Consecutive oral administration of Bifidobacterium longum MM‐2 improves the defense system against influenza virus infection by enhancing natural killer cell activity in a murine model
Abstract
Bifidobacterium, one of the major components of intestinal microflora, shows anti‐influenza virus (IFV) potential as a probiotic, partly through enhancement of innate immunity by modulation of the intestinal immune system. Bifidobacterium longum MM‐2 (MM‐2), a very safe bacterium in humans, was isolated from healthy humans and its protective effect against IFV infection in a murine model shown. In mice that were intranasally inoculated with IFV, oral administration of MM‐2 for 17 consecutive days improved clinical symptoms, reduced mortality, suppressed inflammation in the lower respiratory tract, and decreased virus titers, cell death, and pro‐inflammatory cytokines such as IL‐6 and TNF‐α in bronchoalveolar lavage fluid. The anti‐IFV mechanism of MM‐2 involves innate immunity through significant increases in NK cell activities in the lungs and spleen and a significant increase in pulmonary gene expression of NK cell activators such as IFN‐γ, IL‐2, IL‐12 and IL‐18. Even in non‐infected mice, MM‐2 administration also induced significant enhancement of both IFN‐γ production by Peyer's patch cells (PPs) and splenetic NK cell activity. Oral administration of MM‐2 for 17 days activates systemic immunoreactivity in PPs, which contributes to innate immunity, including NK cell activation, resulting in an anti‐IFV effect. MM‐2 as a probiotic may function as a prophylactic agent in the management of an IFV epidemic.
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Even in non-infected mice, probiotic administration induced significant enhancement in both IFN-γ production and splenetic NK cell activity.
“Even in non-infected mice, probiotic administration also induced significant enhancement in both IFN-γ production and splenetic NK cell activity [12].”
From Gut microbiota-mediated immunomodulation in tumor (2021) · cites this paper as [12]
Oral administration with Bifidobacterium longum can exert an anti-influenza virus effect in mice through inducing an increase in NK cell activities and gene expression of IFN-γ, IL-2, IL-12 and IL-18 in the lungs.
“Kawahara et al. showed that oral administration with Bifidobacterium longum can exert anti-influenza virus effect in mice through inducing an increase in NK cell activities and gene expression of IFN-γ, IL-2, IL-12 and IL-18 in the lungs [12].”
From Gut microbiota-mediated immunomodulation in tumor (2021) · cites this paper as [12]
Cites
Mortality Associated With Influenza and Respiratory Syncytial Virus in the United States
Thompson, W. W., Shay, D. K., Weintraub, E., Brammer, L., Cox, N., Anderson, L. J., & Fukuda, K. (2003) · JAMA · doi:10.1001/jama.289.2.179 · Cited by 3,673 · see citing works
Bifidobacteria can protect from enteropathogenic infection through production of acetate
Fukuda, S., Toh, H., Hase, K., Oshima, K., Nakanishi, Y., Yoshimura, K., Tobe, T., Clarke, J. M., Topping, D. L., Suzuki, T., et al. (2011) · Nature · doi:10.1038/nature09646 · Cited by 2,387 · see citing works
Self-citationRespiratory Viral Infections in Infants: Causes, Clinical Symptoms, Virology, and Immunology
Tregoning, J. S., & Schwarze, J. (2010) · Clinical Microbiology Reviews · doi:10.1128/cmr.00032-09 · Cited by 746 · see citing works
Hayden, F. G., Fritz, R., Lobo, M. C., Alvord, W. G., Strober, W., & Straus, S. E. (1998) · Journal of Clinical Investigation · doi:10.1172/jci1355 · Cited by 680 · see citing works
The role of nasopharyngeal lymphoid tissue
Kuper, C. F., Koornstra, P. J., Hameleers, D. M. H., Biewenga, J., Spit, B. J., Duijvestijn, A. M., Vriesman, P. J. C. V. B., & Sminia, T. (1992) · Immunology Today · doi:10.1016/0167-5699(92)90158-4 · Cited by 537 · see citing works
New low-viscosity overlay medium for viral plaque assays.
Matrosovich, M. N., Matrosovich, T. Y., Garten, W., & Klenk, H. D. (2006) · Virology Journal · doi:10.1186/1743-422x-3-63 · Cited by 476 · see citing works
<i><i>Bifidobacterium infantis</i></i>35624 modulates host inflammatory processes beyond the gut
Groeger, D., O’Mahony, L., Murphy, E. F., Bourke, J. F., Dinan, T. G., Kiely, B., Shanahan, F., & Quigley, E. M. M. (2013) · Gut Microbes · doi:10.4161/gmic.25487 · Cited by 448 · cited 1× · see citing works
“Bifidobacterium is one of the major components of the intestinal microflora and modulates the intestinal immune system (16).”
