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

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. The outcomes of SARS-CoV-2 infection and COVID-19 show enormous variation among individuals. Given that the sources of this variation are largely unknown, they have been described as ‘immunological dark matter’.Emerging studies suggest that the gut microbiome contributes to immunological dark matter. Gut microbial composition and function are associated with several key risk factors for severe COVID-19 outcomes, including host inflammatory status, age, and biological sex. Crucially, the gut microbiome regulates host inflammation and endocrine function in ways that may alter susceptibility to SARS-CoV-2 infection.Efforts to study the gut microbiome alongside other host demographic and physiological variables may shed light on differential susceptibility to SARS-CoV-2 infection, and may thereby contribute to improving patient care and epidemiological modelling.