Progressive deterioration of the upper respiratory tract and the gut microbiomes in children during the early infection stages of COVID-19

Rong Xu; Pengcheng Liu; Tao Zhang; Qunfu Wu; Mei Zeng; Yingying Ma; Xia Jin; Jin Xu; Zhigang Zhang; Chiyu Zhang

doi:10.1016/j.jgg.2021.05.004

Volume 48 Issue 9

Sep. 2021

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Article Navigation > Journal of Genetics and Genomics > 2021 > 48(9): 803-814

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Progressive deterioration of the upper respiratory tract and the gut microbiomes in children during the early infection stages of COVID-19

doi: 10.1016/j.jgg.2021.05.004

a. Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China;
b. Pathogen Discovery and Evolution Unit, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China;
c. Children's Hospital of Fudan University, Shanghai 201102, China;
d. State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming, Yunnan 650091, China

Funds:

We thank Mr. Kai Liu at Institut Pasteur of Shanghai, Chinese Academy of Sciences for his technical support. This work was supported by the grants from the National Key Research and Development Program of China (2018YFC2000500 and 2017ZX10103009-002), Major Science and Technology Project in Yunnan Province of China (202001BB050001), the Second Tibetan Plateau Scientific Expedition and Research (STEP) program (2019QZKK0503), the Key Research Program of the Chinese Academy of Sciences (FZDSW-219), the Chinese National Natural Science Foundation of China (31970571), and grants specific for coronavirus disease 2019 from the Children's Hospital of Fudan University (EKXGZX006).

Received Date: 2021-02-04
Accepted Date: 2021-05-16
Rev Recd Date: 2021-05-13
Publish Date: 2021-08-13

Abstract

Abstract

Children are less susceptible to coronavirus disease 2019 (COVID-19), and they have manifested lower morbidity and mortality after infection, for which a multitude of mechanisms may be considered. Whether the normal development of the gut-airway microbiome in children is affected by COVID-19 has not been evaluated. Here, we demonstrate that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection alters the upper respiratory tract and the gut microbiomes in nine children. The alteration of the microbiome is dominated by the genus Pseudomonas, and it sustains for up to 25-58 days in different individuals. Moreover, the patterns of alternation are different between the upper respiratory tract and the gut. Longitudinal investigation shows that the upper respiratory tract and the gut microbiomes are extremely variable among children during the course of COVID-19. The dysbiosis of microbiome persists in 7 of 8 children for at least 19-24 days after discharge from the hospital. Disturbed development of both the gut and the upper respiratory microbiomes and prolonged dysbiosis in these nine children imply possible long-term complications after clinical recovery from COVID-19, such as predisposition to the increased health risk in the post-COVID-19 era.
- SARS-CoV-2/COVID-19,
- Upper respiratory microbiome,
- Gut microbiota,
- Dysbiosis,
- Children

These authors contributed equally to this work.

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References(55)

References

Amir, A., McDonald, D., Navas-Molina, J.A., Kopylova, E., Morton, J.T., Xu, Z.Z., Kightley, E.P., Thompson, L.R., Hyde, E.R., Gonzalez, A., Deblur rapidly resolves single-nucleotide community sequence patterns. mSystems 2 e00191-00116.

Beier, D., Gross, R., 2006. Regulation of bacterial virulence by two-component systems. Curr. Opin. Microbiol. 9, 143-152.

Blanton, L.V., Charbonneau, M.R., Salih, T., Barratt, M.J., Venkatesh, S., Ilkaveya, O., Subramanian, S., Manary, M.J., Trehan, I., Jorgensen, J.M., 2016. Gut bacteria that prevent growth impairments transmitted by microbiota from malnourished children. Science 351, aad3311.

Cai, J., Xu, J., Lin, D., Yang, Z., Xu, L., Qu, Z., Zhang, Y., Zhang, H., Jia, R., Liu, P., 2020. A case series of children with 2019 novel coronavirus infection: clinical and epidemiological features. Clin. Infect. Dis. 71, 1547-1551.

Caporaso, J.G., Kuczynski, J., Stombaugh, J., Bittinger, K., Bushman, F.D., Costello, E.K., Fierer, N., Pena, A.G., Goodrich, J.K., Gordon, J.I., 2010. QIIME allows analysis of high-throughput community sequencing data. Nat. Methods 7, 335-336.

