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Post-acute COVID-19 syndrome and gut dysbiosis linger beyond 1 year after SARS-CoV-2 clearance
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  1. Qi Su1,2,3,4,
  2. Raphaela Iris Lau1,2,3,4,
  3. Qin Liu1,2,3,4,
  4. Francis Ka Leung Chan1,2,3,4,
  5. Siew Chien Ng1,2,3,4
  1. 1Microbiota I-Center (MagIC), Hong Kong SAR, People's Republic of China
  2. 2Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, People's Republic of China
  3. 3Li Ka Shing Institute of Health Sciences, State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, People's Republic of China
  4. 4Center for Gut Microbiota Research, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, People's Republic of China
  1. Correspondence to Professor Siew Chien Ng, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong 999077, Hong Kong; siewchienng{at}cuhk.edu.hk

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We recently published in Gut to show that gut dysbiosis persisted for at least 6 months in patients with post-acute COVID-19 syndrome (PACS).1 Murine and human studies have also reported microbial alterations associated with different PACS symptoms.2 3 With the pandemic entering its third year, PACS could potentially affect recovered individuals for over 1 year.4 It remains unknown whether PACS-associated gut dysbiosis would also linger for such a long time.

Here, we conducted a prospective study to determine long-term alterations in the gut microbiome of patients with COVID-19 using shotgun metagenomic sequencing (online supplemental materials). A total of 155 patients with COVID-19 in Hong Kong were followed up for an average of 14 months after SARS-CoV-2 viral clearance, and 155 age-matched, sex-matched and body mass index-matched subjects without COVID-19 were recruited as controls. Patients with COVID-19 were infected with the original or earlier variants of SARS-CoV-2 from January 2020 to February 2021. Consistent with previous finding that 76.4% of patients had PACS 6 months after recovery from acute COVID-19,1 we found that the prevalence of PACS was 78.7% at an average of 14-month (IQR 11–18 months) follow-up. The three most common symptoms were fatigue (50.9%), memory problems (44.5%) and difficulty in sleeping (35.5%, figure 1A). Gut dysbiosis in these patients did not fully recover. Both bacteria diversity (p=0.0036, figure 1B) and richness (p=0.00032, figure 1C) of patients with COVID-19 were still significantly lower than that of controls. Principal coordinates analysis of beta diversity also showed distinct separation of patients with COVID-19 from controls (F=8.3822, p<0.001, figure 1D). These observations suggest persistent gut dysbiosis beyond 1 year in patients with PACS.

Supplemental material

Figure 1

Post-acute COVID-19 syndrome (PACS) and gut dysbiosis 1 year after SARS-CoV-2 clearance. (A) Prevalence of PACS symptoms at an average of 14-month follow-up after viral clearance. The alpha diversity (B) and richness (C) in patients with post-acute COVID-19 compared with subjects without COVID-19. (D) Principal coordinates analysis (PCoA) of gut microbiota composition of patients with post-acute COVID-19 compared with subjects without COVID-19. (E) Volcano plot for the general associations between PACS and microbes at species level calculated by MaAsLin2. False discovery rate (FDR) below 0.05 was considered as significant. (F) Heatmap of microbial species associated with different PACS symptoms. Associations were coloured by direction of effect (red, positive; blue, negative), with associations significant at FDR <0.05 marked with a plus (positive correlations (PC)) or minus (negative correlations (NC)), respectively.

Specifically, the gut microbiome of recovered patients with COVID-19 was characterised by enrichment of potentially pathogenic bacteria, Erysipelatoclostridium ramosum5 and Ruminococcus gnavus,6 as well as depletion of beneficial bacteria such as Bifidobacterium adolescentis and B. pseudocatenulatum (figure 1E and online supplemental table 1). The latter two beneficial bacteria could potentially improve inflammation and neurological symptoms.7 8 Interestingly, PACS affecting different bodily systems showed a similar pattern of microbial alterations (figure 1F). Almost all PACS symptoms were significantly associated with depletion of beneficial bacteria such as Gemmiger formicilis9 and B. adolescentis,7 suggesting the possibility to develop universal microbiome-based therapies or interventions targeting various symptoms. It is worth noting that some beneficial bacteria were not associated with specific PACS symptoms. For example, B. pseudocatenulatum were not found to be associated with any of the respiratory symptoms suggesting that possible functions of different beneficial bacteria should be carefully considered when conducting clinical studies. Consistent with the key microbial species identified thus far,1–3 the enrichment of potentially pathogenic bacteria including R. gnavus, Clostridium bolteae, Flavonifractor plautii and E. ramosum was associated with the majority of the PACS symptoms. Thus, effective elimination or inhibition of these bacteria via dietary intervention, microbiota modulation or drugs may also have significant implications for alleviating PACS. To move forward, more extensive validation on the above associations is needed to address the potential confounders that could possibly alter the microbiome, such as host milieu, diet or medication history.

Supplemental material

Taken together, our findings showed that post-COVID-19 gut dysbiosis could linger beyond 1 year and is closely associated with PACS. Although the exact mechanism underlying the pathogenesis of PACS is largely unknown, these data further support the emerging role of gut microbiota alterations in PACS. Current management of PACS relies heavily on symptomatic treatment of individual symptoms. Gut microbiota modulation could potentially be developed as a novel holistic approach that targets multiple systems and symptoms. In the future, more clinical trials are needed to shed light on the efficacy and safety of microbiome-based interventions for PACS.

Ethics statements

Patient consent for publication

Ethics approval

The study was approved by The Joint Chinese University of Hong Kong – New Territories East Cluster Clinical Research Ethics Committee (The Joint CUHK-NTEC CREC). All subjects provided written informed consent.

References

Supplementary materials

  • Supplementary Data

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Footnotes

  • Twitter @QiSu_123, @Iris_R_Lau, @Siew_C_Ng

  • QS and RIL contributed equally.

  • Contributors QS and RIL conceptualised and designed the study. QS conducted data analyses. RIL collected and interpreted subjects' clinical data. QL provided critical suggestions on data analysis. FKLC contributed to the study design and data interpretation. SCN contributed to the study design, data analysis and manuscript writing. All authors gave final approval for the version to be published.

  • Funding This work was supported by The Health and Medical Research Fund, the Food and Health Bureau, The Government of the Hong Kong Special Administrative Region. The authors are partially supported by InnoHK, The Government of Hong Kong, Special Administrative Region of the People’s Republic of China. R.I.L. received additional support from the Hong Kong PhD Fellowship Scheme (HKPFS).

  • Competing interests FKLC and SCN are the scientific co-founders and sit on the board of Directors of GenieBiome Ltd. SCN has served as an advisory board member for Pfizer, Ferring, Janssen, and Abbvie and a speaker for Ferring, Tillotts, Menarini, Janssen, Abbvie, and Takeda. She has received research grants from Olympus, Ferring, and Abbvie. FKLC has served as an advisor and lecture speaker for Eisai Co. Ltd., AstraZeneca, Pfizer Inc., Takeda Pharmaceutical Co., and Takeda (China) Holdings Co. Ltd. All other co-authors declare no competing interests.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.