COVID-19 severity is associated with population-level gut microbiome variations

Abstract

The human gut microbiome interacts with many diseases, with recent small studies suggesting a link with COVID-19 severity. Exploring this association at the population-level may provide novel insights and help to explain differences in COVID-19 severity between countries. We explore whether there is an association between the gut microbiome of people within different countries and the severity of COVID-19, measured as hospitalisation rate. We use data from the large (n = 3,055) open-access gut microbiome repository curatedMetagenomicData, as well as demographic and country-level metadata. Twelve countries were placed into two groups (high/low) according to COVID-19 hospitalisation rate before December 2020 (ourworldindata.com). We use an unsupervised machine learning method, Topological Data Analysis (TDA). This method analyses both the local geometry and global topology of a high-dimensional dataset, making it particularly suitable for population-level microbiome data. We report an association of distinct baseline population-level gut microbiome signatures with COVID-19 severity. This was found both with a PERMANOVA, as well as with TDA. Specifically, it suggests an association of anti-inflammatory bacteria, including Bifidobacteria species and Eubacterium rectale, with lower severity, and pro-inflammatory bacteria such as Prevotella copri with higher severity. This study also reports a significant impact of country-level confounders, specifically of the proportion of over 70-year-olds in the population, GDP, and human development index. Further interventional studies should examine whether these relationships are causal, as well as considering the contribution of other variables such as genetics, lifestyle, policy, and healthcare system. The results of this study support the value of a population-level association design in microbiome research in general and for the microbiome-COVID-19 relationship, in particular. Finally, this research underscores the potential of TDA for microbiome studies, and in identifying novel associations.

Altered infective competence of the human gut microbiome in COVID-19

“…These include changes in diversity including stark enrichments and/or loss of specific taxa [27]. Several Studies have focused on differences in the gut microbiome between patients with severe COVID-19 and controls [7,28]. Though these findings are essential, the effect on the larger population, wherein the infection is asymptomatic-to-moderate, is not readily represented.…”

Altered infective competence of the human gut microbiome in COVID-19

“…These include changes in diversity [39] including stark enrichments and/or loss of specific taxa [40]. Several Studies have focused on differences in the gut microbiome between patients with severe COVID-19 and controls [7,41,42]. Though these findings are essential, the effect on the larger population, wherein the infection is asymptomatic-to-moderate, is not readily represented.…”

“…For the data preprocessing, raw metagenomic reads were first trimmed to the maximal read length of 150 bases using Cutadapt (v3.4) [40]. The preprocessed metagenomic and raw metatranscriptomic reads were processed using IMP: reads were trimmed using Trimmomatic (v.39) [41], reads mapping to the human genome (hg38 genome) or PhiX genome (gi|9626372|ref|NC_001422.1, Enterobacteria phage phiX174 sensu lato, complete genome) were removed using BWA (v. 0.7.9a) [42], and the metatranscriptomic reads were further filtered using SortMeRNA (v.4.2.0-238-g90cdf6c) [43]. In addition, alpha-diversity estimation was performed from metagenomic reads using Nonpareil (v. 3.4.1) [44] as part of the IMP preprocessing step.…”

Host genetics and gut microbiota composition: Baseline gut microbiota composition as a possible prognostic factor for the severity of COVID-19 in patients with familial Mediterranean fever disease

“…According to Yeoh et al, the differences were found in several gut bacterial diversities of the phyla Bacteroidetes and Actinobacteria between the non-COVID-19 non-FMF people and patients with COVID-19; representatives of the Bacteroidetes were described to be more abundant and Actinobacteria were described to be less in patients with COVID-19 (Yeoh et al, 2021 ). Furthermore, recently, not only the gut commensals with known immunomodulatory potential described to be underrepresented in patients with COVID-19 but also COVID-19 severity in association with population-level gut microbiome variations was discussed (Lymberopoulos et al, 2022 ). These results, in parallel with other studies, highlight the potential utility of multi-kingdom host phenotype and microbiota profiling as a predictive tool for patients with COVID-19 (Liu et al, 2022 ).…”