Chen, Y.J., Wu, H., Wu, S.D., Lu, N., Wang, Y.T., Liu, H.N., Dong, L., Liu, T.T., Shen, X.Z., 2018. Parasutterella, in association with irritable bowel syndrome and intestinal chronic inflammation. J. Gastroenterol. Hepatol. 33, 1844-1852.

Cheuk, W., Woo, P.C.Y., Yuen, K.Y., Yu, P.H., Chan, J.K.C., 2000. Intestinal inflammatory pseudotumour with regional lymph node involvement: identification of a new bacterium as the aetiological agent. J. Pathol. 192, 289-292.

Clarke, K.R., 1993. Nonparametric multivariate analyses of changes in community structure. Aust. J. Ecol. 18, 117-143.

Cole, J.R., Wang, Q., Fish, J.A., Chai, B.L., McGarrell, D.M., Sun, Y.N., Brown, C.T., Porras-Alfaro, A., Kuske, C.R., Tiedje, J.M., 2014. Ribosomal database project: data and tools for high throughput rRNA analysis. Nucleic Acids Res. 42, D633-D642.

Cox, L.M., Yamanishi, S., Sohn, J., Alekseyenko, A.V., Leung, J.M., Cho, I., Kim, S.G., Li, H., Gao, Z., Mahana, D., 2014. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell 158, 705-721.

D'Amore, R., Ijaz, U.Z., Schirmer, M., Kenny, J.G., Gregory, R., Darby, A.C., Shakya, M., Podar, M., Quince, C., Hall, N., 2016. A comprehensive benchmarking study of protocols and sequencing platforms for 16s rRNA community profiling. BMC Genom. 17, 55.

De Caceres, M., Legendre, P., Moretti, M., 2010. Improving indicator species analysis by combining groups of sites. Oikos 119, 1674-1684.

De Muinck, E.J., Trosvik, P., Gilfillan, G.D., Hov, J.R., Sundaram, A.Y.M., 2017. A novel ultra high-throughput 16S rRNA gene amplicon sequencing library preparation method for the Illumina HiSeq platform. Microbiome 5, 68.

Derrien, M., Alvarez, A.S., de Vos, W.M., 2019. The gut microbiota in the first decade of life. Trends Microbiol. 27, 997-1010.

Ding, T., Schloss, P.D., 2014. Dynamics and associations of microbial community types across the human body. Nature 509, 357-360.

Douglas, G.M., Maffei, V.J., Zaneveld, J.R., Yurgel, S.N., Brown, J.R., Taylor, C.M., Huttenhower, C., Langille, M.G.I., 2020. PICRUSt2 for prediction of metagenome functions. Nat. Biotechnol. 38, 685-688.

Dubourg, G., Edouard, S., Raoult, D., 2019. Relationship between nasopharyngeal microbiota and patient's susceptibility to viral infection. Expert Rev. Anti-Inf. 17, 437-447.

Edgar, R.C., 2013. UPARSE: highly accurate OTU sequences from microbial amplicon reads. Nat. Methods 10, 996-998.

Ferretti, P., Pasolli, E., Tett, A., Asnicar, F., Gorfer, V., Fedi, S., Armanini, F., Truong, D.T., Manara, S., Zolfo, M., 2018. Mother-to-infant microbial transmission from different body sites shapes the developing infant gut microbiome. Cell Host Microbe 24, 133-145.

Fujimura, K.E., Sitarik, A.R., Haystad, S., Lin, D.L., Levan, S., Fadrosh, D., Panzer, A.R., LaMere, B., Rackaityte, E., Lukacs, N.W., 2016. Neonatal gut microbiota associates with childhood multisensitized atopy and T cell differentiation. Nat. Med. 22, 1187-1191.

Fukuda, T., Matsumura, T., Ato, M., Hamasaki, M., Nishiuchi, Y., Murakami, Y., Maeda, Y., Yoshimori, T., Matsumoto, S., Kobayashi, K., Critical roles for lipomannan and lipoarabinomannan in cell wall integrity of mycobacteria and pathogenesis of tuberculosis. Mbio 4 e00472-00412.

