet, antibiotic exposure, infections, medications, and environmental or social determinants also affect both the microbiota and vaccine outcomes. Current research explores approaches to improve vaccine potency through microbiota modulation using probiotics, prebiotics, synbiotics, postbiotics, and engineered microbes, though clinical results remain inconsistent. A greater understanding of microbiota\u2013vaccine interactions may enable personalized immunization strategies; however, further research is required to establish causality and identify actionable microbial targets. Longitudinal studies using multi-omics, advanced cellular analyses, robust clinical trials, and in silico modeling are essential to determine whether microbiome-based interventions can improve vaccine efficacy and durability.<\/jats:p>","DOI":"10.3390\/vaccines14090791","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T09:24:02Z","timestamp":1788945842000},"page":"791","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Insights into Microbiota\u2013Vaccine Crosstalk in Humans: Mechanisms, Modulators, and Translational Horizons"],"prefix":"10.3390","volume":"14","author":[{"given":"Ahmad R.","family":"Shakri","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7586-846X","authenticated-orcid":false,"given":"Sidharth P.","family":"Mishra","sequence":"additional","affiliation":[{"name":"USF Center for Microbiome Research, Microbiomes Institute, University of South Florida, Tampa, FL 33612, USA"},{"name":"Center for Excellence of Aging and Brain Repair, Department of Neurosurgery, Brain and Spine, University of South Florida, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarina","family":"Lawless","sequence":"additional","affiliation":[{"name":"USF Health, University of South Florida Morsani College of Medicine, Tampa, FL 33602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saswati","family":"Pani","sequence":"additional","affiliation":[{"name":"Immunology Laboratory, Fish Health Management Division, CIFA, Indian Council of Agricultural Research, Bhubaneswar 751002, Odisha, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priyanka","family":"Mishra","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, GITAM School of Sciences, GITAM University, Visakhapatnam 530045, Andhra Pradesh, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney L.","family":"Page","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4470-9612","authenticated-orcid":false,"given":"Gaurav","family":"Dutta","sequence":"additional","affiliation":[{"name":"Department of Animal Science, University of Connecticut, Storrs, CT 06269, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chanchal","family":"Sharma","sequence":"additional","affiliation":[{"name":"School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore 639798, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2549585","DOI":"10.1080\/19490976.2025.2549585","article-title":"The emerging role of the gut microbiota in vaccination responses","volume":"17","author":"Decker","year":"2025","journal-title":"Gut Microbes"},{"key":"ref_2","first-page":"168","article-title":"The Gut and the Translocated Microbiomes in HIV Infection: Current Concepts and Future Avenues","volume":"9","author":"Douek","year":"2024","journal-title":"Pathog. 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