Skip to main content

Improved gut microbiota features after the resolution of SARS‑CoV‑2 infection

Abstract

Background

The severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) has a tropism for the gastrointestinal tract and several studies have shown an alteration of the gut microbiota in hospitalized infected patients. However, long-term data on microbiota changes after recovery are lacking.

Methods

We enrolled 30 patients hospitalized for SARS‑CoV‑2-related pneumonia. Their gut microbiota was analyzed within 48 h from the admission and compared with (1) that of other patients admitted for suspected bacterial pneumonia (control group) (2) that obtained from the same subject 6 months after nasopharyngeal swab negativization.

Results

Gut microbiota alpha-diversity increased 6 months after the resolution of SARS-CoV-2 infection. Bacteroidetes relative abundance was higher (≈ 36.8%) in patients with SARS-CoV-2, and declined to 18.7% when SARS-CoV-2 infection resolved (p  =  0.004). Conversely, Firmicutes were prevalent (≈ 75%) in controls and in samples collected after SARS-CoV-2 infection resolution (p  =  0.001). Ruminococcaceae, Lachnospiraceae and Blautia increased after SARS-CoV-2 infection resolution, rebalancing the gut microbiota composition.

Conclusion

SARS-CoV-2 infection is associated with changes in the gut microbiome, which tend to be reversed in long-term period.

Background

Several studies to date have analyzed the gut microbiota of patients with severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection both during and after disease resolution [1, 2]. However, information on long-term follow-up is lacking. Therefore, we evaluated changes to the gut microbiome six months after SARS-CoV-2 infection resolution in 30 Italian patients hospitalized for pneumonia in our center during the first wave of the pandemic.

Study design and results

Faecal samples of 31 SARS-CoV-2-positive patients were harvested within 48 h from admission and prior to transfer to the intensive care unit (ICU), in order to minimize any impact of the pharmaceutical treatment on the gut microbiome, and again six months after discharge. During this , patients were regularly interviewed and none of them reported any infection/antibiotic treatment or symptoms of new onset. Eighteen patients hospitalized in the same period for SARS-CoV-2-unerlated pneumonia served as control group. Following hospital admission, at the time of fecal specimen collection, both control group (94.7%) and patients showing SARS-CoV-2 related pneumonia (71%) were receiving the same antibiotic treatment schedule, as per Hospital protocol. Faecal samples analysis was conducted as described in the Additional file 4. Characteristics of the study population are shown in Table 1. Gut microbiota alpha-diversity was similar between patients affected by either SARS-CoV-2 or non-SARS-CoV-2 pneumonia; it showed a slight enhanced trend after SARS-CoV-2 negativization, increasing significantly after the resolution of SARS-CoV-2 infection when compared with the control group (p  =  0.346, p  =  0.043 and p  =  0.048, Kruskal–Wallis Test, for Shannon index, inverse Simpson index and Pielou’s Evenness, respectively). In particular, equitability among bacterial species increased and appeared to be driven by microbial changes ensuing SARS-CoV-2 infection resolution (Fig. 1A). The PCoA of inter-individual variation based on weighted UniFrac distance showed a slender split among the study groups, although it was not statistically significant (p  =  0.114, PERMANOVA; Additional file 1: Figure S1). As shown in Fig. 1B, Bacteroidetes relative abundance was higher (≈ 36.8%) in SARS-CoV-2 positive patients than in those with SARS-CoV-2 negative pneumonia (≈13.6%), and declined to 18.7% when SARS-CoV-2 infection resolved (p  =  0.004, Kruskal–Wallis Test). Conversely, Firmicutes were prevalent (≈ 75%) in controls and in samples collected after SARS-CoV-2 infection resolution, while the relative abundance was lower (≈ 50%) in SARS-CoV-2 positive pneumonia group (p  =  0.001, Kruskal–Wallis Test).

Table 1 Clinical and demographic features of patients included in the study
Fig. 1
figure1

Gut microbiota analysis of patients with or without severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection. A alpha diversity measures; B, C phyla and genera distribution; D linear discriminant analysis (LDA) effect size (LEfSe) highlighting differently abundant taxa between the study groups

Focusing on the twenty most represented bacterial genera, we observed specific patterns of Bacteroides, Blautia and Enterococcus variations among groups (Fig. 1C). Particularly, Bacteroides and Enterococcus genera appeared to correlate inversely, with the former genus being increased in SARS-CoV-2 positive patients compared to the other groups (p  =  0.003), whereas the latter genus showed a decreasing trend (p  =  0.082). Finally, Blautia increased after SARS-CoV-2 infection resolution, rebalancing the gut microbiota composition (p  =  0.029). As expected, linear discriminant analysis (LDA) showed that bacterial elements belonging to Bacteroidetes (i. e., Oscillibacter, Ruminococcaceae DTU089, Bacteroidaceae, Bacteroidia, Parabacteroides and Tannerellaceae) were enriched in SARS-CoV-2 positive patients, whereas Lactobacillales, Streptococcus, Staphylococcus and Acidoaminococcus were increased in those with SARS-CoV-2-unrelated pneumonia (p  <  0.05, Kruskal–Wallis Test; Fig. 1D). Conversely, Lachnospiraceae (i. e., NK4A136 group, Fusicantibacter and Roseburia) and Ruminococcaceae UCG-013 were increased after SARS-CoV-2 infection resolution. DESeq2 analysis reported substantially the same results (Additional file 2: Table S1, Additional file 3: Table S2).

