Taxa of the nasal microbiome are associated with influenza-specific IgA response to live attenuated influenza vaccine
Open accessAbstract
Live attenuated influenza vaccine (LAIV) has demonstrated varying levels of efficacy against seasonal influenza; however, LAIV may be used as a tool to measure interactions between the human microbiome and a live, replicating virus. To increase our knowledge of this interaction, we measured changes to the nasal microbiome in subjects who received LAIV to determine if associations between influenza-specific IgA production and the nasal microbiome exist after immunization with a live virus vaccine. The anterior nares of 47 healthy subjects were swabbed pre- (Day 0) and post- (Days 7 and 28) LAIV administration, and nasal washes were conducted on Days 0 and 28. We performed next-generation sequencing on amplified 16s rRNA genes and measured mucosal influenza-specific IgA titers via enzyme-linked immunosorbent assay (ELISA). A significant increase in alpha diversity was identified (Observed, CHAO, and ACE) between Days 7 vs 0 (p-values = 0.017, 0.005, 0.005, respectively) and between Days 28 vs 0 (p-values = 0.054, 0.030, 0.050, respectively). Several significant associations between the presence of different microbial species, including Lactobacillus helveticus, Prevotella melaninogenica, Streptococcus infantis, Veillonella dispar, and Bacteroides ovatus, and influenza-specific H1 and H3 IgA antibody response were demonstrated. These data suggest that LAIV alters the nasal microbiome, allowing several less-abundant OTUs to establish a community niche. Additionally, specific alterations in the nasal microbiome are significantly associated with variations in influenza-specific IgA antibody production and could be clinically relevant.
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A longitudinal study of healthy subjects found a significant association between the presence of Lactobacillus helveticus, Prevotella melaninogenica, Streptococcus infantis, Veillonella dispar, and Bacteroides ovatus and influenza-specific H1 and H3 IgA antibody response.
“A longitudinal study of healthy subjects found a significant association between the presence of Lactobacillus helveticus, Prevotella melaninogenica, Streptococcus infantis, Veillonella dispar, and Bacteroides ovatus and influenza-specific H1 and H3 IgA antibody response (122).”
From Respiratory viral infection-induced microbiome alterations and secondary bacterial pneumonia. (2018) · cites this paper as [122]
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Cites
A Mathematical Theory of Communication
Shannon, C. E. (1948) · Bell System Technical Journal · doi:10.1002/j.1538-7305.1948.tb00917.x · Cited by 49,574 · see citing works
phyloseq: An R Package for Reproducible Interactive Analysis and Graphics of Microbiome Census Data
McMurdie, P. J., & Holmes, S. (2013) · PLoS ONE · doi:10.1371/journal.pone.0061217 · Cited by 21,013 · cited 1× · see citing works
“4 Statistical analysis Alpha diversity was calculated using four different measures using the “phyloseq” package in R [19].”
MethodRegularization Paths for Generalized Linear Models via Coordinate Descent
Friedman, J., Hastie, T., & Tibshirani, R. (2010) · Journal of Statistical Software · doi:10.18637/jss.v033.i01 · Cited by 19,927 · see citing works
Differential expression analysis for sequence count data
Anders, S., & Huber, W. (2010) · Genome Biology · doi:10.1186/gb-2010-11-10-r106 · Cited by 15,581 · see citing works
Richness of human gut microbiome correlates with metabolic markers
Le Chatelier, E., Nielsen, T., Qin, J., Prifti, E., Hildebrand, F., Falony, G., Almeida, M., Arumugam, M., Batto, J.-M., Kennedy, S., et al. (2013) · Nature · doi:10.1038/nature12506 · Cited by 4,662 · see citing works
Waste Not, Want Not: Why Rarefying Microbiome Data Is Inadmissible
McMurdie, P. J., & Holmes, S. (2014) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003531 · Cited by 2,894 · see citing works
Estimating the Population Size for Capture-Recapture Data with Unequal Catchability
Chao, A. (1987) · Biometrics · doi:10.2307/2531532 · Cited by 2,459 · cited 1× · see citing works
“The observed number of OTUs, Chao’s estimator, [20] and ACE estimator [21,22] provides estimates of species richness, while the Shannon diversity index accounts for both species evenness and richness [23].”
BackgroundDisordered Microbial Communities in Asthmatic Airways
Hilty, M., Burke, C. M., Pedro, H., Cárdenas, P., Bush, A., Bossley, C. J., Davies, J. C., Ervine, A., Poulter, L. W., Pachter, L. S., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0008578 · Cited by 1,825 · see citing works
Microbiota regulates immune defense against respiratory tract influenza A virus infection
Ichinohe, T., Pang, I. K., Kumamoto, Y., Peaper, D. R., Ho, J. H., Murray, T. S., & Iwasaki, A. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1019378108 · Cited by 1,502 · see citing works
Morris, E. K., Caruso, T., Buscot, F., Fischer, M., Hancock, C., Maier, T. S., Meiners, T., Müller, C., Obermaier, E., Prati, D., et al. (2014) · Ecology and Evolution · doi:10.1002/ece3.1155 · Cited by 1,179 · see citing works
Commensal bacteria calibrate the activation threshold of innate antiviral immunity
Abt, M. C., Osborne, L. C., Monticelli, L. A., Doering, T. A., Alenghat, T., Sonnenberg, G. F., Paley, M. A., Antenus, M., Williams, K. L., Erikson, J., et al. (2012) · Immunity · doi:10.1016/j.immuni.2012.04.011 · Cited by 993 · see citing works
The role of the gut microbiota in energy metabolism and metabolic disease
Cani, P., & Delzenne, N. (2009) · Current Pharmaceutical Design · doi:10.2174/138161209788168164 · Cited by 974 · see citing works
The immune system and the gut microbiota: friends or foes?
