The hygiene hypothesis, the COVID pandemic, and consequences for the human microbiome

At this writing, we have little direct evidence of interactions between the human microbiome and SARS-CoV-2 infection (21). We do not know how the composition or metabolic activity of microbial populations living on mucosal surfaces (airway epithelial cells, gastrointestinal enterocytes) of the human body affect initial susceptibility to SARS-CoV-2 infection, subsequent pathogenesis, or outcome. Some intriguing observations, however, make this possibility difficult to ignore. Framing these unknown biological interactions are demographic and socioeconomic factors—reflected in diet and other social determinants of health—that render the elderly, racial and ethnic minorities, and those with lower socioeconomic status more likely to suffer worse outcomes from COVID-19 infection; these same groups have existing pathologies that correlate with dysbiosis of gut microbiota (22).

Recent studies in small groups of COVID-19 patients have identified major dysbiosis of the intestinal microbiome, with enrichment by opportunistic bacterial (Coprobacillus, Clostridium species) and fungal pathogens (Candida, Aspergillus species), and depletion of beneficial symbionts (Faecalibacterium) that are positively and inversely correlated with COVID-19 severity (23, 24). In addition, an inverse correlation was noted between abundance of Bacteroides and SARS-Co-V2 load in fecal material during the course of hospitalization of these patients. Recently, there have been reports of viable virus particles in the stool (25, 26), although the significance and impact of these viral particles on the gut microbiome and infection transmission is not known. Recent demographic analyses of COVID-19−associated mortality rates (death/10⁶) in 122 countries have suggested that inadequate sanitation and exposure to microbial diversity (including Gram-negative bacteria) may be associated with reduced COVID-19−associated mortality in developing and underdeveloped countries. The authors noted an inverse correlation between COVID-19−associated death rates and water quality scores, fraction of the population living in slums, and fraction with diarrhea. With these data, the authors proposed that microbially stimulated, innately enhanced levels of type I interferon (IFN) may be protective against COVID-19 mortality in these populations (27).

In addition to certain microbial taxa correlating with severity of COVID-19, several chronic conditions act as comorbidity factors for COVID-19, including cardiovascular disease and associated hypertension, diabetes, obesity, and asthma. Among these conditions, obesity, type 2 diabetes, and hypertension are the most important predisposing conditions for COVID-19 severe disease (28). Changes in the microbiome at times may modulate genetic susceptibility to these diseases in humans and animal models (29).

Recent data have shown that a major driver of the above-mentioned phenomena is the host immune system. The gut microbiome plays a major role in “training” the immune system, and changes in microbiome composition or activity may affect activity of several immune cell types (lymphoid, myeloid) (29). These effects may be mediated in part by direct exposure of developing immune cells in situ in the gut, or by the production of different microbial metabolites that can act in other organs distant from the gut. COVID-19 fatalities are often associated with an overwhelming and pathological inflammatory response in the lungs (30), caused by overproduction of proinflammatory cytokines (cytokine storm), as well as exhaustion of populations of immune cells (CD8⁺ T cells) (31). IFNs play an important role in the antiviral host response (32), which could be influenced by microbiome composition. Might differences in gut microbiome and associated immune cell programing influence individual host responses to SARS-CoV2 infection? Altering the microbiome composition through oral probiotics has been shown to alter the course and severity of other respiratory infections, such as influenza (33).

Finally, SARS-CoV2 infection may directly affect the gut and airway microbiomes. The cell surface receptor for the virus (ACE2, angiotensin converting enzyme 2) is expressed on airway epithelial cells and on enterocytes along the digestive tract. Studies are underway to characterize the respiratory microbiome and COVID-19 infections. Although the data are limited, the probiotics Lactobacillus and Bifidobacterium appear depleted in the intestines of COVID-19 patients (33), indicating an abnormal state (termed dysbiosis). Moreover, hospitalized COVID-19 patients may receive high-dose antibiotics, which dramatically alters microbial populations. More detailed knowledge of microbiota changes during COVID-19 awaits further results.

“Hygiene” has long been associated with conditions and practices that promote health and prevent disease. Although hygiene is not the same as “sterilization,” it can shade into other practices that not only clean but can also reduce microbial load, as a review of hand hygiene has noted (34). Hygiene is of crucial importance in keeping people across the globe healthy. That said, the COVID-19 pandemic has provoked radical and immediate changes in hygienic measures, especially in high-resource countries, at individual and societal levels. Measures include deployment of personal protective equipment for health workers and certain essential workers, extensive use of surgical masks, frequent handwashing and application of hand sanitizer, and continuous cleaning with bleach in public areas and with disinfectants in homes. Cleaning is essential in high-density public locations, but we need more social investigations of the array of home cleaning practices, which are likely undertaken together. From a microbial perspective, these measures may affect microbiome transmission (Table 1). Prior to the COVID-19 pandemic, some public recognition of these insights in high-resource countries seemed to be loosening hygienic practices and accepting exposure to varied microbes (35).