BackgroundOrange, J. S., & Biron, C. A. (1996) · The Journal of Immunology · doi:10.4049/jimmunol.156.3.1138 · Cited by 381 · see citing works
Altered cytokine production in the elderly
Rink, L., Cakman, I., & Kirchner, H. (1998) · Mechanisms of Ageing and Development · doi:10.1016/s0047-6374(97)00153-x · Cited by 378 · see citing works
Zhang, Y., Wallace, D. L., De Lara, C. M., Ghattas, H., Asquith, B., Worth, A., Griffin, G. E., Taylor, G. P., Tough, D. F., Beverley, P. C. L., et al. (2007) · Immunology · doi:10.1111/j.1365-2567.2007.02573.x · Cited by 376 · see citing works
Bakkouri, K. E., Descamps, F. J., Filette, M. D., Smet, A., Festjens, E., Birkett, A. J., van Rooijen, N., Verbeek, S. J., Fiers, W. C., & Saelens, X. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0902147 · Cited by 335 · see citing works
NK phenotypic markers and IL2 response in NK cells from elderly people
Borrego, F., Alonso, M. C., Galiani, M. D., Carracedo, J., Ramı́rez, R., Ostos, B., Peña, J., & Solana, R. (1999) · Experimental Gerontology · doi:10.1016/s0531-5565(98)00076-x · Cited by 278 · see citing works
Natural killer cells in infection and inflammation of the lung
Culley, F. J. (2009) · Immunology · doi:10.1111/j.1365-2567.2009.03167.x · Cited by 242 · see citing works
Wang, K. S., Frank, D. A., & Ritz, J. (2000) · Blood · doi:10.1182/blood.v95.10.3183 · Cited by 241 · see citing works
Probiotic Lactobacillus reuteri suppress proinflammatory cytokines via c-Jun
Lin, Y. P., Thibodeaux, C., Peña, J. A., Ferry, G. D., & Versalovic, J. A. (2008) · Inflammatory Bowel Diseases · doi:10.1002/ibd.20448 · Cited by 235 · see citing works
Stein‐Streilein, J., & Guffee, J. (1986) · The Journal of Immunology · doi:10.4049/jimmunol.136.4.1435 · Cited by 204 · see citing works
Natural Killer Cell Responses to Viral Infection
Brandstadter, J. D., & Yang, Y. (2011) · Journal of Innate Immunity · doi:10.1159/000324176 · Cited by 201 · see citing works
IFN-α and IL-12 Induce IL-18 Receptor Gene Expression in Human NK and T Cells
Sareneva, T., Julkunen, I., & Matikainen, S. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.4.1933 · Cited by 172 · see citing works
T cell–dependent production of IFN-γ by NK cells in response to influenza A virus
He, X.-S., Draghi, M., Mahmood, K., Holmes, T. H., Kemble, G. W., Dekker, C. L., Arvin, A. M., Parham, P., & Greenberg, H. B. (2004) · Journal of Clinical Investigation · doi:10.1172/jci22797 · Cited by 156 · see citing works
NK Cells in Healthy Aging and Age-Associated Diseases
Camous, X., Pera, A., Solana, R., & Larbi, A. (2012) · BioMed Research International · doi:10.1155/2012/195956 · Cited by 154 · 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 · see citing works
Liu, B., Mori, I., Hossain, M. J., Dong, L., Takeda, K., & Kimura, Y. (2004) · Journal of General Virology · doi:10.1099/vir.0.19596-0 · Cited by 143 · see citing works
Lung dendritic cells induce migration of protective T cells to the gastrointestinal tract
Ruane, D., Brane, L., Reis, B. S., Cheong, C., Poles, J., Do, Y., Zhu, H., Velinzon, K., Choi, J., Studt, N., et al. (2013) · The Journal of Experimental Medicine · doi:10.1084/jem.20122762 · Cited by 141 · see citing works
Yu, X., Zhang, X., Zhao, B., Wang, J., Zhu, Z., Teng, Z., Shao, J., Shen, J., Gao, Y., Yuan, Z., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0028680 · Cited by 135 · see citing works
Villena, J., Chiba, E., Tomosada, Y., Salva, S., Marranzino, G., Kitazawa, H., & Alvarez, S. (2012) · BMC Immunology · doi:10.1186/1471-2172-13-53 · Cited by 130 · see citing works
Fang, M., Roscoe, F., & Sigal, L. J. (2010) · The Journal of Experimental Medicine · doi:10.1084/jem.20100282 · Cited by 121 · see citing works
Takeda, S., Takeshita, M., Kikuchi, Y., Dashnyam, B., Kawahara, S., Yoshida, H., Watanabe, W., Muguruma, M., & Kurokawa, M. (2011) · International Immunopharmacology · doi:10.1016/j.intimp.2011.08.007 · Cited by 100 · see citing works
Transcriptional Regulation of EGR-1 by the Interleukin-1-JNK-MKK7-c-Jun Pathway