Cerf-Bensussan, N., & Gaboriau-Routhiau, V. (2010) · Nature Reviews Immunology · doi:10.1038/nri2850 · Cited by 704 · see citing works
Oh, J. Z., Ravindran, R., Chassaing, B., Carvalho, F. A., Maddur, M. S., Bower, M., Hakimpour, P., Gill, K. P., Nakaya, H. I., Yarovinsky, F., et al. (2014) · Immunity · doi:10.1016/j.immuni.2014.08.009 · Cited by 541 · cited 2× · see citing works
“Influenza-specific studies have shown that commensal bacteria influence the immune responses to both influenza infection [4] and vaccination [9,10,11].”
BackgroundIntestinal microbiota in health and disease: Role of bifidobacteria in gut homeostasis
Tojo, R. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i41.15163 · Cited by 533 · cited 1× · see citing works
“immunomodulatory roles in non-intestinal mucosal surfaces, such as the respiratory mucosa [4,5], and even systemically [5,6,7].”
BackgroundHall, J. A., Bouladoux, N. J., Sun, C., Wohlfert, E. A., Blank, R. B., Zhu, Q., Grigg, M. E., Berzofsky, J. A., & Belkaid, Y. (2008) · Immunity · doi:10.1016/j.immuni.2008.08.009 · Cited by 490 · see citing works
Regulation of lung immunity and host defense by the intestinal microbiota
Samuelson, D. R., Welsh, D. A., & Shellito, J. E. (2015) · Frontiers in Microbiology · doi:10.3389/fmicb.2015.01085 · Cited by 434 · see citing works
Southam, D. S., DOLOVICH, M. B., O’Byrne, P. M., & Inman, M. D. (2002) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00173.2001 · Cited by 349 · see citing works
Chiu, C., Wang, Y., Walther, B. A., & Chao, A. (2014) · Biometrics · doi:10.1111/biom.12200 · Cited by 288 · see citing works
Treanor, J. J., Kotloff, K. L., Betts, R. F., Belshe, R. B., Newman, F. K., Iacuzio, D. A., Wittes, J., & Bryant, M. L. (1999) · Vaccine · doi:10.1016/s0264-410x(99)00334-5 · Cited by 270 · see citing works
Dysbiosis of upper respiratory tract microbiota in elderly pneumonia patients
de Steenhuijsen Piters, W. A. A., Huijskens, E. G. W., Wyllie, A. L., Biesbroek, G., van den Bergh, M. R., Veenhoven, R. H., Wang, X., Trzciński, K., Bonten, M. J., Rossen, J. W. A., et al. (2016) · The ISME Journal · doi:10.1038/ismej.2015.99 · Cited by 235 · see citing works
Rizzardini, G., Eskesen, D., Calder, P. C., Capetti, A., Jespersen, L., & Clerici, M. (2012) · British Journal Of Nutrition · doi:10.1017/s000711451100420x · Cited by 217 · see citing works
Species richness estimators: how many species can dance on the head of a pin?
O’Hara, R. B. (2005) · Journal of Animal Ecology · doi:10.1111/j.1365-2656.2005.00940.x · Cited by 205 · cited 1× · see citing works
“The observed number of OTUs, Chao’s estimator, [20] and ACE estimator [21,22] provides estimates of species richness, while the Shannon diversity index accounts for both species evenness and richness [23].”
BackgroundComparative effects of six probiotic strains on immune functionin vitro
Dong, H., Rowland, I. R., & Yaqoob, P. (2011) · British Journal Of Nutrition · doi:10.1017/s0007114511005824 · Cited by 196 · see citing works
Two Lactobacillus strains, isolated from breast milk, differently modulate the immune response
Díaz-Ropero, M. P., Martı́n, R., Sierra, S., Lara‐Villoslada, F., Rodríguez, J. M., Xaus, J., & Olivares, M. M. (2006) · Journal of Applied Microbiology · doi:10.1111/j.1365-2672.2006.03102.x · Cited by 178 · see citing works
Davidson, L. E., Fiorino, A.-M., Snydman, D. R., & Hibberd, P. L. (2011) · European Journal of Clinical Nutrition · doi:10.1038/ejcn.2010.289 · Cited by 170 · see citing works
Seto, C. T., Jeraldo, P., Orenstein, R., Chia, N., & DiBaise, J. K. (2014) · Microbiome · doi:10.1186/2049-2618-2-42 · Cited by 163 · see citing works
Tomosada, Y., Chiba, E., Zelaya, H., Takahashi, T., Tsukida, K., Kitazawa, H., Alvarez, S., & Villena, J. (2013) · BMC Immunology · doi:10.1186/1471-2172-14-40 · Cited by 162 · see citing works
Yasui, H., Kiyoshima‐Shibata, J., & Hori, T. (2004) · Clinical and Vaccine Immunology · doi:10.1128/cdli.11.4.675-679.2004 · Cited by 157 · see citing works
Hori, T., Kiyoshima, J., Shida, K., & Yasui, H. (2002) · Clinical and Vaccine Immunology · doi:10.1128/cdli.9.1.105-108.2002 · Cited by 145 · cited 2× · see citing works
“Oral administration of the same bacterial strain in mice mitigated influenza virus infection by significantly lowering viral titers detected in nasal washings and significantly increasing survival rate after infection in two different studies [36,37].”
BackgroundResultThe intestinal epithelium as guardian of gut barrier integrity
Zhang, K., Hornef, M. W., & Dupont, A. (2015) · Cellular Microbiology · doi:10.1111/cmi.12501 · Cited by 138 · see citing works
Poland, G. A., Kennedy, R. B., McKinney, B. A., Ovsyannikova, I. G., Lambert, N. D., Jacobson, R. M., & Oberg, A. L. (2013) · Seminars in Immunology · doi:10.1016/j.smim.2013.04.007 · Cited by 121 · cited 1× · see citing works
“Further studies using systems biology approaches to understand the mechanisms that allow for increased species richness after vaccination, as well as the colonization of the particular bacterial species associated with increased influenzaspecific titers post-vaccination, could significantly advance the field of vaccin…”
BackgroundRepertoire of intensive care unit pneumonia microbiota
Bousbia, S., Papazian, L., Saux, P., Forel, J. M., Auffray, J.-P., Martin, C., Raoult, D., & La Scola, B. (2012) · PLoS ONE · doi:10.1371/journal.pone.0032486 · Cited by 118 · see citing works
Koeppel, A. F., & Wu, M. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt241 · Cited by 115 · cited 1× · see citing works
“Operational taxonomic units (OTUs)–sequence clusters defined based on DNA sequence similarity at a conserved locus [24]–were used to report sequencing data.”
