Gastrointestinal symptoms of long COVID-19 related to the ectopic colonization of specific bacteria that move between the upper and lower alimentary tract and alterations in serum metabolites

Study information

Needs review

study design

case-control

Citation

PMID PubMed identifier for scientific articles.

37468867

DOI Digital object identifier for electronic documents.

10.1186/s12916-023-02972-x

URI

Authors

Zhang D, Weng S, Xia C, Ren Y, Liu Z, Xu Y, Yang X, Wu R, Peng L, Sun L, Zhu J, Liang X, Jia Y, Wang H, Chen Q, Liu D, Chen Y, Guo H, Han X, Jin Z, Chen C, Yang X, Li Z, Huang H

Journal

BMC medicine

Year

2023

Keywords:

Coronavirus, Gut microbiome, Microbial functions, Serum metabolomics

BACKGROUND: Since the coronavirus disease 2019 (COVID-19) outbreak, many COVID-19 variants have emerged, causing several waves of pandemics and many infections. Long COVID-19, or long-term sequelae after recovery from COVID-19, has aroused worldwide concern because it reduces patient quality of life after rehabilitation. We aimed to characterize the functional differential profile of the oral and gut microbiomes and serum metabolites in patients with gastrointestinal symptoms associated with long COVID-19. METHODS: We prospectively collected oral, fecal, and serum samples from 983 antibiotic-naïve patients with mild COVID-19 and performed a 3-month follow-up postdischarge. Forty-five fecal and saliva samples, and 25 paired serum samples were collected from patients with gastrointestinal symptoms of long COVID-19 at follow-up and from healthy controls, respectively. Eight fecal and saliva samples were collected without gastrointestinal symptoms of long COVID-19 at follow-up. Shotgun metagenomic sequencing of fecal samples and 2bRAD-M sequencing of saliva samples were performed on these paired samples. Two published COVID-19 gut microbiota cohorts were analyzed for comparison. Paired serum samples were analyzed using widely targeted metabolomics. RESULTS: Mild COVID-19 patients without gastrointestinal symptoms of long COVID-19 showed little difference in the gut and oral microbiota during hospitalization and at follow-up from healthy controls. The baseline and 3-month samples collected from patients with gastrointestinal symptoms associated with long COVID-19 showed significant differences, and ectopic colonization of the oral cavity by gut microbes including 27 common differentially abundant genera in the Proteobacteria phylum, was observed at the 3-month timepoint. Some of these bacteria, including Neisseria, Lautropia, and Agrobacterium, were highly related to differentially expressed serum metabolites with potential toxicity, such as 4-chlorophenylacetic acid, 5-sulfoxymethylfurfural, and estradiol valerate. CONCLUSIONS: Our study characterized the changes in and correlations between the oral and gut microbiomes and serum metabolites in patients with gastrointestinal symptoms associated with long COVID-19. Additionally, our findings reveal that ectopically colonized bacteria from the gut to the oral cavity could exist in long COVID-19 patients with gastrointestinal symptoms, with a strong correlation to some potential harmful metabolites in serum.

Experiment 1

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Curated date: 2023/10/07

Curator: Chiwendeee

Revision editor(s): Chiwendeee

Subjects

Location of subjects: China

Host species Species from which microbiome was sampled. Contact us to have more species added.: Homo sapiens

Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology: Feces Cow dung,Cow pat,Droppings,Dung,Excrement,Excreta,Faeces,Fecal material,Fecal matter,Fewmet,Frass,Guano,Matières fécales@fr,Merde@fr,Ordure,Partie de la merde@fr,Piece of shit,Porción de mierda@es,Portion of dung,Portion of excrement,Portion of faeces,Portion of fecal material,Portion of fecal matter,Portion of feces,Portion of guano,Portion of scat,Portionem cacas,Scat,Spoor,Spraint,Stool,Teil der fäkalien@de,Feces

Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology: post-COVID-19 disorder post-COVID-19 disorder

Group 0 name Corresponds to the control (unexposed) group for case-control studies: healthy controls

Group 1 name Corresponds to the case (exposed) group for case-control studies: long COVID-19

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: patients with gastrointestinal symptoms associated with long COVID-19

Group 0 sample size Number of subjects in the control (unexposed) group: 25

Group 1 sample size Number of subjects in the case (exposed) group: 45

Antibiotics exclusion Number of days without antibiotics usage (if applicable) and other antibiotics-related criteria used to exclude participants (if any): 3 months before enrollment

Lab analysis

Sequencing type: WMS

16S variable region One or more hypervariable region(s) of the bacterial 16S gene: Not specified

Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance: Illumina

Statistical Analysis

Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).: relative abundances

Statistical test: LEfSe

Significance threshold p-value or FDR threshold used for differential abundance testing (if any): 0.05

MHT correction Have statistical tests be corrected for multiple hypothesis testing (MHT)?: Yes

LDA Score above Threshold for the linear discriminant analysis (LDA) score for studies using the popular LEfSe tool: 1

Matched on Factors on which subjects have been matched on in a case-control study: age, sex

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness: decreased

Chao1 Abundance-based estimator of species richness: decreased

Simpson Estimator of species richness and species evenness: more weight on species evenness: decreased

Signature 1

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Curated date: 2023/10/08

Curator: Chiwendeee

Revision editor(s): Chiwendeee

Source: Figure 3b

Description:

Abundance in Group 1: increased abundance in long COVID-19

NCBI	Quality Control	Links

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Signature 2

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Source: Figure 3b

Description: The microbiomes with significantly reduced relative abundance in follow-up patient fecal samples

Abundance in Group 1: decreased abundance in long COVID-19

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Prevotella
Streptococcus
Veillonella
Haemophilus
Neisseria
Alloprevotella

Revision editor(s): Chiwendeee

Experiment 2

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Curated date: 2023/10/13

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Differences from previous experiment shown

Subjects

Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology: Mouth Adult mouth,Cavital oralis,Cavitas oris,Cavum oris,Mouth cavity,Oral region,Oral vestibule,Regio oralis,Rima oris,Stoma,Stomatodaeum,Trophic apparatus,Vestibule of mouth,Vestibulum oris,Mouth

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: patients with GI symptoms of long COVID-19 after 3 months follow-up

Sequencing type: Not specified

Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance: Not specified

Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).: Not specified

Statistical test: Not specified

Significance threshold p-value or FDR threshold used for differential abundance testing (if any): Not specified

MHT correction Have statistical tests be corrected for multiple hypothesis testing (MHT)?: Not specified

LDA Score above Threshold for the linear discriminant analysis (LDA) score for studies using the popular LEfSe tool: Not specified

Matched on Factors on which subjects have been matched on in a case-control study: Not specified

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness: increased

Chao1 Abundance-based estimator of species richness: increased

Simpson Estimator of species richness and species evenness: more weight on species evenness: increased

Signature 1

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Mark reviewed

Your review change was submitted

Needs review

Curated date: 2023/10/13

Curator: Chiwendeee

Revision editor(s): Chiwendeee, Hodan Issah

Source: Figure 4H

Description: microbiomes with significantly increased relative abundance in follow-up patient saliva samples

Abundance in Group 1: increased abundance in long COVID-19

NCBI	Quality Control	Links
Fusobacterium
Lautropia
Neisseria
Pauljensenia
Porphyromonas
Streptococcus
Veillonella
Candidatus Saccharibacteria
Micrococcaceae
Haemophilus

Revision editor(s): Chiwendeee, Hodan Issah