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

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.

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Review:

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”.