Localized Mucosal Response to Intranasal Live Attenuated Influenza Vaccine in Adults
Barría, M. I., Garrido, J. L. V., Stein, C. R., Scher, E., Ge, Y., Engel, S. M., Kraus, T., Banach, D. B., & Moran, T. M. (2012) · The Journal of Infectious Diseases · doi:10.1093/infdis/jis641 · Cited by 114 · cited 2× · see citing works
“[15] Studies evaluating influenza H3-specific IgA titers could not be found.”
BackgroundPlanet, P. J., Parker, D., Cohen, T. S., Smith, H., Leon, J. D., Ryan, C., Hammer, T. J., Fierer, N., Chen, E. I., & Prince, A. S. (2016) · mBio · doi:10.1128/mbio.01939-15 · Cited by 113 · cited 2× · see citing works
“While the specific mechanisms leading to increased species richness following intra-nasal administration of LAIV– along with the mechanisms impacting immune response–require further investigation, it has been suggested that activation of the type-III interferon response after influenza infection has an effect on incre…”
BackgroundProbiotics and immunology: separating the wheat from the chaff
Shida, K., & Nanno, M. (2008) · Trends in Immunology · doi:10.1016/j.it.2008.07.011 · Cited by 109 · cited 1× · see citing works
“Discussion Studies have demonstrated the importance of commensal bacteria in immune responsiveness to influenza vaccination and infection in various ways, including the positive impact of probiotic supplements on the immune system [28,29,30,31].”
BackgroundPoland, G. A., Kennedy, R. B., & Ovsyannikova, I. G. (2011) · PLoS Pathogens · doi:10.1371/journal.ppat.1002344 · Cited by 109 · cited 1× · see citing works
“Further studies using systems biology approaches to understand the mechanisms that allow for increased species richness after vaccination, as well as the colonization of the particular bacterial species associated with increased influenzaspecific titers post-vaccination, could significantly advance the field of vaccin…”
BackgroundHow can probiotics and prebiotics impact mucosal immunity?
O'Flaherty, S., Saulnier, D., Pot, B., & Versalovic, J. (2010) · Gut Microbes · doi:10.4161/gmic.1.5.12924 · Cited by 103 · see citing works
IM-TORNADO: A Tool for Comparison of 16S Reads from Paired-End Libraries
Jeraldo, P., Kalari, K. R., Chen, X., Bhavsar, J., Mangalam, A. K., White, B. A., Nelson, H., Kocher, J.-P. A., & Chia, N. (2014) · PLoS ONE · doi:10.1371/journal.pone.0114804 · Cited by 99 · cited 1× · see citing works
“From this data, taxonomy was assigned and phylogenetic trees were constructed using the Illinois Mayo Taxon Organization from RNA Dataset Operations (IM-TORNADO) pipeline [18].”
MethodVaccinomics and a New Paradigm for the Development of Preventive Vaccines Against Viral Infections
Poland, G. A., Ovsyannikova, I. G., Kennedy, R. B., Haralambieva, I. H., & Jacobson, R. M. (2011) · OMICS A Journal of Integrative Biology · doi:10.1089/omi.2011.0032 · Cited by 95 · cited 1× · see citing works
“Further studies using systems biology approaches to understand the mechanisms that allow for increased species richness after vaccination, as well as the colonization of the particular bacterial species associated with increased influenzaspecific titers post-vaccination, could significantly advance the field of vaccin…”
BackgroundMina, M. J., McCullers, J. A., & Klugman, K. P. (2014) · mBio · doi:10.1128/mbio.01040-13 · Cited by 91 · cited 3× · see citing works
“This ratio was used as an exploratory quantitation of the localized mucosal response to vaccination with LAIV, and not considered a correlate of protection.”
BackgroundTarabichi, Y., Li, K., Hu, S., Nguyen, C., Wang, X., Elashoff, D., Saira, K., Frank, B., Bihan, M., Ghedin, E., et al. (2015) · Microbiome · doi:10.1186/s40168-015-0133-2 · Cited by 77 · see citing works
Profiling bacterial community in upper respiratory tracts
Yi, H., Yong, D., Lee, K., Cho, Y.-J., & Chun, J. (2014) · BMC Infectious Diseases · doi:10.1186/s12879-014-0583-3 · Cited by 75 · see citing works
Bek-Thomsen, M., Tettelin, H., Hance, I. R., Nelson, K. E., & Kilian, M. (2008) · Infection and Immunity · doi:10.1128/iai.01511-07 · Cited by 61 · cited 1× · see citing works
“infantis are quite limited and do not offer sufficient information to allow for further interpretation of our results [45]; however, the Streptococcus genus has been demonstrated to be in increased abundance in healthy individuals compared with those with respiratory infections [46].”
