Respiratory syncytial virus (RSV) is leading cause of respiratory tract infections in early childhood. Gut microbiota is closely related with the pulmonary antiviral immunity. Recent evidence shows that gut dysbiosis is involved in the pathogenesis of RSV infection. Therefore; pharmacological and therapeutic strategies aiming to readjust the gut dysbiosis are increasingly important for the treatment of RSV infection. In this study, we evaluated the therapeutic effects of a probiotic mixture on RSV-infected mice. This probiotic mixture consisted of Lactobacillus rhamnosus GG, Escherichia coli Nissle 1917 and VSL#3 was orally administered to neonatal mice on a daily basis either for 1 week in advance or for 3 days starting from the day of RSV infection. We showed that administration of the probiotics protected against RSV-induced lung pathology by suppressing RSV infection and exerting an antiviral response via alveolar macrophage (AM)-derived IFN-β. Furthermore, administration of the probiotics reversed gut dysbiosis and significantly increased the abundance of short-chain fatty acid (SCFA)-producing bacteria in RSV-infected mice, which consequently led to elevated serum SCFA levels. Moreover, administration of the probiotics restored lung microbiota in RSV-infected mice. We demonstrated that the increased production of IFN-β in AMs was attributed to the increased acetate in circulation and the levels of Corynebacterium and Lactobacillus in lungs. In conclusion, we reveal that probiotics protect against RSV infection in neonatal mice through a microbiota-AM axis, suggesting that the probiotics may be a promising candidate to prevent and treat RSV infection, and deserve more research and development in future.
Subscribe to Journal
Get full journal access for 1 year
only $41.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Li Y, Reeves RM, Wang X, Bassat Q, Brooks WA, Cohen C, et al. Global patterns in monthly activity of influenza virus, respiratory syncytial virus, parainfluenza virus, and metapneumovirus: a systematic analysis. Lancet Glob Health. 2019;7:e1031–e1045.
Groves HT, Cuthbertson L, James P, Moffatt MF, Cox MJ, Tregoning JS. Respiratory disease following viral lung infection alters the murine gut microbiota. Front Immunol. 2018;9:182.
Burgess SL, Leslie JL, Uddin MJ, Oakland DN, Gilchrist CA, Moreau GB, et al. Gut microbiome communication with bone marrow regulates susceptibility to amebiasis. J Clin Invest. 2020;130:4019–24.
Sencio V, Barthelemy A, Tavares LP, Machado MG, Soulard D, Cuinat C, et al. Gut Dysbiosis during influenza contributes to pulmonary pneumococcal superinfection through altered short-chain fatty acid production. Cell Rep. 2020;30:2934–2947.e6.
Yildiz S, Mazel Sanchez B, Kandasamy M, Manicassamy B, Schmolke M. Influenza A virus infection impacts systemic microbiota dynamics and causes quantitative enteric dysbiosis. Microbiome. 2018;6:9.
Groves HT, Higham SL, Moffatt MF, Cox MJ, Tregoning JS. Respiratory viral infection alters the gut microbiota by inducing inappetence. mBio. 2020;11:e03236–19.
Dang AT, Marsland BJ. Microbes, metabolites, and the gut-lung axis. Mucosal Immunol. 2019;12:843–50.
Hagan T, Cortese M, Rouphael N, Boudreau C, Linde C, Maddur MS, et al. Antibiotics-driven gut microbiome perturbation alters immunity to vaccines in humans. Cell. 2019;178:1313–1328.e13.
Nemet I, Saha PP, Gupta N, Zhu W, Romano KA, Skye SM, et al. A Cardiovascular disease-linked gut microbial metabolite acts via adrenergic receptors. Cell. 2020;180:862–877.e22.
Abt MC, Osborne LC, Monticelli LA, Doering TA, Alenghat T, Sonnenberg GF, et al. Commensal bacteria calibrate the activation threshold of innate antiviral immunity. Immunity. 2012;37:158–70.
