J Korean Med Sci.  2023 Apr;38(15):e120. 10.3346/jkms.2023.38.e120.

Gut Microbiota Dysbiosis Correlates With Long COVID-19 at One-Year After Discharge

• Zhang D
• Zhou Y
• Ma Y
• Chen P
• Tang J
• Yang B
• Li H
• Liang M
• Xue Y
• Liu Y
• Zhang J
• Wang X

• KMID: 2541558
• DOI: http://doi.org/10.3346/jkms.2023.38.e120

Abstract

Background
Long coronavirus disease 2019 (COVID-19) in recovered patients (RPs) is gradually recognized by more people. However, how long it will last and the underlining mechanism remains unclear.
Methods
We conducted a prospective follow-up study to evaluate the long-term symptoms and clinical indices of RPs at one-year after discharge from Union Hospital, Wuhan, China between December 2020 to May 2021. We also performed the 16S rRNA sequencing of stool samples from RPs and healthy controls (HCs) and analyzed the correlation between the gut microbiota and long COVID-19.
Results
In total, 187 RPs were enrolled, among them, 84 (44.9%) RPs reported long COVID-19 symptoms at one-year after discharge. The most common long-term symptoms were cardiopulmonary symptoms, including chest tightness after activity (39/187, 20.9%), palpitations on exercise (27/187, 14.4%), sputum (21/187, 11.2%), cough (15/187, 8.0%) and chest pain (13/187, 7.0%), followed by systemic symptoms including fatigue (34/187, 18.2%) and myalgia (20/187, 10.7%), and digestive symptoms including constipation (14/187, 7.5%), anorexia (13/187, 7.0%), and diarrhea (8/187, 4.3%). Sixty-six (35.9%) RPs presented either anxiety or depression (42/187 [22.8%] and 53/187 [28.8%] respectively), and the proportion of anxiety or depression in the long symptomatic group was significantly higher than that in the asymptomatic group (41/187 [50.6%] vs. 25/187 [24.3%]). Compared with the asymptomatic group, scores of all nine 36-Item Short Form General Health Survey domains were lower in the symptomatic group (all P < 0.05). One hundred thirty RPs and 32 HCs (non-severe acute respiratory syndrome coronavirus 2 infected subjects) performed fecal sample sequencing. Compared with HCs, symptomatic RPs had obvious gut microbiota dysbiosis including significantly reduced bacterial diversities and lower relative abundance of short-chain fatty acids (SCFAs)-producing salutary symbionts such as Eubacterium_hallii_group, Subdoligranulum, Ruminococcus, Dorea, Coprococcus, and Eubacterium_ventriosum_group. Meanwhile, the relative abundance of Eubacterium_hallii_group, Subdoligranulum, and Ruminococcus showed decreasing tendencies between HCs, the asymptomatic group, and the symptomatic group.
Conclusion
This study demonstrated the presence of long COVID-19 which correlates with gut microbiota dysbiosis in RPs at one-year after discharge, indicating gut microbiota may play an important role in long COVID-19.

Keyword

Long COVID-19; Persistent Symptoms; Gut Microbiota; Lung-Gut Axis

Figure

• 

  Fig. 1 Correlations between long-term symptoms and laboratory findings, lung functions, total CT scores as well as 6MWD of RPs with COVID-19 at one-year after discharge. Spearman correlation coefficient is indicated using a color gradient: yellow indicates positive correlation; purple indicates negative correlation.CT = computed tomography, 6MWD = 6-minute walk distance, RPs = recovered patients, COVID-19 = coronavirus disease 2019, WBC = white blood cells, ALT = alanine aminotransferase, AST = aspartate aminotransferase, TBIL = total bilirubin, BUN = blood urea nitrogen, Scr = serum creatinine, CRP = C-reactive protein, NK = natural killer, FEV1 = forced expiratory volume in 1 second, FVC = forced vital capacity, DLCO = carbon monoxide diffusing capacity, TLC = total lung capacity, VC = vital capacity.*P < 0.05, **P < 0.01.

• 

  Fig. 2 Differences of alpha diversity (A, B), Venn diagram of OTUs (C) and beta diversity (D) in symptomatic RPs, asymptomatic RPs, and HCs. P value < 0.05 is considered to be statistically significant.RPs = recovered patients, HCs = healthy controls, OTU = operational taxonomic unit.**P < 0.01.

• 

  Fig. 3 The relative abundance of gut microbiota at the phylum (A) and class (B) levels in symptomatic RPs, asymptomatic RPs, and HCs. The category “Other” covers all other phyla or classes with a low taxa abundance.RPs = recovered patients, HCs = healthy controls.

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  Fig. 4 Taxonomic differences of gut microbiota between symptomatic RPs, asymptomatic RPs, and HCs at family (A) and genus (B) levels. Bars indicate mean ± standard deviation. P value < 0.05 is considered to be statistically significant.RPs = recovered patients, HCs = healthy controls.*P < 0.05, **P < 0.01, ***P < 0.001.

• 

  Fig. 5 Correlation analysis of altered gut bacteria and laboratory findings. Spearman correlation coefficient is indicated using a color gradient: yellow indicates positive correlation; purple indicates negative correlation.WBC = white blood cell, ALT = alanine aminotransferase, AST = aspartate aminotransferase, TBIL = total bilirubin, BUN = blood urea nitrogen, Scr = serum creatinine, CRP = C-reactive protein, NK = natural killer.*P < 0.05, **P < 0.01.

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