ResultAkatsu, H., Nagafuchi, S., Kurihara, R., Okuda, K., Kanesaka, T., Ogawa, N., Kanematsu, T., Takasugi, S., Yamaji, T., Takami, M., et al. (2015) · Geriatrics and gerontology international/Geriatrics & gerontology international · doi:10.1111/ggi.12454 · Cited by 49 · see citing works
Gut Microbiota: A Natural Adjuvant for Vaccination
Pabst, O., & Hornef, M. W. (2014) · Immunity · doi:10.1016/j.immuni.2014.09.002 · Cited by 41 · see citing works
Chowdhury, M. Y. E., Li, R., Kim, J.-H., Park, M.-E., Kim, T.-H., Pathinayake, P. S., Weeratunga, P., Song, M., Son, H., Hong, S.-P., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0094051 · Cited by 41 · see citing works
Vaccinomics, Predictive Vaccinology And The Future of Vaccine Development
Haralambieva, I. H., & Poland, G. A. (2010) · Future Microbiology · doi:10.2217/fmb.10.146 · Cited by 41 · see citing works
Probiotics and the immune response to vaccines
MacDonald, T. T., & Bell, I. (2010) · Proceedings of The Nutrition Society · doi:10.1017/s0029665110001758 · Cited by 41 · cited 1× · see citing works
“Other studies examining the effects of administration of various Lactobacillus strains on influenza H1- and H3-specific IgA antibody titers post-influenza vaccination show differences in levels of correlation between the probiotic strain of interest and the two influenza antibody titers [39,40].”
BackgroundAgeing, immunity and influenza: a role for probiotics?
Yaqoob, P. (2013) · Proceedings of The Nutrition Society · doi:10.1017/s0029665113003777 · Cited by 40 · see citing works
Li, R., Chowdhury, M. Y. E., Kim, J., Kim, T.-H., Pathinayake, P. S., Koo, W.-S., Park, M.-E., Yoon, J., Roh, J.-B., Hong, S.-P., et al. (2015) · Veterinary Microbiology · doi:10.1016/j.vetmic.2015.07.020 · Cited by 35 · see citing works
Minton, K. (2014) · Nature reviews. Immunology · doi:10.1038/nri3745 · Cited by 4 · see citing works
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Microbiota in health and diseases
Hou, K., Wu, Z.-X., Chen, X.-Y., Wang, J.-Q., Zhang, D., Xiao, C., Zhu, D., Koya, J. B., Wei, L., Li, J., et al. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-00974-4 · Cited by 3,171 · see citing works
“Salk et al. reported that the influenzaspecific lgA production is significantly associated with levels of Lactobacillus, Prevotella, Veillonella, Bacteroide, and Streptococcus.227 Interestingly, recent studies suggested that commensal microbes can play a crucial role in the development of pneumonia.”
BackgroundFactors That Influence the Immune Response to Vaccination
Zimmermann, P., & Curtis, N. C. (2019) · Clinical Microbiology Reviews · doi:10.1128/cmr.00084-18 · Cited by 940 · see citing works
Respiratory viral infection-induced microbiome alterations and secondary bacterial pneumonia.
Hanada, S., Pirzadeh, M., Carver, K. Y., & Deng, J. C. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02640 · Cited by 495 · see citing works
Lynn, D. J., Benson, S. C., Lynn, M. A., & Pulendran, B. (2021) · Nature reviews. Immunology · doi:10.1038/s41577-021-00554-7 · Cited by 300 · see citing works
Bifidobacterium Abundance in Early Infancy and Vaccine Response at 2 Years of Age
Huda, M. N., Ahmad, S. M., Alam, J., Khanam, A., Kalanetra, K. M., Taft, D. H., Raqib, R., Underwood, M. A., Mills, D. A., & Stephensen, C. B. (2019) · PEDIATRICS · doi:10.1542/peds.2018-1489 · Cited by 156 · see citing works
“In another study, the abundance of Bacteroides ovatus and Streptococcus geniculate in nasal microbiota were positively and negatively associated with IgA responses, respectively, to intranasal influenza vaccination.(51) We also report that the B breve was negatively associated with polio-specific plasma”
BackgroundEarly Life Microbiota and Respiratory Tract Infections
Piters, W. A. A. D. S., Binkowska, J. M., & Bogaert, D. (2020) · Cell Host & Microbe · doi:10.1016/j.chom.2020.07.004 · Cited by 148 · see citing works
Soffritti, I., D’Accolti, M., Fabbri, C., Passaro, A., Manfredini, R., Zuliani, G., Libanore, M., Franchi, M., Contini, C., & Caselli, E. (2021) · Frontiers in Microbiology · doi:10.3389/fmicb.2021.687513 · Cited by 163 · see citing works
AIM2 Inflammasome Is Critical for Influenza-Induced Lung Injury and Mortality
Zhang, H., Luo, J., Alcorn, J. F., Chen, K., Fan, S., Pilewski, J. M., Liu, A., Chen, W., Kolls, J. K., & Wang, J. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1600714 · Cited by 122 · see citing works
“Also, the different animal facility may affect the microbiome of the animals and result in different host innate and adaptive responses against influenza (55, 56).”
BackgroundThe respiratory microbiome and susceptibility to influenza virus infection
Lee, K. H., Gordon, A. L., Shedden, K., Kuan, G. M., Ng, S., Balmaseda, Á., & Foxman, B. (2019) · PLoS ONE · doi:10.1371/journal.pone.0207898 · Cited by 106 · see citing works
The microbiota in pneumonia: From protection to predisposition
Thibeault, C., Suttorp, N., & Opitz, B. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.aba0501 · Cited by 108 · see citing works
The Microbiome of the Nose—Friend or Foe?
Dimitri‐Pinheiro, S., Soares, R. A., & Barata, P. (2020) · Allergy & Rhinology · doi:10.1177/2152656720911605 · Cited by 101 · see citing works
“measured changes to the nasal microbiome in young adults who received intranasal administration of live attenuated influenza vaccine (LAIV) and found that LAIV altered the nasal microbiome, with increased taxa richness and variations in influenza-specific IgA antibody production.(42) Furthermore, molecular profiling s…”
BackgroundInfluentialComposition and immunological significance of the upper respiratory tract microbiota
Schenck, L. P., Surette, M. G., & Bowdish, D. M. E. (2016) · FEBS Letters · doi:10.1002/1873-3468.12455 · Cited by 105 · see citing works
Association Between the Respiratory Microbiome and Susceptibility to Influenza Virus Infection
Tsang, T. K., Lee, K. H., Foxman, B., Balmaseda, Á., Gresh, L., Sánchez, N., Ojeda, S., López, R., Yang, Y., Kuan, G., et al. (2019) · Clinical Infectious Diseases · doi:10.1093/cid/ciz968 · Cited by 109 · see citing works
“Among healthy young adults inoculated with live attenuated influenza vaccine, Streptococcus infantis was positively associated with influenza H1 immunoglobulin A (IgA) titers [27].”
