Gut microbiota dynamics in a prospective cohort of patients with post-acute COVID-19 syndrome

Qin Liu, Joyce Wing Yan Mak, Qi Su, Yun Kit Yeoh, Grace Chung-Yan Lui, Susanna So Shan Ng, Fen Zhang, Amy Y L Li, Wenqi Lu, David Shu-Cheong Hui, Paul Ks Chan, Francis K L Chan, Siew C Ng, Qin Liu, Joyce Wing Yan Mak, Qi Su, Yun Kit Yeoh, Grace Chung-Yan Lui, Susanna So Shan Ng, Fen Zhang, Amy Y L Li, Wenqi Lu, David Shu-Cheong Hui, Paul Ks Chan, Francis K L Chan, Siew C Ng

Abstract

Background: Long-term complications after COVID-19 are common, but the potential cause for persistent symptoms after viral clearance remains unclear.

Objective: To investigate whether gut microbiome composition is linked to post-acute COVID-19 syndrome (PACS), defined as at least one persistent symptom 4 weeks after clearance of the SARS-CoV-2 virus.

Methods: We conducted a prospective study of 106 patients with a spectrum of COVID-19 severity followed up from admission to 6 months and 68 non-COVID-19 controls. We analysed serial faecal microbiome of 258 samples using shotgun metagenomic sequencing, and correlated the results with persistent symptoms at 6 months.

Results: At 6 months, 76% of patients had PACS and the most common symptoms were fatigue, poor memory and hair loss. Gut microbiota composition at admission was associated with occurrence of PACS. Patients without PACS showed recovered gut microbiome profile at 6 months comparable to that of non-COVID-19 controls. Gut microbiome of patients with PACS were characterised by higher levels of Ruminococcus gnavus, Bacteroides vulgatus and lower levels of Faecalibacterium prausnitzii. Persistent respiratory symptoms were correlated with opportunistic gut pathogens, and neuropsychiatric symptoms and fatigue were correlated with nosocomial gut pathogens, including Clostridium innocuum and Actinomyces naeslundii (all p<0.05). Butyrate-producing bacteria, including Bifidobacterium pseudocatenulatum and Faecalibacterium prausnitzii showed the largest inverse correlations with PACS at 6 months.

Conclusion: These findings provided observational evidence of compositional alterations of gut microbiome in patients with long-term complications of COVID-19. Further studies should investigate whether microbiota modulation can facilitate timely recovery from post-acute COVID-19 syndrome.

Keywords: COVID-19; intestinal microbiology.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Post-acute COVID-19 syndrome (PACS) after virus clearance. (A) The proportion of 30 symptoms in 106 patients at 3 months and 6 months after acute COVID-19; (B) Multivariable analysis on factors associated with development of PACS. The centre dot denotes the mean value, the boxes denote the upper and lower interquartile ranges.
Figure 2
Figure 2
Compositional differences in gut microbiota of in-hospital patients (antibiotic-naïve) and their follow-up stools after negative SARS-CoV-2, and non-COVID-19 individuals. (A) Principal coordinates analysis (PCoA) of gut microbiota composition of patients with COVID-19 before and after negative SARS-CoV-2 compared with non-COVID-19 subjects. (B) Diversity and richness (C) Analysis of gut microbiota in patients with COVID-19 at 1 month and 6 months after virus clearance. (D) Average relative abundance of top five phyla and top 10 microbial genera (E) detected in stools from in-hospital patient and their follow-up within 1 month and longer than 6 months after negative SARS-CoV-2.
Figure 3
Figure 3
Gut microbiota composition in patients with COVID-19 with and without post-acute COVID-19 syndrome (PACS) at 6 months; (A) Principal coordinates analysis (PCoA) of gut microbiota composition of patients with COVID-19 with and without PACS at 6 months. (B) Bacteria diversity and richness. (C) Analysis of gut microbiota composition of patients with and without PACS. (C) Linear discriminant analysis effect size analysis of discriminant taxa in gut microbiome of patients with PACS at 6 months. LDA, linear discriminant analysis.
Figure 4
Figure 4
Compositional differences in gut microbiota of baseline and follow-up samples at different time points after virus clearance. (A) Principal coordinates analysis (PCoA) of gut microbiota composition of patients with COVID-19 with or without post-acute COVID-19 syndrome (PACS) before and after negative reverse transcriptase-quantitative polymerase chain reaction for SARS-CoV-2 compared with non-COVID-19 subjects. (B) Diversity and richness analysis (as measured in Simpson diversity and Chao1 richness index, respectively) of gut microbiota in patients with COVID-19 at baseline compared with non-COVID-19 subjects. (C) Diversity and richness analysis of gut microbiota in patients with COVID-19 at 6 months' follow-up compared with non-COVID-19 subjects. (D) Change of gut microbial composition from baseline to 6 months' follow-up after virus clearance in patients with COVID-19 with or without PACS. (E) Linear discriminant analysis effect size in gut microbiome of recovered patients with PACS at baseline.
Figure 5
Figure 5
Factors affecting the gut microbiome in follow-up stools from patients after clearing the virus. (A) Effect size of subject metadata on gut microbiome composition determined by permutational multivariate analysis of variance (PERMANOVA) test. (B) Overall associations between gut microbiome composition with different subgroups of post-acute COVID-19 syndrome (PACS) determined by PERMANOVA test. (C) Associations of bacteria species with different categories of PACS at 6 months. MaAsLin, multivariate association with linear model.
Figure 6
Figure 6
Gut microbiota composition at admission of patients with COVID-19 who had or had not any persistent symptoms at 6 months. (A) Principal coordinates analysis (PCoA) of gut microbiota composition of patients with COVID-19 who had or had not any persistent symptoms at month 6 after clearing SARS-CoV-2. (B) Gut microbiota composition of first stool samples after confirmed positive reverse transcriptase-quantitative polymerase chain reaction for SARS-CoV-2 during hospitalisation. (C) Associations between persistent symptoms in recovered patients with COVID-19 and baseline microbial features as determined by multivariate association with linear model (p

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