Researchers 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 is increasingly being shown to be a crucial factor. It has been estimated that there are as many bacterial cells in the human body as human cells[6], and numerous microbial metabolites from the microbiome reach the blood stream and are increasingly being investigated[7]. This has led to the human microbiome being called the second genome[8]. 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[9].

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[10] and its newer forms, such as the altered microflora hypothesis[11] and an extension of these earlier hypotheses that focuses on the potentially pathogenic microbes within the post-hunter-gatherer era microbiota (PHM)[12]. 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.