BackgroundThe potential of the microbiota to influence vaccine responses
Lynn, D. J., & Pulendran, B. (2017) · Journal of Leukocyte Biology · doi:10.1189/jlb.5mr0617-216r · Cited by 97 · see citing works
“to the live attenuated influenza vaccine [65].”
The Lung Microbiome and Its Role in Pneumonia
Wu, B. G., & Segal, L. N. (2018) · Clinics in Chest Medicine · doi:10.1016/j.ccm.2018.07.003 · Cited by 90 · see citing works
Piters, W. A. A. D. S., Jochems, S. P., Mitsi, E., Rylance, J., Pojar, S., Nikolaou, E., German, E. L., Holloway, M., Carniel, B. F., Chu, M. L. J. N., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-10814-9 · Cited by 81 · see citing works
Do parasite infections interfere with immunisation? A review and meta-analysis
Wait, L. F., Dobson, A. P., & Graham, A. L. (2020) · Vaccine · doi:10.1016/j.vaccine.2020.06.064 · Cited by 69 · see citing works
How the gut microbiome regulates host immune responses to viral vaccines
Vlasova, A. N., Takanashi, S., Miyazaki, A., Rajashekara, G., & Saif, L. J. (2019) · Current Opinion in Virology · doi:10.1016/j.coviro.2019.05.001 · Cited by 67 · see citing works
“In addition, the nasal microbiota also contributes to immune responses to live influenza vaccine, by modifying antiviral IgA Ab production [30].”
BackgroundInfluence of Obesity on Pneumococcus Infection Risk in the Elderly
Frasca, D., & McElhaney, J. E. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00071 · Cited by 56 · see citing works
“It has been shown that efficacy of intranasal vaccination with a live attenuated influenza virus, measured by mucosal IgA secretion, depends on the specific bacterial composition of the nasal cavity, suggesting the importance of nasal microbiota for nasal immunity (84).”
BackgroundThe Microbiota/Host Immune System Interaction in the Nose to Protect from COVID-19
Stadio, A. D., Costantini, C., Renga, G., Pariano, M., Ricci, G., & Romani, L. R. (2020) · Life · doi:10.3390/life10120345 · Cited by 55 · see citing works
“Importantly, the nasal microbiome cannot only influence the susceptibility to infection, but may also affect the efficacy of a live attenuated influenza vaccine [43], thus modulating its therapeutic efficacy.”
BackgroundDing, T., Song, T., Zhou, B., Geber, A. B., Ma, Y., Zhang, L., Volk, M., Kapadia, S. N., Jenkins, S. G., Salvatore, M., et al. (2019) · mBio · doi:10.1128/mbio.01296-19 · Cited by 52 · see citing works
Maternal Immunization: Nature Meets Nurture
Saso, A., & Kampmann, B. (2020) · Frontiers in Microbiology · doi:10.3389/fmicb.2020.01499 · Cited by 53 · see citing works
Salzano, F. A., Marino, L., Salzano, G., Botta, R. M., Cascone, G., Fiorenza, U. D., Selleri, C., & Casolaro, V. (2018) · Journal of Immunology Research · doi:10.1155/2018/2724951 · Cited by 49 · see citing works
“In addition, recent work has identified significant associations between the development of influenza-specific nasal IgA responses and the presence of such microbial species in the nasal mucosa, as certain Lactobacillus and Bacteroides strains [75].”
BackgroundPneumococcal colonization impairs mucosal immune responses to live attenuated influenza vaccine
Carniel, B. F., Marcon, F., Rylance, J., German, E. L., Zaidi, S. R., Reiné, J., Negera, E., Nikolaou, E., Pojar, S., Solórzano, C., et al. (2021) · JCI Insight · doi:10.1172/jci.insight.141088 · Cited by 48 · see citing works
“Many underlying causes for this variation have been suggested, including poor matching with circulating strains (12, 16); differential ability of some LAIV types to induce immunity, in particular against H1N1 strains (15); and the microbial community composition at times of LAIV administration (17).”
BackgroundImpact of the Respiratory Microbiome on Host Responses to Respiratory Viral Infection
Pichon, M., Lina, B., & Josset, L. (2017) · Vaccines · doi:10.3390/vaccines5040040 · Cited by 42 · see citing works
Beirão, B. C. B., Ingberman, M., Fávaro, C., Mesa, D., Bittencourt, L. C., Fascina, V. B., & Caron, L. F. (2018) · Avian Pathology · doi:10.1080/03079457.2018.1450487 · Cited by 41 · see citing works
“This assay was performed as described previously (Dal Bérto et al., 2015; Salk et al., 2016).”
MethodTang, B., Tang, L., He, W., Jiang, X., Hu, C.-J., Li, Y., Zhang, Y., Pang, K., Lei, Y., Li, S., et al. (2022) · Cell Reports Medicine · doi:10.1016/j.xcrm.2022.100752 · Cited by 41 · see citing works
“dispar is dominant in the PD-L1 immunotherapy responder group(47) and is associated with influenza-specific H1 and H3 IgA antibody responses.(48) Although we used machine learning classifiers to investigate the potential utility of gutmicrobial in predicting the ACE2-RBD inhibiting antibody response, a lack of an inde…”
Murray, P. E., Coffman, J. A., & Garcı́a-Godoy, F. (2024) · Pathogens · doi:10.3390/pathogens13121084 · Cited by 44 · see citing works
“Additionally, specific levels of IgA production against pathogens like Lactobacillus , Prevotella , Veillonella , Bacteroides , and Streptococcus are linked to reduced pneumonia risk [147].”