Gehrig, J.L., Venkatesh, S., Chang, H.W., Hibberd, M.C., Kung, V.L., Cheng, J.Y., Chen, R.Y., Subramanian, S., Cowardin, C.A., Meier, M.F., 2019. Effects of microbiota-directed foods in gnotobiotic animals and undernourished children. Science 365, eaau4732.

Gilbert, J.A., Blaser, M.J., Caporaso, J.G., Jansson, J.K., Lynch, S.V., Knight, R., 2018. Current understanding of the human microbiome. Nat. Med. 24, 392-400.

Green, E.R., Mecsas, J., Bacterial Secretion Systems: an Overview. Microbiol Spectr 4, 10.1128.

Grier, A., McDavid, A., Wang, B.K., Qiu, X., Java, J., Bandyopadhyay, S., Yang, H.M., Holden-Wiltse, J., Kessler, H.A., Gill, A.L., 2018. Neonatal gut and respiratory microbiota: coordinated development through time and space. Microbiome 6, 193.

Gu, S., Chen, Y., Wu, Z., Chen, Y., Gao, H., Lv, L., Guo, F., Zhang, X., Luo, R., Huang, C., 2020. Alterations of the gut microbiota in patients with Coronavirus Disease 2019 or H1N1 influenza. Clin. Infect. Dis. 159, 944-955.

Guan, W., Ni, Z., Hu, Y., Liang, W., Ou, C., He, J., Liu, L., Shan, H., Lei, C., Hui, D.S.C., 2020. Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 382, 1708-1720.

Haiko, J., Westerlund-Wikstrom, B., 2013. The role of the bacterial flagellum in adhesion and virulence. Biology (Basel) 2, 1242-1267.

Hannon, G.J., 2010. Fastx-toolkit. http://hannonlabcshledu/fastx_toolkit.

Holmes, I., Harris, K., Quince, C., 2012. Dirichlet multinomial mixtures: generative models for microbial metagenomics. PLoS One 7, e30126.

Jones, A.M., Dodd, M.E., Govan, J.R.W., Barcus, V., Doherty, C.J., Morris, J., Webb, A.K., 2004. Burkholderia cenocepacia and Burkholderia multivorans: influence on survival in cystic fibrosis. Thorax 59, 948-951.

Langevin, S., Pichon, M., Smith, E., Morrison, J., Bent, Z., Green, R., Barker, K., Solberg, O., Gillet, Y., Javouhey, E., 2017. Early nasopharyngeal microbial signature associated with severe influenza in children: a retrospective pilot study. J. Gen. Virol. 98, 2425-2437.

Lee, S.A., Wrona, L.J., Cahoon, A.B., Crigler, J., Eiteman, M.A., Altman, E., 2016. Isolation and characterization of bacteria that use furans as the sole carbon source. Appl. Biochem. Biotechnol. 178, 76-90.

Li, Y.P., Fu, X.M., Ma, J.M., Zhang, J.H., Hu, Y.H., Dong, W., Wan, Z.Z., Li, Q.F., Kuang, Y.Q., Lan, K., 2019. Altered respiratory virome and serum cytokine profile associated with recurrent respiratory tract infections in children. Nat. Commun. 10, 2288.

Liu, P., Cai, J., Jia, R., Xia, S., Wang, X., Cao, L., Zeng, M., Xu, J., 2020. Dynamic surveillance of SARS-CoV-2 shedding and neutralizing antibody in children with COVID-19. Emerg. Microb. Infect. 9, 1254-1258.

Livanos, A.E., Greiner, T.U., Vangay, P., Pathmasiri, W., Stewart, D., McRitchie, S., Li, H.L., Chung, J., Sohn, J., Kim, S., 2016. Antibiotic-mediated gut microbiome perturbation accelerates development of type 1 diabetes in mice. Nat. Microbiol. 1, 16140.

Lopez-Siles, M., Duncan, S.H., Garcia-Gil, L.J., Martinez-Medina, M., 2017. Faecalibacterium prausnitzii: from microbiology to diagnostics and prognostics. ISME J. 11, 841-852.

Man, W.H., Piters, W.A.A.D., Bogaert, D., 2017. The microbiota of the respiratory tract: gatekeeper to respiratory health. Nat. Rev. Microbiol. 15, 259-270.

