Gut microbiota from patients with COVID-19 cause alterations in mice that resemble post-COVID symptoms

ABSTRACT

Long-term sequelae of coronavirus disease (COVID)-19 are frequent and of major concern. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection affects the host gut microbiota, which is linked to disease severity in patients with COVID-19. Here, we report that the gut microbiota of post-COVID subjects had a remarkable predominance of Enterobacteriaceae strains with an antibiotic-resistant phenotype compared to healthy controls. Additionally, short-chain fatty acid (SCFA) levels were reduced in feces. Fecal transplantation from post-COVID subjects to germ-free mice led to lung inflammation and worse outcomes during pulmonary infection by multidrug-resistant Klebsiella pneumoniae. transplanted mice also exhibited poor cognitive performance. Overall, we show prolonged impacts of SARS-CoV-2 infection on the gut microbiota that persist after subjects have cleared the virus. Together, these data demonstrate that the gut microbiota can directly contribute to post-COVID sequelae, suggesting that it may be a potential therapeutic target.

KEYWORDS:

• COVID-19
• SARS-CoV-2
• post-COVID
• microbiota
• inflammation
• antimicrobial-resistance

Acknowledgments

Prof. Vasco Azevedo provided the K. pneumonia B31 clinical isolate, Prof. Vivian Vasconcelos Costa and Prof. Mauro Martins Teixeira provided the mouse hepatitis virus MHV-3, and Prof. Flaviano S. Martins provided the probiotic strain B. longum 5^1A. Daniela M. Nolasco and Prof. Leda Quercia Vieira for technical support; Eduardo Zimmer, Andreza F. de Bem, and Ana Maria Caetano de Faria for their valuable discussions.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author Contributions

Study conception, methodology, supervision, project administration and funding acquisition: A.T.V.

Investigation: V.M., D.F.E., M.F.R., C.S.C., D.A.A., M.A., J.M., E.C.M., V.M.R., T.G.C., L.S.B.L., J.C.P., M.A., G.S.Z., B.J.S., V.C.C., E.S.R., I.G., and C.C.G.

Formal analysis and interpretation of the data: V. M., M. F. R., D. F. E., C. S. C., E. R. G. R. A, I. S. L., D. A. A., T. G. C., G. D. C., and D. M. S.

Data curation: V.M., E.R.G.R.A, and I.S.L.

Resources: F.S.M., J.T.M., F.M.R., L.C.A., M.M.T., V.V.C., R.S.S.

Writing – original draft: V.M., A.T.V., M.F.R., D.F.E.

Writing – review & editing: J.T.M., P.M.H., M.M.T., and A.T.V.

Visualization: V.M., C.S.C. A.T.V., and M.F.R.

Data availability statement

The 16S rRNA gene libraries produced in this study were deposited in the NCBI SRA database under the project number PRJNA843134. The data are available upon request from the corresponding author.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2249146

Additional information

Funding

This work was supported by the National Council for Scientific and Technological Development – CNPq (call MCTIC/CNPq/FNDCT/MS/SCTIE/Decit 07/2020 [process number: 402530/2020-9], Universal MCTIC/CNPq [process number: 408703/2021-0]), Fundação de Amparo à Pesquisa de Minas Gerais (FAPEMIG) (APQ-03328-18; APQ-00686-21; Rede Mineira de Investigação em Mucosas e Pele 0096-22), and Instituto Serrapilheira (No. 03/2019).Coordenação de Aperfeiçoamento de Pessoal de Nı́vel Superior, Brazil (CAPES) Finance Code 001: V.M.A and D.A.A.CAPES-Print: I.G.Pró-Reitoria de Pesquisa da Universidade Federal de Minas Gerais – PRPq/UFMGSão Paulo Research Foundation (grants 2017/25588-1, 2018/14666-4, 2019/00098-7, 2019/05155-9 and 2020/04746-0): R.S.S. and D.M.S.National Health and Medical Research Council of Australia (105,9238, 1175134, 2010287): P.M.M.