From the Role of Microbiota in Gut‐Lung Axis to SARS‐CoV‐2 Pathogenesis
Badi, S. A., Tarashi, S., Fateh, A., Rohani, P., Masotti, A., & Siadat, S. D. (2021) · Mediators of Inflammation · doi:10.1155/2021/6611222 · Cited by 37 · see citing works
“demonstrated a significant association between the increased alpha diversity and the presence of Lactobacillus helveticus, Prevotella melaninogenica, Streptococcus infantis, Veillonella dispar, and Bacteroides ovatus in the nasal microbiota and specific IgGs after LAIV administration [83].”
Marsh, R. L., Aho, C., Beissbarth, J., Bialasiewicz, S., Binks, M., Cervin, A., Kirkham, L. S., Lemon, K. P., Slack, M., & Smith‐Vaughan, H. (2019) · International Journal of Pediatric Otorhinolaryngology · doi:10.1016/j.ijporl.2019.109836 · Cited by 37 · see citing works
“Other vaccines may also affect the NP microbiota [72,73].”
BackgroundIs the oral microbiome a source to enhance mucosal immunity against infectious diseases?
Zenobia, C., Herpoldt, K., & Freire, M. (2021) · npj Vaccines · doi:10.1038/s41541-021-00341-4 · Cited by 37 · see citing works
“This work was supported in part by The Conrad Prebys Foundation Grant (20-122), U.S. Public Health Service Grants (R00 DE0234804) from the National Institute of Dental and Cranial Research (given to MF).”
BackgroundLi, H., Wu, X., Zeng, H., Chang, B., Cui, Y. J., Zhang, J., Wang, R., & Ding, T. (2023) · Microbiome · doi:10.1186/s40168-023-01597-9 · Cited by 36 · see citing works
“infantis was positively associated with influenza H1 immunoglobulin A (IgA) titers [80].”
BackgroundThe Unexpected Impact of Vaccines on Secondary Bacterial Infections Following Influenza
Smith, A. M., & Huber, V. C. (2017) · Viral Immunology · doi:10.1089/vim.2017.0138 · Cited by 36 · see citing works
“Similarly, host responses from vaccination have the ability to directly alter the resident microbiota (175,205,241).”
BackgroundThe Upper Airway Microbiota, Environmental Exposures, Inflammation, and Disease
Elgamal, Z., Singh, P., & Geraghty, P. M. (2021) · Medicina · doi:10.3390/medicina57080823 · Cited by 39 · see citing works
“Intranasal live attenuated influenza vaccine significantly increased the nasal microbial taxa richness and increased the variation in influenza-specific IgA production [137].”
BackgroundDeterminants of the Nasal Microbiome: Pilot Study of Effects of Intranasal Medication Use
Ramakrishnan, V. R., Holt, J. W., Nelson, L. F., Ir, D., Robertson, C. E., & Frank, D. N. (2018) · Allergy & Rhinology · doi:10.1177/2152656718789519 · Cited by 32 · see citing works
Links between fecal microbiota and the response to vaccination against influenza A virus in pigs
Borey, M., Blanc, F., Lemonnier, G., Leplat, J. J. J. J., Jardet, D., Rossignol, M., Ravon, L., Billon, Y., Bernard, M., Estellé, J., et al. (2021) · npj Vaccines · doi:10.1038/s41541-021-00351-2 · Cited by 32 · see citing works
Gosens, R., Hiemstra, P. S., Adcock, I. M., Bracke, K. R., Dickson, R. P., Hansbro, P. M., Krauss‐Etschmann, S., Smits, H. H., Stassen, F. R. M., & Bartel, S. (2020) · European Respiratory Journal · doi:10.1183/13993003.02320-2019 · Cited by 26 · see citing works
Factors Limiting the Translatability of Rodent Model–Based Intranasal Vaccine Research to Humans
Cai, L., Xu, H., & Cui, Z. (2022) · AAPS PharmSciTech · doi:10.1208/s12249-022-02330-9 · Cited by 25 · see citing works
“ovatus were associated with increased IgA titers after LAIV administration in humans [118], suggesting that specific species of commensal bacteria can impact vaccine response.”
BackgroundRole of nutrition, infection, and the microbiota in the efficacy of oral vaccines
Bhattacharjee, A., & Hand, T. W. (2018) · Clinical Science · doi:10.1042/cs20171106 · Cited by 22 · see citing works
Munyaka, P. M., Kommadath, A., Fouhse, J. M., Wilkinson, J. M., Diether, N. E., Stothard, P., Estellé, J., Rogel-Gaillard, C., Plastow, G. S., & Willing, B. P. (2019) · Vaccine · doi:10.1016/j.vaccine.2019.02.016 · Cited by 20 · see citing works
Hernández‐Terán, A., Vega-Sánchez, Á. E., Mejía-Nepomuceno, F., Serna-Muñoz, R., Rodríguez‐Llamazares, S., Salido-Guadarrama, I., Romero-Espinoza, J. A., Guadarrama-Pérez, C., Sandoval-Gutiérrez, J. L., Campos, F., et al. (2023) · Virology Journal · doi:10.1186/s12985-023-01979-3 · Cited by 15 · see citing works
“Regarding the genus level, in the microbiota associated to deceased 357 patients we found Granulicatella and Staphylococcus to be enriched (Fig 2B-C), which 358 have been associated to severe forms of Influenza in both children and adults [25,41,42].”
BackgroundAutoimmunity: A New Focus on Nasal Polyps
Huang, J., & Xu, Y. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24098444 · Cited by 15 · see citing works
“Some studies show that mucosal influenza-specific IgA is significantly correlated with some bacteria, such as Streptococcus pneumoniae, Bifidobacterium animalis, and Lactobacillus casei, which have been studied as mucosal adjuvants for influenza vaccines in mice [40].”
