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Review 1: "Guild-level microbiome signature associated with COVID-19 severity and prognosis"

This study identifies microbial guilds associated with mild or severe cases of COVID-19, and uses ML to predict the clinical outcome of SARS-COV-2 infection in other cohorts based on the 2 guilds. Reviewers encourage decision-makers to consider the claims potentially actionable.

Published onOct 24, 2022
Review 1: "Guild-level microbiome signature associated with COVID-19 severity and prognosis"
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key-enterThis Pub is a Review of
Guild-level microbiome signature associated with COVID-19 severity and prognosis

AbstractCOVID-19 severity has been associated with alterations of the gut microbiota. However, the relationship between gut microbiome alterations and COVID-19 prognosis remains elusive. Here, we performed a genome-resolved metagenomic analysis on fecal samples collected from 300 in-hospital COVID-19 patients at time of admission. Among the 2,568 high quality metagenome-assembled genomes (HQMAGs), Redundancy Analysis identified 33 HQMAGs which showed differential distribution among mild, moderate, and severe/critical severity groups. Random Forest model based on these 33 HQMAGs classified patients from different severity groups (average AUC = 0.79). Co-abundance network analysis found that the 33 HQMAGs were organized as two competing guilds. Guild 1 harbored more genes for short-chain fatty acid biosynthesis, and fewer genes for virulence and antibiotic resistance, compared with Guild 2. Random Forest regression showed that these 33 HQMAGs at admission had the capacity to predict 8 clinical parameters, which are predictors for COVID-19 prognosis, at Day 7 in hospital. Moreover, the dominance of Guild 1 over Guild 2 at admission predicted the death/discharge outcome of the critical patients (AUC = 0.92). Random Forest models based on these 33 HQMAGs classified patients with different COVID-19 symptom severity, and differentiated COVID-19 patients from healthy subjects, non-COVID-19, and pneumonia controls in three independent datasets. Thus, this genome-based guild-level signature may facilitate early identification of hospitalized COVID-19 patients with high risk of more severe outcomes at time of admission.

RR:C19 Evidence Scale rating by reviewer:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.



This is an important paper describing the identification of microbial consortia that are linked to either mild or more serious outcomes of Sars-COV-2 infection. The paper is solid and should be published, provided the following amendments are made:

  • Page 12: Are the loadings for principal components 1 and 2 of the PCA performed on other COVID-19 cohorts, as exemplified in Figure 5A, identical to those of the PCA for the original cohort that was studied (as shown in Figure 1A)? Different loadings would indicate varying importance of the parameters on which the separation between mild, moderate, etc patients groups is performed. In the case of different loadings, the underlying microbial composition still differs for the different cohorts, despite their being separated. This should be discussed in the text.

  • The methods section is thorough but also highly technical. The authors should keep this in mind depending on the target audience of this paper, such as bioinformaticians, statisticians, medical clinicians, and microbiota researchers in general. I would like to have more context regarding all the methods used in order to make the paper more accessible to the general scientific audience, which is important considering the interesting results the authors obtained.

  • The authors claim to identify two microbial guilds. However, considering the current redefinition of a microbial guild as postulated by some of the authors of this paper (“we redefine guild as a group of bacteria that show consistent co-abundant behavior and likely to work together to contribute to the same ecological function”, Genome Medicine volume 13, Article number: 22 (2021)), it is not clear what the actual ecological function consists of. Indeed, it seems that the guilds have different capabilities for the production of butyrate. However, many differences in clinical markers seem to be related to the dominance of either guild 1 or 2, but no overall consistent behavior (for example: overall (anti)inflammatory) seems to characterize either guild. As such, it may be a bit too early to speak of real guilds. Please elaborate on this in the discussion.

  • Page 7: typo in line 156, “underlying”.

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