Ganal SC, Sanos SL, Kallfass C, Oberle K, Johner C, Kirschning C, et al. Priming of natural killer cells by nonmucosal mononuclear phagocytes requires instructive signals from commensal microbiota. Immunity. 2012;37:171–86.
Winkler ES, Thackray LB. A long-distance relationship: the commensal gut microbiota and systemic viruses. Curr Opin Virol. 2019;37:44–51.
Antunes KH, Fachi JL, de Paula R, da Silva EF, Pral LP, Dos Santos AA, et al. Microbiota-derived acetate protects against respiratory syncytial virus infection through a GPR43-type 1 interferon response. Nat Commun. 2019;10:3273.
Swimm A, Giver CR, DeFilipp Z, Rangaraju S, Sharma A, Ulezko Antonova A, et al. Indoles derived from intestinal microbiota act via type I interferon signaling to limit graft-versus-host disease. Blood. 2018;132:2506–19.
Trompette A, Gollwitzer ES, Pattaroni C, Lopez-Mejia IC, Riva E, Pernot J, et al. Dietary fiber confers protection against Flu by shaping Ly6c(-) patrolling monocyte hematopoiesis and CD8+ T cell metabolism. Immunity. 2018;48:992–1005.e8.
Yitbarek A, Taha Abdelaziz K, Hodgins DC, Read L, Nagy E, Weese JS, et al. Gut microbiota-mediated protection against influenza virus subtype H9N2 in chickens is associated with modulation of the innate responses. Sci Rep. 2018;8:13189.
Man WH, van Houten MA, Merelle ME, Vlieger AM, Chu M, Jansen NJG, et al. Bacterial and viral respiratory tract microbiota and host characteristics in children with lower respiratory tract infections: a matched case-control study. Lancet Respir Med. 2019;7:417–26.
Gollwitzer ES, Saglani S, Trompette A, Yadava K, Sherburn R, McCoy KD, et al. Lung microbiota promotes tolerance to allergens in neonates via PD-L1. Nat Med. 2014;20:642–7.
Yang D, Chen X, Wang J, Lou Q, Lou Y, Li L, et al. Dysregulated Lung commensal bacteria drive interleukin-17B production to promote pulmonary fibrosis through their outer membrane vesicles. Immunity 2019;50:692–706.e7.
Dumas A, Bernard L, Poquet Y, Lugo-Villarino G, Neyrolles O. The role of the lung microbiota and the gut-lung axis in respiratory infectious diseases. Cell Microbiol. 2018;20:e12966.
Marsh RL, Smith Vaughan HC, Chen ACH, Marchant JM, Yerkovich ST, Gibson PG, et al. Multiple respiratory microbiota profiles are associated with lower airway inflammation in children with protracted bacterial bronchitis. Chest 2019;155:778–86.
Stewart CJ, Mansbach JM, Ajami NJ, Petrosino JF, Zhu Z, Liang L, et al. Serum metabolome is associated with nasopharyngeal microbiota and disease severity among infants with bronchiolitis. J Infect Dis. 2019;219:2005–14.
Kanmani P, Clua P, Vizoso Pinto MG, Rodriguez C, Alvarez S, Melnikov V, et al. Respiratory commensal bacteria Corynebacterium pseudodiphtheriticum improves resistance of infant mice to respiratory dyncytial virus and Streptococcus pneumoniae duperinfection. Front Microbiol. 2017;8:1613.
Korpela K, Salonen A, Vepsalainen O, Suomalainen M, Kolmeder C, Varjosalo M, et al. Probiotic supplementation restores normal microbiota composition and function in antibiotic-treated and in caesarean-born infants. Microbiome. 2018;6:182.
Suez J, Zmora N, Segal E, Elinav E. The pros, cons, and many unknowns of probiotics. Nat Med. 2019;25:716–29.
van den Elsen LWJ, Tims S, Jones AM, Stewart A, Stahl B, Garssen J, et al. Prebiotic oligosaccharides in early life alter gut microbiome development in male mice while supporting influenza vaccination responses. Benef Microbes. 2019;10:279–91.
