AbstractThe human microbiome, especially the microbiomes of the gastrointestinal and respiratory tracts, are potentially important in determining susceptibility to COVID-19 and the immunopathology that leads to severe disease. Data is beginning to be gathered on the risk factors for severe disease in the coronavirus disease of 2019 (COVID-19). This data will be discussed in connection with some highlights of what is being learned about the human microbiome and its relationship with viral illnesses and inflammation-related chronic diseases. In particular, possible roles for diet, lifestyle, and microbiota manipulation as means of reducing rates of severe viral disease will be explored. Some potential pharmaceutical approaches to treating severe COVID-19 disease, involving the microbiome, mast cells and hypersensitivity responses, are also discussed. It is proposed that chronic low-grade infections and/or dysbiosis may underlie the age-related diseases that are risk factors for severe disease from SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). It is also suggested that the connection between these chronic diseases and COVID-19 may have implications for understanding some of the reasons for the severity of COVID-19 in a proportion of patients. Whether or not the hypothesis of a causal role for dysbiosis or prior infection is correct, some of the suggested treatment approaches might still be worth investigating.Keywords: microbiome, COVID-19, Westernized diet, exercise, stress, mast cells, cytokine storm, IL-6, plant-based diet, inflammation, dysbiosisIntroductionResearchers are rapidly gaining knowledge about COVID-19 to help address the current global pandemic, with a focus on treatment and prevention of the spread of the disease[1–3]. This article has two primary aims. The first aim is to examine the characteristics of the disease and the individuals who are most susceptible to severe disease to see if they can help reveal how humans can become less susceptible. A second aim is to explore whether these considerations might suggest treatment approaches that have potential to help at least some of those who are already suffering from severe disease. It is hoped that this review will be able to suggest areas of research that could be helpful in dealing with both the current pandemic and with other similar diseases or future epidemics.The emphasis here will be on the human microbiome and the diet, lifestyle and medical intervention factors that often affect it. This emphasis arises from the increasing research showing the profound impact of the human microbiome on immune function and many aspects of diverse disease processes[4,5]. The human genetic makeup is certainly important; however, the microbiotas inhabiting different parts of the human body are increasingly being shown to be crucial factors. It has been estimated that there are as many bacterial cells in the human body as human cells, and numerous microbial metabolites from the microbiome reach the blood stream and are increasingly being investigated. This has led to the human microbiome being called the second genome. One advantage of focusing on this second genome is that studies are showing that it can be altered much more easily than the human genome, apparently with beneficial effects, such as in the treatment of antibiotic-associated diarrhea due to Clostridiodes dificile infection using fecal microbiota transplants.The rapid changes in diet, lifestyle, environmental exposures and medical interventions in the last 75 years has led to changes in the human microbiome that may not be optimally compatible with our evolved immune responses to pathogens. This perspective is closely related to the hygiene hypothesis and its newer forms, such as the altered microflora hypothesis and an extension of these earlier hypotheses that focuses on the potentially pathogenic microbes within the post-hunter-gatherer era microbiota (PHM). Throughout this review, attention will be paid to factors that might lead to the establishment of these potentially pathogenic microbes, which include environmental microbes that are less coevolved with their human hosts and thus could have greater immune suppressing/dysregulating potential.