Plasma Markers of Disrupted Gut Permeability in Severe COVID-19 Patients
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Abstract
A disruption of the crosstalk between the gut and the lung has been implicated as a driver of severity during respiratory-related diseases. Lung injury causes systemic inflammation, which disrupts gut barrier integrity, increasing the permeability to gut microbes and their products. This exacerbates inflammation, resulting in positive feedback. We aimed to test whether severe Coronavirus disease 2019 (COVID-19) is associated with markers of disrupted gut permeability. We applied a multi-omic systems biology approach to analyze plasma samples from COVID-19 patients with varying disease severity and SARS-CoV-2 negative controls. We investigated the potential links between plasma markers of gut barrier integrity, microbial translocation, systemic inflammation, metabolome, lipidome, and glycome, and COVID-19 severity. We found that severe COVID-19 is associated with high levels of markers of tight junction permeability and translocation of bacterial and fungal products into the blood. These markers of disrupted intestinal barrier integrity and microbial translocation correlate strongly with higher levels of markers of systemic inflammation and immune activation, lower levels of markers of intestinal function, disrupted plasma metabolome and glycome, and higher mortality rate. Our study highlights an underappreciated factor with significant clinical implications, disruption in gut functions, as a potential force that may contribute to COVID-19 severity.
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SciScore for 10.1101/2020.11.13.20231209: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: All research protocols of the study were approved by the institutional review boards (IRB) at Rush University and The Wistar Institute. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable The study cohort was also chosen to have a 35 to 60% representation of female gender per disease status group (Supplementary Table 1). Table 2: Resources
Software and Algorithms Sentences Resources Metabolites were identified by accurate mass and retention time using an in-house database generated from pure standards or by MS2 spectra using the mzCloud spectral database (mzCloud.org) and selecting the best matches with scores … SciScore for 10.1101/2020.11.13.20231209: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: All research protocols of the study were approved by the institutional review boards (IRB) at Rush University and The Wistar Institute. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable The study cohort was also chosen to have a 35 to 60% representation of female gender per disease status group (Supplementary Table 1). Table 2: Resources
Software and Algorithms Sentences Resources Metabolites were identified by accurate mass and retention time using an in-house database generated from pure standards or by MS2 spectra using the mzCloud spectral database (mzCloud.org) and selecting the best matches with scores of 50 or greater. mzCloudsuggested: (mzCloud, RRID:SCR_014669)IgA was concentrated using Amicon® filters (Milipore catalogue #UFC805024) and purity was confirmed by SDS gel. Amicon®suggested: NoneStatistical analyses were performed in R 4.0.2 and Prism 7.0 (GraphPad) Prismsuggested: (PRISM, RRID:SCR_005375)GraphPadsuggested: (GraphPad Prism, RRID:SCR_002798)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:Caveats of our study include the sample size and sampling of blood. As noted above, correcting for potential confounders will require larger cohorts from varying geographic and demographic settings. Independent test sets and samples from non-COVID1-9 hospitalized and ICU-admitted patients will also be needed. In addition, longitudinal analyses will be required to examine the long-term implications of our findings and their potential value as prognostic biomarkers. Analysis of gut biopsies, stool, and bronchial lavage will be needed to determine the precise contributions of the gut-lung axis in COVID-19. Finally, mechanistic studies in vitro and in animal models of SARS-CoV2 infection will be needed to examine the direct versus the indirect impact of the infection on intestinal barrier integrity and function. In summary, while this study was exploratory in nature, our data strongly suggest for the first time: (1) severe COVID-19 is associated with disrupted intestinal barrier integrity, higher microbial translocation, and gut dysfunction; (2) severe COVID-19 is associated with a dramatic shift in levels of several biologically active molecules, which likely contribute to disease severity by inducing inflammation. Our study is beginning to shed light on the potentially critical role of a previously unappreciated factor, disruption of intestinal barrier integrity, in the pathophysiology of severe COVID-19. By understanding these unappreciated underpinnings of COVID-19, this work...
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.
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SciScore for 10.1101/2020.11.13.20231209: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources Metabolites 406 were identified by accurate mass and retention time using an in-house database generated from 407 pure standards or by MS2 spectra using the mzCloud spectral database (mzCloud.org) and 408 selecting the best matches with scores of 50 or greater. mzCloudsuggested: (mzCloud, RRID:SCR_014669)IgA was concentrated using Amicon® filters 435 (Milipore catalogue #UFC805024) and purity was confirmed by SDS gel. Amico…SciScore for 10.1101/2020.11.13.20231209: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources Metabolites 406 were identified by accurate mass and retention time using an in-house database generated from 407 pure standards or by MS2 spectra using the mzCloud spectral database (mzCloud.org) and 408 selecting the best matches with scores of 50 or greater. mzCloudsuggested: (mzCloud, RRID:SCR_014669)IgA was concentrated using Amicon® filters 435 (Milipore catalogue #UFC805024) and purity was confirmed by SDS gel. Amicon®suggested: NoneStatistical analyses were performed in R 4.0.2 and Prism 7.0 473 (GraphPad) Prismsuggested: (PRISM, RRID:SCR_005375)GraphPadsuggested: (GraphPad Prism, RRID:SCR_002798)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:
340 Caveats of our study include the sample size and sampling of blood. As noted above, correcting 341 for potential confounders will require larger cohorts from varying geographic and demographic 342 settings. Independent test sets and samples from non-COVID1-9 hospitalized and ICU-admitted 343 patients will also be needed. In addition, longitudinal analyses will be required to examine the 344 long-term implications of our findings and their potential value as prognostic biomarkers. Analysis 345 of gut biopsies, stool, and bronchial lavage will be needed to determine the precise contributions 346 of the gut-lung axis in COVID-19. Finally, mechanistic studies in vitro and in animal models of 347 SARS-CoV2 infection will be needed to examine the direct versus the indirect impact of the 348 infection on intestinal barrier integrity and function. 349 In summary, while this study was exploratory in nature, our data strongly suggest for the first time: 350 (1) severe COVID-19 is associated with disrupted intestinal barrier integrity, higher microbial 351 translocation, and gut dysfunction; (2) severe COVID-19 is associated with a dramatic shift in 352 levels of several biologically active molecules, which likely contribute to disease severity by 353 inducing inflammation. Our study is beginning to shed light on the potentially critical role of a 354 previously unappreciated factor, disruption of intestinal barrier integrity, in the pathophysiology 355 of severe COVID-19. By unders...
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.
About SciScore
SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.
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