Kumova OK, Fike AJ, Thayer JL, Nguyen LT, Mell JC, Pascasio J, et al. Lung transcriptional unresponsiveness and loss of early influenza virus control in infected neonates is prevented by intranasal Lactobacillus rhamnosus GG. PLoS Pathog. 2019;15:e1008072.
Vlasova AN, Shao L, Kandasamy S, Fischer DD, Rauf A, Langel SN, et al. Escherichia coli Nissle 1917 protects gnotobiotic pigs against human rotavirus by modulating pDC and NK-cell responses. Eur J Immunol. 2016;46:2426–37.
De Angelis M, Scagnolari C, Oliva A, Cavallari EN, Celani L, Santinelli L, et al. Short-term probiotic administration increases fecal-anti candida activity in healthy dbjects. Microorganisms. 2019;7:162.
Li J, Sung CY, Lee N, Ni Y, Pihlajamaki J, Panagiotou G, et al. Probiotics modulated gut microbiota suppresses hepatocellular carcinoma growth in mice. Proc Natl Acad Sci USA. 2016;113:E1306–15.
Kolli D, Gupta MR, Sbrana E, Velayutham TS, Chao H, Casola A, et al. Alveolar macrophages contribute to the pathogenesis of human metapneumovirus infection while protecting against respiratory syncytial virus infection. Am J Respir Cell Mol Biol. 2014;51:502–15.
Shen C, Zhang Z, Xie T, Xu J, Yan J, Kang A, et al. Jinxin oral liquid inhibits human respiratory syncytial virus-induced excessive inflammation associated with blockade of the NLRP3/ASC/Caspase-1 pathway. Biomed Pharmacother. 2018;103:1376–83.
Dong Y, Yan H, Zhao X, Lin R, Lin L, Ding Y, et al. Gu-Ben-Fang-Xiao decoction ameliorated murine asthma in remission stage by modulating microbiota-acetate-Tregs axis. Front Pharmacol. 2020;11:549.
Zhang X, Goncalves R, Mosser DM. The isolation and characterization of murine macrophages. Curr Protoc Immunol. 2008 Nov;Chapter 14:Unit 14.1.
Haeberle HA, Takizawa R, Casola A, Brasier AR, Dieterich HJ, Van Rooijen N, et al. Respiratory syncytial virus-induced activation of nuclear factor-kappaB in the lung involves alveolar macrophages and toll-like receptor 4-dependent pathways. J Infect Dis. 2002;186:1199–206.
Amato KR, Yeoman CJ, Kent A, Righini N, Carbonero F, Estrada A, et al. Habitat degradation impacts black howler monkey (Alouatta pigra) gastrointestinal microbiomes. ISME J. 2013;7:1344–53.
Schloss PD, Westcott SL, Ryabin T, Hall JR, Hartmann M, Hollister EB, et al. Introducing mothur: open-source, platform-independent, community-supported software for describing and comparing microbial communities. Appl Environ Microbiol. 2009;75:7537–41.
Ji J, Ge X, Chen Y, Zhu B, Wu Q, Zhang J, et al. Daphnetin ameliorates experimental colitis by modulating microbiota composition and Treg/Th17 balance. FASEB J. 2019;33:9308–22.
Barcik W, Boutin RCT, Sokolowska M, Finlay BB. The role of lung and gut microbiota in the pathology of asthma. Immunity 2020;52:241–55.
Shenoy MK, Fadrosh DW, Lin DL, Worodria W, Byanyima P, Musisi E, et al. Gut microbiota in HIV-pneumonia patients is related to peripheral CD4 counts, lung microbiota, and in vitro macrophage dysfunction. Microbiome 2019;7:37. Mar 11
Trompette A, Gollwitzer ES, Yadava K, Sichelstiel AK, Sprenger N, Ngom Bru C, et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med. 2014;20:159–66.
Nagre N, Cong X, Pearson AC, Zhao X. Alveolar macrophage phagocytosis and bacteria clearance in mice. J Vis Exp. 2019;10.3791/59088.
