SARS-CoV-2 triggered excessive inflammation and abnormal energy metabolism in gut microbiota

  1. Tuoyu Zhou
  2. Yufei Zeng
  3. Jingyuan Wu
  4. Junfeng Li
  5. Jun Yan
  6. Wenbo Meng
  7. Hawen Han
  8. Fengya Feng
  9. Jufang He
  10. Shuai Zhao
  11. Ping Zhou
  12. Ying Wu
  13. Yanling Yang
  14. Rong Han
  15. Weiling Jin
  16. Xun Li
  17. Yunfeng Yang
  18. Xiangkai Li

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Abstract

Specific roles of gut microbes in COVID-19 progression are critical. However, the circumstantial mechanism remains elusive. In this study, shotgun metagenomic or metatranscriptomic sequencing were performed on fecal samples collected from 13 COVID-19 patients and controls. We analyzed the structure of gut microbiota, identified the characteristic bacteria and selected biomarkers. Further, GO, KEGG and eggNOG annotation were employed to correlate the taxon alteration and corresponding functions. The gut microbiota of COVID-19 patients was characterized by the enrichment of opportunistic pathogens and depletion of commensals. The abundance of Bacteroides spp. displayed an inverse relationship to COVID-19 severity, whereas Actinomyces oris , Escherichia coli , and Gemmiger formicilis were positively correlated with disease severity. The genes encoding oxidoreductase were significantly enriched in SARS-CoV-2 infection. KEGG annotation indicated that the expression of ABC transporter was up regulated, while the synthesis pathway of butyrate was aberrantly reduced. Furthermore, increased metabolism of lipopolysaccharide, polyketide sugar, sphingolipids and neutral amino acids was found. These results suggested the gut microbiome of COVID-19 patients was correlated with disease severity and in a state of excessive inflammatory response. Healthy gut microbiota may enhance antiviral defenses via butyrate metabolism, whereas the accumulation of opportunistic and inflammatory bacteria may exacerbate the disease progression.

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    SciScore for 10.1101/2021.11.08.467715: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsConsent: 4.5 Ethics approval: All participants provided written informed consents prior to starting the study.
    IRB: Research protocols were approved and supervised (LDYYL-2020-24) by the Institutional Review Board of the First Hospital of Lanzhou University and conformed to the ethical guidelines of the 1975 Declaration of Helsinki.
    IACUC: Research protocols were approved and supervised (LDYYL-2020-24) by the Institutional Review Board of the First Hospital of Lanzhou University and conformed to the ethical guidelines of the 1975 Declaration of Helsinki.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Next, qualified reads were aligned to the human genome by employing Bowtie2 v2.2.0 to remove host contamination, followed by de novo assembly to construct the contigs for each sample by respectively applying IDBA-UD v1.1.1 and Trinity v2.2.0.
    Bowtie2
    suggested: (Bowtie 2, RRID:SCR_016368)
    IDBA-UD
    suggested: (IDBA-UD, RRID:SCR_011912)
    Trinity
    suggested: (Trinity, RRID:SCR_013048)
    And then, the contigs were clustered to by CD-HIT v4.6.1 to obtain unigenes.
    CD-HIT
    suggested: (CD-HIT, RRID:SCR_007105)
    Then, unigenes were aligned against the NCBI NR database to obtain the lowest common ancestor taxonomy of them with DIAMOND v 0.9.14.
    NCBI NR
    suggested: None
    DIAMOND
    suggested: (DIAMOND, RRID:SCR_009457)
    Alpha diversity was calculated using QIIME v1.8.0.
    QIIME
    suggested: (QIIME, RRID:SCR_008249)
    Differential bacterial taxa between groups were identified conducting Linear discrimination analysis (LDA) effect size (LEfSe) analysis, and taxon with an LDA◻>◻3.0-fold were considered significantly different.
    LEfSe
    suggested: (LEfSe, RRID:SCR_014609)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Some limitations of the study should be mentioned. First, this is a single-center study with a moderate sample size, which does not apply to all COVID-19 patients. The corresponding relationship between SARS-CoV-2 infection and intestinal flora dysbiosis should be validated in a larger cohort, including subgroups at different stages of the disease. Though several species that may be central players for COVID-19 progression were discussed and reviewed (Table S9 and S10), meta-analysis from current multicenter and different studies to obtain universal conclusions is urgently warranted [18, 31, 32, 34, 35, 44, 58]. Moreover, this study depicted the alterations between patients at different stages of COVID-19, while no specific assessment has been conducted on the changes in COVID-19 microbiota and functions over time. Albeit we tried to control the variation degree between COVID-19 patients and the healthy controls, the alternations of gut microbiota may be influenced by other confounding factors, such as lifestyle, dietary habits, underlying diseases, complications, and clinical management. Lastly, the disease stage of COVID-19 at the time of stool sample collection is uncertain and there is a lack of information on pre-infection stool samples. Collectively, this study further revealed alterations in the composition and function of active intestinal microflora in COVID-19 cases. Specific microbial biomarkers of COVID-19 patients were screened and correlated with clinical indica...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

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  2. Version published to 10.1101/2021.11.08.467715v1 on bioRxiv