Hoffmann, E., Ashouri, J. F., Wolter, S., Doerrie, A., Dittrich‐Breiholz, O., Schneider, H., Wagner, E. F., Troppmair, J., Mackman, N., & Kracht, M. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m800583200 · Cited by 97 · see citing works
Weiss, I. D., Wald, O., Wald, H., Beider, K., Abraham, M., Galun, E., Nagler, A., & Peled, A. (2010) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2009.0084 · Cited by 88 · see citing works
Sulphatide binds to human and animal influenza A viruses, and inhibits the viral infection
Suzuki, T., Sometani, A., YAMAZAKI, Y., et al. (1996) · Biochemical Journal · doi:10.1042/bj3180389 · Cited by 86 · see citing works
Self-citationSakai, S., Kawamata, H., Mantani, N., Kogure, T., Shimada, Y., TERASAWA, K., Sakai, T., Imanishi, N., & Ochiai, H. (2000) · Journal of Virology · doi:10.1128/jvi.74.5.2472-2476.2000 · Cited by 82 · see citing works
IL-1βand IL-6 Upregulation in Children with H1N1 Influenza Virus Infection
Chiaretti, A., Pulitanò, S., Barone, G., Ferrara, P., Romano, V., Capozzi, D., & Riccardi, R. (2013) · Mediators of Inflammation · doi:10.1155/2013/495848 · Cited by 77 · see citing works
Beli, E., Clinthorne, J. F., Duriancik, D. M., Hwang, I., Kim, S., & Gardner, E. M. (2011) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2011.08.005 · Cited by 76 · see citing works
Kiso, M., Takano, R., Sakabe, S., Katsura, H., Shinya, K., Uraki, R., Watanabe, S., Saito, H., Toba, M., Kohda, N., et al. (2013) · Scientific Reports · doi:10.1038/srep01563 · Cited by 75 · see citing works
Philippe, D., Heupel, E., Blum-Sperisen, S., & Riedel, C. U. (2011) · International Journal of Food Microbiology · doi:10.1016/j.ijfoodmicro.2010.12.020 · Cited by 73 · see citing works
Oral Administration of Bifidobacterium longum Ameliorates Influenza Virus Infection in Mice
Iwabuchi, N., Xiao, J., Yaeshima, T., & Iwatsuki, K. (2011) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.34.1352 · Cited by 66 · see citing works
Sulfatide Is Required for Efficient Replication of Influenza A Virus
Takahashi, T., Murakami, K., Nagakura, M., et al. (2008) · Journal of Virology · doi:10.1128/jvi.02496-07 · Cited by 61 · see citing works
Self-citationOhno, H., Tsunemine, S., Isa, Y., et al. (2005) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.28.1462 · Cited by 54 · see citing works
Neff‐LaFord, H. D., Vorderstrasse, B. A., & Lawrence, B. P. (2003) · Cellular Immunology · doi:10.1016/j.cellimm.2003.11.005 · Cited by 50 · see citing works
Ichimiya, I., Kawauchi, H., Tanaka, T., et al. (1991) · Annals of Otology Rhinology & Laryngology · doi:10.1177/000348949110000807 · Cited by 47 · see citing works
Differences in clinical manifestations of influenza‐associated encephalopathy by age
Wada, T., Morishima, T., Okumura, A., et al. (2008) · Microbiology and Immunology · doi:10.1111/j.1348-0421.2008.00100.x · Cited by 38 · see citing works
Takahashi, T., Kurebayashi, Y., Ikeya, K., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0015556 · Cited by 31 · see citing works
Self-citationEffects of the viability ofLactobacillus rhamnosusGG on rotavirus infection in neonatal rats
Ventola, H. (2012) · World Journal of Gastroenterology · doi:10.3748/wjg.v18.i41.5925 · Cited by 24 · see citing works
Role of alveolar epithelial early growth response-1 (Egr-1) in CD8+ T cell-mediated lung injury
Ramana, C. V., Cheng, G., Kumar, A., Kwon, H., & Enelow, R. I. (2009) · Molecular Immunology · doi:10.1016/j.molimm.2009.09.001 · Cited by 21 · see citing works
Takahashi, T., Takaguchi, M., Kawakami, T., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0061092 · Cited by 19 · see citing works
Self-citationEstella, Á. (2011) · The Journal of Infection in Developing Countries · doi:10.3855/jidc.1618 · Cited by 19 · see citing works
Surface localization of the nuclear receptor CAR in influenza A virus-infected cells
Takahashi, T., Moriyama, Y., Ikari, A., et al. (2008) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2008.01.145 · Cited by 12 · see citing works
