Metabolomic and gut microbiome profiles across the spectrum of community-based COVID and non-COVID disease

Abstract

Whilst most individuals with SARS-CoV-2 infection have relatively mild disease, managed in the community, it was noted early in the pandemic that individuals with cardiovascular risk factors were more likely to experience severe acute disease, requiring hospitalisation. As the pandemic has progressed, increasing concern has also developed over long symptom duration in many individuals after SARS-CoV-2 infection, including among the majority who are managed acutely in the community. Risk factors for long symptom duration, including biological variables, are still poorly defined. Here, we examine post-illness metabolomic profiles, using nuclear magnetic resonance (Nightingale Health Oyj), and gut-microbiome profiles, using shotgun metagenomic sequencing (Illumina Inc), in 2561 community-dwelling participants with SARS-CoV-2. Illness duration ranged from asymptomatic (n = 307) to Post-COVID Syndrome (n = 180), and included participants with prolonged non-COVID-19 illnesses (n = 287). We also assess a pre-established metabolomic biomarker score, previously associated with hospitalisation for both acute pneumonia and severe acute COVID-19 illness, for its association with illness duration. We found an atherogenic-dyslipidaemic metabolic profile, including biomarkers such as fatty acids and cholesterol, was associated with longer duration of illness, both in individuals with and without SARS-CoV-2 infection. Greater values of a pre-existing metabolomic biomarker score also associated with longer duration of illness, regardless of SARS-CoV-2 infection. We found no association between illness duration and gut microbiome profiles in convalescence. This highlights the potential role of cardiometabolic dysfunction in relation to the experience of long duration symptoms after symptoms of acute infection, both COVID-19 as well as other illnesses.

Figure 1

Relative risk ratio for each illness phenotype, per 1-SD increase in biomarker. Red indicates P ≤ 0.05 after FDR correction. Reference group (OR 1.0): Asymptomatic. ACI: Acute COVID-19 illness. OSC28: Ongoing symptomatic COVID-19 (28–83 days). PCS84: Post COVID-19 syndrome (≥ 84 days). NC28: Non-COVID-19 illness 28–83 days. NC84: Non-COVID-19 illness ≥ 84 days. Fatty Acids: Ratios& Proportions, and Absolute Values. DHA docosahexaenoic acid, SFA saturated fatty acids, MUFA monounsaturated fatty acids, PUFA polyunsaturated fatty acids. Cholesterol, LDL-C: Low density lipoprotein cholesterol, HDL-C: High density Lipoprotein cholesterol, Total-C: Total cholesterol, Total-Tg: Total Triglycerides, VLDL-C: Very low desnity lipoprotein cholesterol.

Figure 2

Spearman correlation of microbiome profiles and metabolomic profiles. Single microbial taxa correlated with clinically validated metabolomic data using Spearman’s rank sum non-parametric test. FDR P-values are displayed *P < 0.01. Rows and columns are hierarchically clustered (Euclidean distance). The R package ‘corrplot_0.90' (https://github.com/taiyun/corrplot) was used to compute the variance and the covariance or correlation. The packages ‘pheatmap_1.0.12’ (https://cran.r-project.org/web/packages/pheatmap/index.html) and the ‘cor.mtest' function of ‘corrplot_0.90’ were used to visualise the heatmap and calculate associated P values.

Figure 3

Atherogenic-dyslipidaemic biomarkers. Relative risk ratio for each illness phenotype, per 1-SD increase in biomarker. Adjusted for age, sex and body mass index. 95% Confidence intervals displayed with P-values adjusted using Benajmini-Hochberg False Discovery Rate correction. Red indicates FDR corrected P-value ≤ 0.05. ACI: Acute COVID-19 illness, OSC28: Ongoing symptomatic COVID-19 (28–83 days), PCS84: Post COVID-19 syndrome (≥ 84 days), NC28: Non-COVID-19 illness 28–83 days, NC84: Non-COVID-19 illness ≥ 84 days, ApoB_by_ApoA1: Ratio of apolipoprotein B to apolipoprotein A1, HDL_C: High density lipoprotein cholesterol, HDL_L: Total Lipids in high density lipoprotein, LDL_TG: Triglycerides in low density Lipoprotein, L_HDL_P: Concentration of large high density lipoprotein particles, MUFA: Monounsaturated Fatty Acids, PUFA_by_MUFA: Ratio of polyunsaturated fatty acids to monounsaturated fatty acids, Remnant_C: Remnant cholesterol (non-HDL, non-LDL -cholesterol), S_HDL_TG: Cholesterol in small HDL, VLDL_C: Very low density lipoprotein cholesterol, VLDL_L: Total lipids in VLDL, VLDL_TG: Triglycerides in VLDL, VLDL_size: Average diameter for VLDL particles.