Implementing much stricter hygienic practices now to contain COVID-19 transmission is necessary, but increased hygiene may come at a microbial cost by decreasing microbial acquisition and reinoculation following loss, although that cost is not yet known. For wealthier populations that can strictly adhere to hygienic measures in this pandemic, this cost may compromise useful microbiota functions. How hygiene measures affect the microbiome is a crucial research question. If loss of microbiome diversity occurs, and potentially even microbial extinction, could these microbial changes ultimately affect rates of asthma, obesity, or diabetes and other diseases that have microbial links? More critically, are there possible measures that might be taken during the pandemic to counterbalance the potential damage to the microbiome and ultimately catalyze other diseases associated with microbiome shifts? Over time, fear of pathogenic microbes can be balanced with a more nuanced attitude recognizing that taxonomically diverse microbiomes are known to strengthen immune systems and provide other benefits.

At the same time, the consequences of COVID for hygienic practices, and by implication microbiomes, differ across the planet. The World Health Organization (WHO) and UNICEF estimated in 2019 that one in three people around the world do not have access to safe drinking water, and that at least 2 billion people use water sources contaminated with feces (36). Moreover, a recent investigation in 16 sub-Saharan African countries found that the poorest households have serious difficulties gaining access to soap and water for washing (alcohol-based solutions are out of the question), and only 33.5% of households with a handwashing site had water and soap (37). An astonishing 60% of the world’s population (4.5 billion) has no access to safe sanitation, according to the WHO/UNICEF Joint Monitoring Program for Water Supply, Sanitation and Hygiene. Although these shortfalls are concentrated in LMICs, even the wealthiest countries contain populations with limited or no access to clean water and good sanitation systems. Intensifying hygienic practices may have little relevance for a sizeable proportion of the world’s people without the means to follow recommended hygienic practices to prevent COVID-19 transmission.

A potential consequence of COVID-19 across wealthy countries and LMICs is the use of antimicrobial treatments because of misdiagnoses, treatment of secondary infections from COVID, or self-medication (38). Early in the pandemic, hydroxychloroquine, which has a lengthy history in Africa as an antimalarial, was proposed as a possible COVID treatment. With the onset of the global pandemic and the publication of a widely viewed video in France and West Africa, West African pharmacies and street sellers experienced skyrocketing demand for chloroquine and hydroxychloroquine (39). Use of this drug to treat or prevent COVID has continued in 2020 (40, 41). The drug has also been shown to affect substantially gut microbiota (42). More generally, increased use of antimicrobials during this pandemic (especially during the early stages of the outbreak) may affect human microbiomes across the globe, although its effects remain unknown.

The COVID-19 pandemic and control measures have also affected how the world’s populations are eating, although in different ways, and with varied consequences for the gut microbiome, human physiology, and health. These altered dietary practices have resulted from disrupted food supply chains. Decreased global trade, ruptured transportation networks, infection of food workers, runs on specific foodstuffs, privateering, closures of restaurants and food outlets, and increased home cooking have all exerted huge stress on food supply chains at a time of increased demand (43). The pandemic has thus profoundly transformed food access and consumption patterns in a short time. Depending on their economic status and location, some people have increasingly relied on food retailers that provide locally available foodstuffs (44). For some of those working from home, snacking and eating frequency may have increased (45). Closures of school cafeterias, decreased physical activity, and stress-related consumption of processed, unhealthy foods seems to be fueling obesity during the pandemic (46). Lockdowns and restaurant, café, and takeaway closures have also encouraged dietary improvements through home cooking and reduced processed food consumption in some locations and among some demographic groups (47).

Vulnerable populations include those facing food insecurity from the economic effects of pandemic response, predisposing conditions to COVID-19, and experiencing war, or other types of pest and disease outbreaks. The Food and Agriculture Organization expects that, for vulnerable groups facing these challenges, COVID-related lockdowns, economic declines, and uneven recoveries will exacerbate hunger and malnutrition: These populations simply will not have the income to gain access to food, or, elsewhere, may have to rely on expensive packaged and processed foods (43). Foods available through food banks and donation programs, and sometimes even schools, rarely meet the dietary needs of people with conditions like obesity, diabetes, and hypertension, and may even exacerbate them (48).