Man, W.H., van Houten, M.A., Merelle, M.E., Vlieger, A.M., Chu, M.L.J.N., Jansen, N.J.G., Sanders, E.A.M., Bogaert, D., 2019. Bacterial and viral respiratory tract microbiota and host characteristics in children with lower respiratory tract infections: a matched case-control study. Lancet Resp. Med. 7, 417-426.

Mitchell, J., 2011. Italic walking the line between commensalism and pathogenesis. Mol. Oral Microbiol. 26, 89-98.

Murphy, T.F., Brauer, A.L., Grant, B.J., Sethi, S., 2005. Moraxella catarrhalis in chronic obstructive pulmonary disease: burden of disease and immune response. Am. J. Respir. Crit. Care Med. 172, 195-199.

Murphy, T.F., Parameswaran, G.I., 2009. Moraxella catarrhalis a human respiratory tract pathogen. Clin. Infect. Dis. 49, 124-131.

Onder, G., Rezza, G., Brusaferro, S., 2020. Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy. JAMA-J Am Med Assoc 323, 1775-1776.

Otasek, D., Morris, J.H., Boucas, J., Pico, A.R., Demchak, B., 2019. Cytoscape automation: empowering workflow-based network analysis. Genome Biol. 20, 185.

Piters, W.A.A.D., Heinonen, S., Hasrat, R., Bunsow, E., Smith, B., Suarez-Arrabal, M.C., Chaussabel, D., Cohen, D.M., Sanderl, E.A.M., Ramilo, O., 2016. Nasopharyngeal microbiota, host transcriptome, and disease severity in children with respiratory syncytial virus infection. Am. J. Resp. Crit. Care 194, 1104-1115.

Riviere, A., Selak, M., Lantin, D., Leroy, F., De Vuyst, L., 2016. Bifidobacteria and butyrate-producing colon bacteria: importance and strategies for their stimulation in the human gut. Front. Microbiol. 7, 979.

Santee, C.A., Nagalingam, N.A., Faruqi, A.A., DeMuri, G.P., Gern, J.E., Wald, E.R., Lynch, S.V., 2016. Nasopharyngeal microbiota composition of children is related to the frequency of upper respiratory infection and acute sinusitis. Microbiome 4, 34.

Schloss, P.D., Westcott, S.L., Ryabin, T., Hall, J.R., Hartmann, M., Hollister, E.B., Lesniewski, R.A., Oakley, B.B., Parks, D.H., Robinson, C.J., 2009. Introducing mothur: open-source, platform-independent, community-supported software for describing and comparing microbial communities. Appl. Environ. Microbiol. 75, 7537-7541.

Spilker, T., Vandamme, P., LiPuma, J.J., 2013. Identification and distribution of achromobacter species in cystic fibrosis. J. Cyst. Fibros. 12, 298-301.

Stewart, C.J., Ajami, N.J., O'Brien, J.L., Hutchinson, D.S., Smith, D.P., Wong, M.C., Ross, M.C., Lloyd, R.E., Doddapaneni, H., Metcalf, G.A., 2018. Temporal development of the gut microbiome in early childhood from the teddy study. Nature 562, 583-588.

Teo, S.M., Mok, D., Pham, K., Kusel, M., Serralha, M., Troy, N., Holt, B.J., Hales, B.J., Walker, M.L., Hollams, E., 2015. The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development. Cell Host Microbe 17, 704-715.

Wang, Q., Garrity, G.M., Tiedje, J.M., Cole, J.R., 2007. Naive bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy. Appl. Environ. Microbiol. 73, 5261-5267.

Wu, Z.Y., McGoogan, J.M., 2020. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China smmary of a report of 72314 cases from the Chinese center for disease control and prevention. JAMA-J. Am. Med. Assoc. 323, 1239-1242.

Xu, R., Lu, R.F., Zhang, T., Wu, Q.F., Cai, W.H., Han, X.D., Wan, Z.Z., Jin, X., Zhang, Z.G., Zhang, C.Y., 2021. Temporal association between human upper respiratory and gut bacterial microbiomes during the course of COVID-19 in adults. Commun. Biol. 4, 240.

Zuo, T., Zhang, F., Lui, G.C.Y., Yeoh, Y.K., Li, A.Y.L., Zhan, H., Wan, Y., Chung, A., Cheung, C.P., Chen, N., 2020. Alterations in gut microbiota of patients with COVID-19 during time of hospitalization. Gastroenterology 159, 944-955 e948.

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