Temporal landscape of human gut RNA and DNA virome in SARS-CoV-2 infection and severity

Abstract

Background Coronavirus disease 2019 (COVID-19) caused by the enveloped RNA virus SARS-CoV-2 primarily affects the respiratory and gastrointestinal tracts. SARS-CoV-2 was isolated from fecal samples, and active viral replication was reported in human intestinal cells. The human gut also harbors an enormous amount of resident viruses (collectively known as the virome) that play a role in regulating host immunity and disease pathophysiology. Understanding gut virome perturbation that underlies SARS-CoV-2 infection and severity is an unmet need. Methods We enrolled 98 COVID-19 patients with varying disease severity (3 asymptomatic, 53 mild, 34 moderate, 5 severe, 3 critical) and 78 non-COVID-19 controls matched for gender and co-morbidities. All subjects had fecal specimens sampled at inclusion. Blood specimens were collected for COVID-19 patients at admission to test for inflammatory markers and white cell counts. Among COVID-19 cases, 37 (38%) patients had serial fecal samples collected 2 to 3 times per week from time of hospitalization until after discharge. Using shotgun metagenomics sequencing, we sequenced and profiled the fecal RNA and DNA virome. We investigated alterations and longitudinal dynamics of the gut virome in association with disease severity and blood parameters. Results Patients with COVID-19 showed underrepresentation of Pepper mild mottle virus (RNA virus) and multiple bacteriophage lineages (DNA viruses) and enrichment of environment-derived eukaryotic DNA viruses in fecal samples, compared to non-COVID-19 subjects. Such gut virome alterations persisted up to 30 days after disease resolution. Fecal virome in SARS-CoV-2 infection harbored more stress-, inflammation-, and virulence-associated gene encoding capacities including those pertaining to bacteriophage integration, DNA repair, and metabolism and virulence associated with their bacterial host. Baseline fecal abundance of 10 virus species (1 RNA virus, pepper chlorotic spot virus, and 9 DNA virus species) inversely correlated with disease COVID-19 severity. These viruses inversely correlated with blood levels of pro-inflammatory proteins, white cells, and neutrophils. Among the 10 COVID-19 severity-associated DNA virus species, 4 showed inverse correlation with age; 5 showed persistent lower abundance both during disease course and after disease resolution relative to non-COVID-19 subjects. Conclusions Both enteric RNA and DNA virome in COVID-19 patients were different from non-COVID-19 subjects, which persisted after disease resolution of COVID-19. Gut virome may calibrate host immunity and regulate severity to SARS-CoV-2 infection. Our observation that gut viruses inversely correlated with both severity of COVID-19 and host age may partly explain that older subjects are prone to severe and worse COVID-19 outcomes. Altogether, our data highlight the importance of human gut virome in severity and potentially therapeutics of COVID-19.

Alterations in the Composition of Intestinal DNA Virome in Patients With COVID-19

“…Microbial diversity analysis revealed a significant decrease in diversity of the gut DNA virome in COVID-19 patients compared to healthy controls, which in accordance with similar recent studies ( Cao et al., 2021 ; Zuo et al., 2021 ). A low diversity of gut microbiota in patients with COVID-19 compared to that in healthy individuals has also been reported earlier ( Gu et al., 2020 ; Zuo et al., 2020 ; Chen et al., 2021 ; Vestad et al., 2021 ).…”

“…Other studies on the gut virome of patients with COVID-19 have shown the presence of Herelleviridae , Virgaviridae , crAss-like phage, Inoviridae , Microviridae , Myoviridae , Podoviridae , and Siphoviridae family of viruses ( Cao et al., 2021 ). Besides, several phages and eukaryote-associated viruses were profiling in the gut virome of COVID-19 patients in another study ( Zuo et al., 2021 ).…”

The Human Virome: Viral Metagenomics, Relations with Human Diseases, and Therapeutic Applications

“…On the other hand, COVID-19 patients exhibited enrichment for eukaryotic viruses, and Escherichia and Enterobacter phages were also prominent. An increase in phage abundance was associated with gut inflammation and the host interferon response [29]. Increased stress-, inflammation-, and virulence-associated gene expression was observed, suggesting that these viruses play a role in the host immune response to SARS-CoV-2 infection [29].…”

“…An increase in phage abundance was associated with gut inflammation and the host interferon response [29]. Increased stress-, inflammation-, and virulence-associated gene expression was observed, suggesting that these viruses play a role in the host immune response to SARS-CoV-2 infection [29]. Moreover, after disease resolution, delayed SARS-CoV-2 viral shedding and persistent gut virome dysbiosis were noted [74].…”

Editorial: Food Additives, Cooking and Processing: Impact on the Microbiome

“…“You are what you eat” has recently become a prevailing proverb describing the relationship between human beings and the foods they consume every day, along with the enormous studies centered on gut microbiome linking human health and diet. Disruption of a “healthy” microbiome can contribute to, even lead to, the occurrence and/or progression of chronic non-communicable diseases as well as infectious diseases [( 1 , 2 ); Zhou et al ]. There is increasing evidence that a person's microbiome is largely impacted by the foods he/she eats among other environmental factors ( 3 – 5 ).…”