Self-citationTakaguchi, M., Takahashi, T., Hosokawa, C., Ueyama, H., Fukushima, K., Hayakawa, T., Itoh, K., Ikeda, K., & Suzuki, T. (2010) · The Journal of Biochemistry · doi:10.1093/jb/mvq139 · Cited by 11 · see citing works
Self-citation
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Commensal <i>Bifidobacterium</i> promotes antitumor immunity and facilitates anti–PD-L1 efficacy
Sivan, A., Corrales, L., Hubert, N., Williams, J. B., Aquino-Michaels, K., Earley, Z. M., Benyamin, F. W., Man Lei, Y., Jabri, B., Alegre, M.-L., et al. (2015) · Science · doi:10.1126/science.aac4255 · Cited by 3,888 · see citing works
Emerging Pathogenic Links Between Microbiota and the Gut-Lung Axis
Budden, K. F., Gellatly, S. L., Wood, D. L. A., Cooper, M. A., Morrison, M., Hugenholtz, P., & Hansbro, P. M. (2017) · Nature Reviews Microbiology · doi:10.1038/nrmicro.2016.142 · Cited by 1,606 · see citing works
The influence of the microbiome on respiratory health
Wypych, T. P., Wickramasinghe, L. C., & Marsland, B. J. (2019) · Nature Immunology · doi:10.1038/s41590-019-0451-9 · Cited by 611 · see citing works
The role of the lung microbiota and the gut–lung axis in respiratory infectious diseases
Dumas, A., Bernard, L., Poquet, Y., Lugo-Villarino, G., & Neyrolles, O. (2018) · Cellular Microbiology · doi:10.1111/cmi.12966 · Cited by 444 · see citing works
Innate immune signaling and regulation in cancer immunotherapy
Corrales, L., Matson, V., Flood, B., Spranger, S., & Gajewski, T. F. (2017) · Cell Research · doi:10.1038/cr.2016.149 · Cited by 408 · see citing works
Gut microbiota-mediated immunomodulation in tumor
Liu, X., Chen, Y., Zhang, S., & Dong, L. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-01983-x · Cited by 112 · see citing works
Lehtoranta, L., Latvala, S., & Lehtinen, M. J. (2020) · Nutrients · doi:10.3390/nu12103163 · Cited by 103 · see citing works
Role of the intestinal microbiota in the immunomodulation of influenza virus infection
Chen, C.-J., Wu, G.-H., Kuo, R.-L., & Shih, S.-R. (2017) · Microbes and Infection · doi:10.1016/j.micinf.2017.09.002 · Cited by 67 · see citing works
Li, Q., Cheng, F., Xu, Q., Su, Y., Cai, X., Zeng, F., & Zhang, Y. (2021) · International Immunopharmacology · doi:10.1016/j.intimp.2021.107531 · Cited by 64 · see citing works
Che, J., Shi, J., Fang, C., Zeng, X., Wu, Z., Du, Q., Tu, M., & Pan, D. (2024) · Microorganisms · doi:10.3390/microorganisms12040704 · Cited by 52 · see citing works
- Authors
- Kawahara, T., Takahashi, T., Oishi, K., Tanaka, H., Masuda, M., Takahashi, S., Takano, M., Kawakami, T., Fukushima, K., Kanazawa, H., & Suzuki, T.
- Affiliations
- Shizuoka University (JP)
- Corresponding author
- Suzuki, Takashi
- ORCID
- Venue
- Microbiology and Immunology
- Publisher
- Wiley
- Published
- 2015-01
- Volume
- 59
- Issue
- 1
- Pages
- 1-12
- ISSN
- 0385-5600 (ISSN-L)
- 1348-0421
- OpenAlex
- W1692592874
- Cited by
- 125
- References
- 48
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 12 · 2023: 11 · 2022: 19 · 2021: 18 · 2020: 24 · 2019: 7 · 2018: 7 · 2017: 8 · 2016: 7 · 2015: 5
- FWCI
- 9.56
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Microbiology and Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (26670064, 15H05644, 13J10690)
- Topics
- Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
- Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Keywords
- probiotics, influenza, natural killer cells, innate immunity, Peyer's patches, interferon-gamma, IL-12, IL-18, interleukin-2, inflammatory cytokines, lower respiratory tract inflammation, oral administration, gut microbiota, prophylaxis
- MeSH terms
- Administration, Oral, Animals, Bifidobacterium, Disease Models, Animal, Female, Killer Cells, Natural, Lung, Mice, Inbred BALB C, Orthomyxoviridae Infections, Spleen, Sulfalene, Survival Analysis, Cytokines, Probiotics, Gene Expression Profiling, Influenza A Virus, H1N1 Subtype
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