BackgroundSARS-CoV-2 and Prevotella spp.: friend or foe? A systematic literature review
Tamanai‐Shacoori, Z., Gall‐David, S. L., Moussouni, F., Sweidan, A., Polard, É., Bousarghin, L., & Jolivet‐Gougeon, A. (2022) · Journal of Medical Microbiology · doi:10.1099/jmm.0.001520 · Cited by 15 · see citing works
Lung Microbiome in Critically Ill Patients
Fromentin, M., Ricard, J.-D., & Roux, D. (2021) · Life · doi:10.3390/life12010007 · Cited by 14 · see citing works
“In contrast, Prevotella melaninogenica in the nasal microbiome reduced the risk of influenza pneumonia due to an increased influenzae-specific IgA antibodies [57].”
BackgroundFerrari, L., Favero, C., Solazzo, G., Mariani, J., Luganini, A., Ferraroni, M., Montomoli, E., Milani, G. P., & Bollati, V. (2022) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2022.882302 · Cited by 13 · see citing works
“Moreover, the BNM composition was demonstrated to influence the efficacy of a live attenuated influenza vaccine, impacting the host’s adaptive immune response and thus modulating the vaccine’s therapeutic efficacy (Salk et al., 2016).”
BackgroundMunyaka, P. M., Blanc, F., Estellé, J., Lemonnier, G., Leplat, J. J. J. J., Rossignol, M., Jardet, D., Plastow, G. S., Billon, Y., Willing, B. P., et al. (2020) · Microorganisms · doi:10.3390/microorganisms8081151 · Cited by 14 · see citing works
“IgA titers post-vaccination [39], function in vivo as an immunological adjuvant [50], improve glucose metabolism [51,52], or exhibit overall anti-inflammatory effects [53,54].”
BackgroundReens, A. L., Cabral, D. J., Liang, X., Norton, J. E., Therien, A. G., Hazuda, D. J., & Swaminathan, G. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.643255 · Cited by 13 · see citing works
Jiang, D.-T., Goswami, R., Dennis, M., Heimsath, H. J., Kozlowski, P., Ardeshir, A., Rompay, K. V. V., Paris, K. D., Permar, S., & Surana, N. K. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1283343 · Cited by 13 · see citing works
Personalizing the Management of Pneumonia
Gautam, S., Sharma, L., & Cruz, C. S. D. (2018) · Clinics in Chest Medicine · doi:10.1016/j.ccm.2018.08.008 · Cited by 10 · see citing works
Bonato, M. A., Borges, L. L., Ingberman, M., Fávaro, C., Mesa, D., Caron, L. F., & Beirão, B. C. B. (2020) · The Journal of Applied Poultry Research · doi:10.1016/j.japr.2020.03.002 · Cited by 9 · see citing works
A user’s guide to designing efficient and safe mucosal vaccines: Challenges & potentials
Sinha, D., Gopalakrishna, P. K., Paul, S., & Longet, S. (2025) · Oxford Open Immunology · doi:10.1093/oxfimm/iqaf007 · Cited by 8 · see citing works
Effects of 10-valent pneumococcal conjugate (PCV10) vaccination on the nasopharyngeal microbiome
Salgado, V. R., Fukutani, K. F., Fukutani, E. R., Lima, J. V., Rossi, E. A., Barral, A. M. P., de Oliveira, C. I., Nascimento-Carvalho, C. M., Weyenbergh, J. V., & Queiroz, A. T. L. (2019) · Vaccine · doi:10.1016/j.vaccine.2019.11.079 · Cited by 8 · see citing works
Effects of aroA deleted E. coli vaccine on intestinal microbiota and mucosal immunity
Beirão, B. C. B., Ingberman, M., Mesa, D., Salles, G. B. C., Muniz, E. C., & Caron, L. F. (2021) · Comparative Immunology Microbiology and Infectious Diseases · doi:10.1016/j.cimid.2021.101612 · Cited by 7 · see citing works
The Effect of Bifidobacterium animalis subsp. lactis Bl-04 on Influenza A Virus Infection in Mice
Zabel, B., Mäkelä, S. M., Nedveck, D. A., Hibberd, A. A., Yeung, N., Latvala, S., Lehtoranta, L., Junnila, J. J. T., Walters, K., Morovic, W., et al. (2023) · Microorganisms · doi:10.3390/microorganisms11102582 · Cited by 7 · see citing works
A Review on the Nasal Microbiome and Various Disease Conditions for Newer Approaches to Treatments
Sarkar, S., Routhray, S., Ramadass, B., & Parida, P. K. (2022) · Indian Journal of Otolaryngology and Head & Neck Surgery · doi:10.1007/s12070-022-03205-y · Cited by 6 · see citing works
Potential Biotics for Nutritional Improvement of Health via Microbiome-Gut-Brain Axis
Niazi, M. K., & Hassan, F. (2022) · Advanced Gut & Microbiome Research · doi:10.1155/2022/9976555 · Cited by 7 · see citing works
“Pneumonia was specifically substantially related with three microbiota profiles dominated by Lactobacilli, Rothia, and Streptococcus [103].”
BackgroundInfluentialClose Encounters of the Viral Kind: Cross‐Kingdom Synergies at the Host–Pathogen Interface
Rowe, H. M., & Rosch, J. W. (2019) · BioEssays · doi:10.1002/bies.201900128 · Cited by 5 · see citing works
Haile, A. F., Woodfint, R. M., Kim, E., Joldrichsen, M. R., Berhe, N., Gebreyes, W. A., & Boyaka, P. N. (2021) · Vaccines · doi:10.3390/vaccines9111240 · Cited by 5 · see citing works
“Furthermore, members of the nasal [23] and gut microbiota [24] were reported to influence the generation of vaccine-specific IgA responses after immunization with a live attenuated influenza vaccine or the polio vaccine, respectively.”
