The gut microbiome as a biomarker of differential susceptibility to SARS-CoV-2

Abstract

Coronavirus disease 2019 (COVID-19) continues to exact a devastating global toll. Ascertaining the factors underlying differential susceptibility and prognosis following viral exposure is critical to improving public health responses. We propose that gut microbes may contribute to variation in COVID-19 outcomes. We synthesise evidence for gut microbial contributions to immunity and inflammation, and associations with demographic factors affecting disease severity. We suggest mechanisms potentially underlying microbially mediated differential susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). These include gut microbiome-mediated priming of host inflammatory responses and regulation of endocrine signalling, with consequences for the cellular features exploited by SARS-CoV-2 virions. We argue that considering gut microbiome-mediated mechanisms may offer a lens for appreciating differential susceptibility to SARS-CoV-2, potentially contributing to clinical and epidemiological approaches to understanding and managing COVID-19.

Keywords: COVID-19; immunity; immunological dark matter; inflammation; microbiota; modelling.

Figure 1

Microbiome-associated inflammation profiles and potential reactions to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). The microbiome influences host inflammation through the regulation of host immunological processes (proinflammatory effects are indicated by the orange arrow, and anti-inflammatory effects by the blue arrow). These include the production of host pro- and anti-inflammatory mediators, and the migration of bacteria or bacterial products, such as lipopolysaccharide, through the gut lining. (A) A microbiome that contributes to a balanced or low-inflammation state (low-inflammation properties are indicated by the blue systemic background and the pale-pink microbial background) with a relatively higher level of anti-inflammatory cytokines. (B) A microbiome that contributes to a proinflammatory state (high-inflammation properties are indicated by the pale-orange systemic background and the darker-pink gut background), with a relatively higher number of proinflammatory mediators, and potential translocation of bacterial products into systemic circulation (the proinflammatory state is indicated by the relatively larger orange arrow). The bottom two images show the putative reactions of these systems to SARS-CoV-2 infection, denoted by the presence of virions. (C) A relatively muted proinflammatory response to viral infection, represented by the pink systemic background behind the immune cells. (D) A strong proinflammatory response to viral infection, represented by the red systemic background behind the immune cells.

Figure 2

Key figure. Microbial contributions to differential susceptibility and immunological dark matter. Viral transmission in a population in which individuals are infected (red silhouettes), susceptible (grey silhouettes), or resistant (blue silhouettes) to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection. While differential susceptibility may be mediated by many factors, this figure emphasises hypothetical effects of the gut microbiome. The microbiome may enhance susceptibility (red microbiomes) or resilience (blue microbiomes), or may be unrelated to risk or resilience (yellow microbiomes). Thus, grey individuals with red microbiomes represent the subpopulation for which the microbiome is a hypothetical source of risk for SARS-CoV-2 infection. Grey individuals with yellow microbiomes are susceptible to SARS-CoV-2 for reasons unrelated to the microbiome. Blue individuals with blue microbiomes represent the subpopulation for which the microbiome is the hypothetical source of resistance to SARS-CoV-2. Blue individuals with yellow microbiomes represent the subpopulation that resists or is less susceptible to SARS-CoV-2 for reasons unrelated to the microbiome. Infected individuals (red silhouettes) have microbiomes that carry a signature of the infection (black microbiomes). Differential susceptibility increases the variability in the propensity of individuals to spread the virus, a phenomenon known as ‘overdispersion’ in epidemiological modelling (put simply: ‘the few infect the many’). Overdispersion can exert profound effects on viral spread at the population level, making it a potentially important source of immunological dark matter. Such dynamics are an important explanation for why an epidemic does not unfold as expected, under often implausible assumptions of homogenous and well-mixed populations.