Discussion

Our study conducted in a Western population confirms that gut microbiota alpha diversity is similar in patients with SARS-CoV-2 related or unrelated pneumonia. Nevertheless, we observed an increase in alpha-diversity after the resolution of SARS-CoV-2 acute infection. This may be related to the effects of SARS-CoV-2 on the gut microbiota, but the contribution of drugs (e.g., antibiotics) administered before hospitalization or during its initial phase may not be negligible. Nevertheless, alpha-diversity modification may be not sufficient to assess recovery of the healthy status.

Previous Chinese studies [3,4,5] compared the gut microbiota of patients with SARS-CoV-2-related and community-acquired pneumonia, confirming a surge of opportunistic pathogens and a reduction in commensals elements. Our data confirm Bacteroidetes enrichment in patients with COVID-19 [3]. Conversely, Firmicutes appeared to decline, whereas no significant variation was observed for Actinobacteria [3]. During SARS-CoV-2 infection, inflammation is a key determinant of disease severity [6,7,8]. Interestingly, cytokine storm is positively associated with Bacteroides relative abundance [3]. Conversely, Blautia with its anti-inflammatory properties may play an important role in the recovery from COVID-19 [9]. Indeed, interleukin-10 (IL-10) serum levels significantly decrease with the reduction of Ruminococcus obeum (otherwise Blautia) abundance [3], and this correlates with the failure in controlling host’s inflammatory response. This study suffers of the limitations of the small sample size, but our results corroborate those achieved on populations with different ethnicity. Even though many factors can affect the gut microbiota, our findings support the hypothesis of a specific impact of SARS-CoV-2 infection on the gut microbiota.

Conclusions

This study supports the previous evidence that SARS-CoV-2 infection is associated with changes in the gut microbiome. However, many gut microbiome-related factors could influence the course of COVID-19, calling for more studies in the next future.

Availability of data and materials

Available upon reasonable request.

References

  1. 1.

    Chhibber-Goel J, Gopinathan S, Sharma A. Interplay between severities of COVID-19 and the gut microbiome: implications of bacterial co-infections? Gut Pathog. 2021;13:14.

    CAS  Article  Google Scholar 

  2. 2.

    Yamamoto S, Saito M, Tamura A, Prawisuda D, Mizutani T, Yotsuyanagi H. The human microbiome and COVID-19: a systematic review. PLoS ONE. 2021. https://doi.org/10.1371/journal.pone.0253293.

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Yeoh KY, Zuo T, Lui GCY, Zhang F, Liu Q, Li AY, et al. Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19. Gut. 2021;70:698–706.

    CAS  Article  Google Scholar 

  4. 4.

    Zuo T, Zhang F, Lui GCY, Yeoh YK, Li AYL, Zhan H, et al. Alterations in gut microbiota of patients with COVID-19 during time of hospitalization. Gastroenterology. 2020;159(3):944-955.e8.

    CAS  Article  Google Scholar 

  5. 5.

    Gu S, Chen Y, Wu Z, Chen Y, Gao H, Lv L, et al. Alterations of the gut microbiota in patients with coronavirus disease 2019 or H1N1 influenza. Clin Infect Dis. 2020;71:2669–78.

    CAS  Article  Google Scholar 

  6. 6.

    Ponziani FR, Del Zompo F, Nesci A, Santopaolo F, Ianiro G, Pompili M, et al. Liver involvement is not associated with mortality: results from a large cohort of SARS-CoV-2-positive patients. Aliment Pharmacol Ther. 2020;52:1060–8.

    CAS  PubMed  Google Scholar 

  7. 7.

    Ponziani FR, Nesci A, Del Zompo F, Santopaolo F, Pompili M, Gasbarrini A, et al. Correlation between liver function tests abnormalities and interleukin-6 serum levels in patients with SARS-CoV-2 infection. Gastroenterology. 2021;160:1891–3.

    CAS  Article  Google Scholar 

  8. 8.

    Del Zompo F, De Siena M, Ianiro G, Gasbarrini A, Pompili M, Ponziani FR. Prevalence of liver injury and correlation with clinical outcomes in patients with COVID-19: systematic review with meta-analysis. Eur Rev Med Pharmacol Sci. 2020;24:13072–88.

    PubMed  Google Scholar 

  9. 9.

    Liu X, Mao B, Gu J, Wu J, Cui S, Wang G, et al. Blautia-a new functional genus with potential probiotic properties? Gut Microbes. 2021;13:1–21.

    Article  Google Scholar 

Download references

Acknowledgements

None.

Funding

None.

Author information

Affiliations

Authors

Contributions

FDM analyzed samples, interpreted data, designed the study, wrote and approved the final version of the paper; FRP interpreted data, designed the study, wrote and approved the final version of the paper; DMB analyzed and interpreted data; GI, FS, VA, GDM, AN, MP, GC, BP, MS, AG interpreted data, approved the final version of the paper; GC, FDZ, ML, AN collected samples, interpreted data, approved the final version of the paper. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Francesca Romana Ponziani.

Ethics declarations

Ethics approval and consent to participate

The local ethics committee of the Fondazione Policlinico Universitario Agostino Gemelli IRCCS approved the study (ID 3042).

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Additional file 1. 

Principal coordinate analysis (PCoA) on weighted UniFrac distance of the gut microbiome of patient with severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2)-related pneumonia, who were tested before and after resolution of the infection, and patients with SARS-CoV-2 unrelated pneumonia.

Additional file 2. 

DESeq2 analysis.

Additional file 3. 

DESeq2 analysis.

Additional file 4. 

Supplementary methods.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

De Maio, F., Ianiro, G., Coppola, G. et al. Improved gut microbiota features after the resolution of SARS‑CoV‑2 infection. Gut Pathog 13, 62 (2021). https://doi.org/10.1186/s13099-021-00459-9

Download citation

Keywords

  • Gut microbiota
  • SARS-CoV-2
  • COVID-19
  • Pneumonia