These changes in food consumption timing, quantity, quality, and frequency may profoundly impact gut microbiome composition and function. At the physiological level, pandemic-induced changes in dietary patterns may influence nutrients available to gut microbiota, possibly tipping the balance from beneficial toward detrimental gut bacterial functions and potentially contributing to intestinal inflammation and a host of chronic diseases (49). To be sure, for specific populations, consumption of healthier, fiber-rich diets may favor a better balance of gut bacteria and greater resistance to the coronavirus (50). Understanding the microbial consequences of these COVID-19−induced dietary shifts and developing interventions, particularly for infants and children, is important. It will be even more critical to do so in vulnerable populations who do not have access to enough or sufficiently nutritious diets during and after the pandemic. Chronic malnutrition and stunting among sub-Saharan African children is associated with gastrointestinal tract bacterial “decompartmentalization,” so that oropharyngeal bacteria are displaced to pathways from the stomach to the colon (51). Such markers are associated with lifelong health problems, from susceptibility to further infection to psychomotor developmental delays. Moreover, a recent Lancet Commission underscored the overlap of malnutrition and obesity, increasingly a problem in LMICs (52). For many populations, then, COVID-19 dietary changes may be exacerbating these already serious conditions associated with microbiome-related dysbiosis.

Social interactions, including mobility, are key contributors to gut microbiota composition (53) and affect human health (Fig. 1). What have been considered “noncommunicable diseases” (obesity, diabetes) have important microbial causality (1). Microbial transmission, then, may be facilitated by shared social practices and interactions. COVID-19 control efforts—including isolation, physical distancing, the implementation of social bubbles, mobility restrictions, and border closures—have all disrupted or transformed social interactions and mobility patterns associated with microbial transfer, and could potentially have a significant impact on human microbiomes.

The COVID-19 pandemic response has entailed restrictions on an unprecedented scale, although most control measures are not new. Broadly denoting restrictions on movement of people, animals, and goods to curtail infectious disease, quarantine first emerged in Dubrovnik in the late 14th century. It eventually comprised multiple measures (sanitary cordons, isolation, lazarettos, restrictions, and sometimes reprisals against those seen as responsible for the epidemic) imposed over time to curtail plague and, in subsequent centuries, to limit smallpox, cholera, and yellow fever, and, more recently, Ebola and SARS transmission (54). COVID-19 measures around the world draw from this long history of social and mobility constraints. State-imposed constraints, self-imposed isolation, and socializing in “social bubbles” lead to fewer social contacts; the result may be microbiomes that resemble those of other household members or socializing partners (55).

The pandemic therefore offers an opportunity to examine the diverse consequences of reduced social contacts, isolation, and physical distancing on human microbiomes. Even within a household, the consequences of these social measures may be multiple. For working adults, shift work affects the microbiome via circadian rhythms (56), so would restructuring of day and nighttime routines influence those remaining at home in isolation? Does isolation—individual, with families, or in social bubbles—reduce diversity of the microbiome? How might stress and anxiety borne of social isolation influence the microbiome (57)? What might be the gendered consequences of lockdown and stress for the microbiome within households? Although men are more likely to die from COVID-19, women suffer disproportionately the secondary effects of this pandemic: They face greater income insecurity as lower-wage, part-time workers, are often home caregivers, and may be subject to domestic violence, and their needs for sexual and reproductive health tend to be deferred (58).

Not all people are able to implement physical distancing for extended periods, and it would be important to examine the consequences of their living and working conditions for the microbiome. Essential workers, including health workers and laborers in meat and poultry processing plants, must go to their workplaces and carry out duties under hazardous conditions (59). Those living in crowded, poor neighborhoods in LMICs and wealthy countries across the planet also face enormous difficulties adhering to lockdowns, physical distancing, and isolating the sick; investigations ranging from Dakar to Detroit reveal important intersections between race, poverty, and difficulties of physical distancing (60). Not only do workers, racial and ethnic minorities, and other at-risk populations tend to live in households with family members suffering from preexisting conditions and thus at high risk for COVID-19 morbidity and mortality, but they frequently have less access to health care, and, in some countries, have no health insurance (61). Is it possible under such circumstances to communicate a dysbiotic microbiome to those living in close proximity? If so, what possible measures could be taken to mediate the impacts on the microbiome?

COVID-19 restrictions to limit short-distance movements, reduced train and car travel, shuttered airports, and border closure will limit diverse environmental exposures and likely impact human microbial diversity during multiple pandemic waves and their aftermath. Hence, examining the variable effects of COVID-19 mobility restrictions on human microbiomes is an important research question, but depends, in part, on implementation and experiences of these restrictions. Implementation of these measures has varied substantially across countries. In the winter and spring of 2020, stricter controls were imposed in, for instance, China, Italy, and France, whereas fewer controls were put in place elsewhere, including Niger, Japan, Tanzania, Sweden, and some US states.