BackgroundInfluence of Commensal Microbiota and Metabolite for Mucosal Immunity
Pope, J. L., Tomkovich, S., & Jobin, C. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-811924-2.00009-2 · Cited by 2 · see citing works
Liang, X., Zhao, C., Chen, C., Zhang, X., Li, L., & Lu, F. (2026) · Microbiology Spectrum · doi:10.1128/spectrum.01272-25 · Cited by 1 · see citing works
“Bacteroides ovatus has shown significant correlations with IgA antibody responses to H1N1 and H3N2 influenza viruses in both univariate and multivariate analyses, likely due to the complementary immune response mechanisms between probiotic strains and proteins (36).”
Hu, C., Yao, S.-F., Li, Y., Wang, Q.-Z., Li, Y., Sun, C., Liu, J., & Zhao, Z. (2025) · Microorganisms · doi:10.3390/microorganisms13092099 · Cited by 1 · see citing works
“Notably, a negative correlation has been observed between influenza-specific H1 IgA titers and Veillonella [42].”
Pharmacomicrobiomics of mRNA vaccines: gut microbiota-driven modulation of vaccine pharmacodynamics
Mehmood, M. S., Ahmed, E., Ahmed, A., Nisa, N. U., Taj, J., Bibi, B., Azam, A., & Nazari, M. J. (2026) · Discover Immunity · doi:10.1007/s44368-026-00033-y · Cited by 1 · see citing works
“…to influenza vaccine was observed in an antibiotic-treated mouse model; it was later enhanced by oral restoration of flagellated Escherichia coli , which prompted enhanced production of cytokines IL-10, IL-6, IL-1beta, TNF-alpha, and MIP-1alpha specific to the seasonal influenza strain [79].”
InfluentialVacinas contra a infecção pelo SARS-CoV-2
Silva, T. C., de Andrade, A. B. M. D. G., Barral-Neto, M., & Boaventura, V. S. (2020) · EDUFBA eBooks · doi:10.9771/9786556300443.009 · Cited by 1 · see citing works
Nasal microbiota exhibit neither reproducible nor orderly dynamics following rhinoviral infectionPreprint
Nimmagadda, S. N., Midani, F. S., Durand, H. K., Reese, A. T., Murdoch, C. C., Nicholson, B. P., Veldman, T., Burke, T. W., Zaas, A. K., Woods, C. W., et al. (2020) · medRxiv · doi:10.1101/2020.04.11.20061911 · Cited by 1 · see citing works
“In the context of viral ARIs, prior work has associated these infections with URT alterations [11-17], and HRV infections specifically have been linked to increases in select genera during infection and a decrease in community diversity [22, 23].”
BackgroundThe microbiota and infectious diseases
Surana, N. K. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-801496-7.00023-x
Elimination and irrigation therapy to optimize the state of the nasal microbiome in children
Chelpachenko, O. E., Danilova, E. I., & In, C. (2021) · Meditsinskiy sovet = Medical Council · doi:10.21518/2079-701x-2021-1-50-58
Hall, L. J. (2020) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.734916344.793574642
Characterization of the Human Microbiome in Health and Disease
Tan, C. Y., & Surana, N. K. (2025) · Wiley eBooks · doi:10.1002/9781683674597.ch7
Hernández‐Terán, A., Vega-Sánchez, Á. E., Mejía-Nepomuceno, F., Serna-Muñoz, R., Rodríguez‐Llamazares, S., Salido-Guadarrama, I., Romero-Espinoza, J. A., Guadarrama-Pérez, C., Sandoval-Gutierrez, J. L., Campos, F., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26565519
Li, H., Wu, X., Zeng, H., Chang, B., Cui, Y., Zhang, J., Wang, R., & Ding, T. (2024) · Figshare · doi:10.6084/m9.figshare.26606047
Li, H., Wu, X., Zeng, H., Chang, B., Cui, Y., Zhang, J., Wang, R., & Ding, T. (2024) · Figshare · doi:10.6084/m9.figshare.26606050
Jung, S.-M., Sunwoo, W., & Son, Y. M. (2026) · Immune Network · doi:10.4110/in.2026.26.e23
“Furthermore, in a longitudinal intranasal live-attenuated influenza vaccine study, anterior nares swabs from healthy individuals collected before and after vaccination showed a significant increase in nasal microbial richness (47).”
Alanazi, A. (2026) · Journal of Clinical Laboratory Analysis · doi:10.1002/jcla.70307
Shakri, A. R., Mishra, S. P., Lawless, S., Pani, S., Mishra, P., Page, C. L., Dutta, G., & Sharma, C. (2026) · Vaccines · doi:10.3390/vaccines14090791
“In adults, baseline microbiota diversity and the presence of taxa that produce short-chain fatty acids (for example, Faecalibacterium prausnitzii and Roseburia spp.) correlate with stronger plasmablast responses to seasonal influenza vaccines [129,130].”
- Authors
- Salk, H. M., Simon, W. L., Lambert, N. D., Kennedy, R. B., Grill, D. E., Kabat, B. F., & Poland, G. A.
- Affiliations
- Mayo Clinic (US)
- Corresponding author
- Poland, Gregory A.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2016-09-19
- Volume
- 11
- Issue
- 9
- Pages
- e0162803
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC5028048
- OpenAlex
- W2522730506
- Cited by
- 75
- References
- 53
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 4 · 2023: 5 · 2022: 7 · 2021: 13 · 2020: 11 · 2019: 14 · 2018: 8 · 2017: 4 · 2016: 1
- FWCI
- 8.43
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Mayo Clinic
- Topics
- Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
- Keywords
- live attenuated influenza vaccine, nasal microbiota, mucosal antibody response, alpha diversity, Lactobacillus helveticus, Prevotella melaninogenica, Streptococcus infantis, Veillonella dispar, Bacteroides ovatus, seasonal influenza, 16S rRNA gene sequencing
- MeSH terms
- Adolescent, Adult, Antibodies, Viral, Bacteria, Female, Humans, Immunoglobulin A, Influenza, Human, Influenza Vaccines, Male, Nasal Cavity, Influenza A virus, Vaccines, Attenuated, Hemagglutinin Glycoproteins, Influenza Virus, Young Adult, Microbiota
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