• COVID-19
• intestinal microbiology

We read with great interest the recent article published in Gut in which Yeoh et al demonstrated that gut microbiota composition of recovered patients with COVID-19 remained significantly distinct from uninfected controls.1 Persisting symptoms, also known as ‘long COVID-19’, have been reported in a significant proportion of patients following hospital discharge.2 3 Gut dysbiosis might link to long COVID-19 risks.1 Few studies have focused on the recovery process of gut microbiota following SARS-CoV-2 infection.

Here, we conducted a prospective study to longitudinally monitor alterations of gut microbiota in patients with COVID-19 using 16S rDNA sequencing (detailed methods in online supplementary materials). Faecal microbiota was monitored at three timepoints, acute phase (from illness onset to viral clearance), convalescence (from viral clearance to 2 weeks after hospital discharge), postconvalescence (6 months after hospital discharge).

The gut microbiota richness, measured by Chao 1 index, was obviously lower (p<0.01, Wilcoxon rank-sum test; figure 1A) in the acute phase of COVID-19 (median 217, IQR 164–266) as compared with uninfected controls (median 432, IQR 332–468). There was a non-significant increase of the Chao 1 index from the acute phase (median 217, IQR 164–266) to the convalescence (median 241, IQR 202–279) and postconvalescence (median 259, IQR 193–302). A Bray-Curtis based principal coordinated analysis revealed that the overall microbial composition of patients with COVID-19 deviated from the uninfected controls (analysis of similarities, R = – 0.20, p=0.001, figure 1B). There was a tendency of the gut microbiota composition moving toward the controls from the acute phase to recovery phase along the first principal coordinate. Notably, the species richness as estimated by Chao 1 index, can explain the differences along the first principal coordinate (figure 1C).

• Download figure
• Open in new tab
• Download powerpoint

Figure 1

Changes of faecal microbial communities in different stages (acute, convalescence, postconvalescence) of patients with COVID-19 (n=30), compared with uninfected controls (n=30). (A) α-Diversity, illustrated by microbiota richness (Chao 1 index), was reduced in COVID-19 (p<0.01, Wilcoxon rank-sum test). Boxes represent the 25th–75th percentile of the distribution; the median is shown as a thick line in the middle of the box; whiskers extend to values with 1.5 times the difference between the 25th and 75th percentiles. ***P<0.001. (B) Principal coordinate analysis (PCoA) of Bray-Curtis distance analysis demonstrated that the overall microbial composition of patients with COVID-19 deviated from the uninfected controls (analysis of similarities, R = – 0.201, p=0.001). (C) The same PCoA plot as (B), coloured by α-diversity measured by Chao 1 index.

The median Chao 1 index in postconvalescence was 259. Patients were further divided into two subgroups according to their Chao 1 index in postconvalescence: low (≤259, n=15) and high (>259, n=15) (table 1). Patients with reduced postconvalescence richness had higher level of CRP (p=0.01), as well as higher occurrence of intensive care unit admission (p=0.03) and high flow nasal catheter oxygen therapy therapy (p=0.03) during the acute phase. In postconvalescence, low richness was associated with reduced pulmonary function of forced vital capacity (p=0.03), forced expiratory volume in the first 1 s of expiration (p=0.02), inspiratory vital capacity (p=0.05) and total lung capacity (p=0.05).

The present study found that microbiota richness was not restored to normal levels after 6-month recovery. Patients with lower postconvalescence richness showed higher level of CRP and illness severity during the acute phase, suggesting close correlations between inflammatory response and gut dysbiosis in COVID-19, as illustrated in previous studies.1 4 Microbial diversity is a critical determinant of microbial ecosystem stability.5 Stable ecosystems provide colonisation resistance to opportunistic pathogens.6 Therefore, the persistent reduction of gut microbiota richness may have long-term biological influence during the COVID-19 pandemic.7 Follow-up studies of 3 months and 6 months have shown pulmonary function impairment along with cardiac abnormalities in patients with COVID-19.2 8 The results here indicated that postconvalescence patients with lower microbial richness had worse pulmonary functions. Gut microbiota is implicated in the pathogenesis of acute lung injury via several potential mechanisms, including direct translocation of bacteria from gut to the lung and immune modulation effects of microbes related metabolites.9 10 Our study corroborates the growing evidence that gut dysbiosis is associated with the recovery process of COVID-19. Due to the relatively small sample size, our results need to be confirmed in further studies with larger sample size and more techniques. Targeted manipulation to promote the microbial diversity could be an important strategy to treat long COVID-19 and speed up recovery.