Another consideration is how these restrictions affect preexisting microbiome diversity among different populations. Populations with differential use of and exposure to disinfecting products, consumption of healthy or processed foods, and access to outdoors would clearly experience diverse impacts on their microbiota (62). Gut microbial composition differs across the world’s populations, with highest diversity observed among people living in more isolated rural settings, consuming high quantities of fibers and very little or no sugar, processed foods, or antimicrobials (63, 64).

Mobility—from globe-crossing business travelers to pastoralists herding their cattle to graze in seasonal pasturelands—can offer exposure to microbial species that may be missing in one’s microbiome (65). Travel restrictions imposed to prevent COVID transmission might be a missed opportunity, and lost diversity may not be easily recoverable (66). Nonetheless, long-distance travelers also risk acquiring antimicrobial drug-resistant bacteria in their journeys, and migrants from certain settings have experienced rapid declines in microbial diversity (67, 68). How different kinds of movement affect the microbiomes of different social groups and populations merits additional attention.

Early and later life constitute critical periods when the microbiome exerts particularly important influences on health, translating into lifelong health and disease concerns and potential disparities in mortality and morbidity. COVID-19 has significantly, although differentially, affected children and seniors. Its influences on the microbiomes of young and old should be further investigated and addressed.

COVID-19 sharpens our focus on how preventive health practices, such as antimicrobial use, may have collateral damage on a collective microbiome. Physical distancing and increased hygiene measures reduce COVID-19 infections, but may also indirectly reduce the general microbial reservoir and its transmission for some, although not all, populations around the world. Populations able to isolate from each other and to disinfect their living and work spaces reduce their exposure to social and environmental microbial pools; they are thus more likely to experience changes in their microbiomes (86). These dynamics will likely further diminish collective microbial diversity, increasing dysbiosis in microbial function, altered immune function, and, possibly, chronic inflammation. An insult to the microbiome through, for instance, antibiotic use, compounded by an already depleted collective microbial reservoir, will make it more difficult to reconstitute a healthy microbiome. The consequence may be heightened susceptibility to infection, more severe symptoms, and greater mortality.

We want to be clear: Preventing COVID-19 transmission is necessary, and the hygienic transformations of the past 100 years have resulted in major reductions in mortality from infectious diseases. But the intersection of the past century’s hygienic practices and recent COVID-19 pandemic control measures may negatively affect the microbiome and thus human health across multiple timescales. As morbidity and mortality increase in relation to these microbial changes, human evolutionary trajectories may also change. Studies in mice, for instance, have shown that once particular microbial taxa are lost from a population over generations, they are difficult to recover (66). The associated loss of microbial function can severely limit host ability to survive in certain environments or to resist infections (66). A fundamental question, then, is what microbial functions might we lose as a result of COVID-19 prevention efforts? What are the consequences as humans continue to encounter nutritional and immune challenges in future generations, and what can be done to mitigate them (Table 1)?

It is worth considering how to deploy physical distancing and hygiene practices to prevent COVID-19 transmission, but also to sustain and protect diversity of the microbiome. It is important to understand more fully how these practices affect the microbiome, and then, in response, to develop public measures and practices that can, if appropriate, increase exposure to beneficial microbes and simultaneously reduce risk of COVID-19 transmission. Public measures could include those already associated with healthy microbial diversity: keeping open urban parks but ensuring the maintenance of physical distancing; offering remote support for breastfeeding mothers and encouraging infant vaccination; and ensuring the provision of healthy food assistance to low-income families and children. Individual practices could include safely spending time outdoors, gardening where possible, eating a fiber-rich diet, avoiding unnecessary antibiotics, and encouraging physical contact among coquarantined family members and pets, all of which have been shown to facilitate retention and transmission of beneficial microbes. In LMICs, expanding access to clean water and soap and masks, tackling food insecurity, and reducing easy access to antibiotics may effectively reduce transmission; we hypothesize that these measures could also sustain microbial variability (87, 88). Our knowledge of COVID-19 and the microbiome is incomplete, and we have only begun to explore their interactions. Nevertheless, these suggested measures and practices could prevent COVID transmission, simultaneously reduce the negative impacts of pandemic control measures on human microbiomes, and, potentially, offer important health benefits for future generations.

The current pandemic has disrupted the world as we knew it. Despite the damage and turmoil that COVID-19 has already caused worldwide, it also reminds us that we live in a microbial world where microbes have a major impact on all facets of our existence. This pandemic presents a significant opportunity to study, in real time, the relationship between an infectious agent, the microbiome, precipitous and uneven social and economic changes, and their combined effects on health and disease. As we track changes in the microbiome during COVID-19, we can apply this knowledge to current pandemic control measures and recovery. These insights and new measures will provide a platform to improve our management of the next pandemic disruption.