Lee H, Ko G. Antiviral effect of vitamin A on norovirus infection via modulation of the gut microbiome. Sci Rep. 2016;6:25835.
Huser AT, Becker A, Brune I, Dondrup M, Kalinowski J, Plassmeier J, et al. Development of a Corynebacterium glutamicum DNA microarray and validation by genome-wide expression profiling during growth with propionate as carbon source. J Biotechnol. 2003;106:269–86.
Gerstmeir R, Wendisch VF, Schnicke S, Ruan H, Farwick M, Reinscheid D, et al. Acetate metabolism and its regulation in Corynebacterium glutamicum. J Biotechnol. 2003;104:99–122.
Wendisch VF, Spies M, Reinscheid DJ, Schnicke S, Sahm H, Eikmanns BJ. Regulation of acetate metabolism in Corynebacterium glutamicum: transcriptional control of the isocitrate lyase and malate synthase genes. Arch Microbiol. 1997;168:262–9.
Grunwell JR, Yeligar SM, Stephenson S, Ping XD, Gauthier TW, Fitzpatrick AM, et al. TGF-beta1 suppresses the type I IFN response and induces mitochondrial dysfunction in alveolar macrophages. J Immunol. 2018;200:2115–28.
Goritzka M, Makris S, Kausar F, Durant LR, Pereira C, Kumagai Y, et al. Alveolar macrophage-derived type I interferons orchestrate innate immunity to RSV through recruitment of antiviral monocytes. J Exp Med. 2015;212:699–714.
Steed AL, Christophi GP, Kaiko GE, Sun L, Goodwin VM, Jain U, et al. The microbial metabolite desaminotyrosine protects from influenza through type I interferon. Science. 2017;357:498–502.
Ye W, Chew M, Hou J, Lai F, Leopold SJ, Loo HL, et al. Microvesicles from malaria-infected red blood cells activate natural killer cells via MDA5 pathway. PLoS Pathog. 2018;14:e1007298.
Marr N, Turvey SE, Grandvaux N. Pathogen recognition receptor crosstalk in respiratory syncytial virus sensing: a host and cell type perspective. Trends Microbiol. 2013;21:568–74.
Kim D, Hofstaedter CE, Zhao C, Mattei L, Tanes C, Clarke E, et al. Optimizing methods and dodging pitfalls in microbiome research. Microbiome. 2017;5:52.
Bachem A, Makhlouf C, Binger KJ, de Souza DP, Tull D, Hochheiser K, et al. Microbiota-derived short-chain fatty acids promote the memory potential of antigen-activated CD8+ T cells. Immunity. 2019;51:285–97.e5.
Cait A, Hughes MR, Antignano F, Cait J, Dimitriu PA, Maas KR, et al. Microbiome-driven allergic lung inflammation is ameliorated by short-chain fatty acids. Mucosal Immunol. 2018;11:785–95.
This work was supported by the National Natural Science Foundation of China (81673412, 013038007001), Key R & D and promotion project of Henan Province (Science and technology tackling, Project No: 192102310431), the Jiangsu Key R&D Plan (Social Development) BE2019618, Six Talent Peaks in Jiangsu Province (YY-013), the Jiangsu Province TCM Science and Technology Development Plan Project (ZD201901), the Grant for Special Professors of Jiangsu (2015), a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and The Open Projects of the Discipline of Chinese Medicine of Nanjing University of Chinese Medicine Supported by the Subject of Academic priority discipline of Jiangsu Higher Education Institutions (ZYX03KF053).
The authors declare no competing interests.
About this article
Cite this article
Ji, Jj., Sun, Qm., Nie, Dy. et al. Probiotics protect against RSV infection by modulating the microbiota-alveolar-macrophage axis. Acta Pharmacol Sin (2021). https://doi.org/10.1038/s41401-020-00573-5
- respiratory syncytial virus
- gut microbiota
- lung microbiota
- alveolar macrophages