Content uploaded by Tamara Giles-Vernick
Author content
All content in this area was uploaded by Tamara Giles-Vernick on Jan 26, 2021
Content may be subject to copyright.
PERSPECTIVE
The hygiene hypothesis, the COVID pandemic, and
consequences for the human microbiome
B. Brett Finlay
a,b,1
, Katherine R. Amato
b,c
,MeghanAzad
b,d
, Martin J. Blaser
b,e
,ThomasC.G.Bosch
b,f
,
Hiutung Chu
b,g
, Maria Gloria Dominguez-Bello
b,h
, Stanislav Dusko Ehrlich
b,i
,EranElinav
b,j,k
,
Naama Geva-Zatorsky
b,l
, Philippe Gros
b,m
, Karen Guillemin
b,n
,Fr´ed ´eric Keck
b,o,p
,TalKorem
b,q,r
,
Margaret J. McFall-Ngai
b,s
, Melissa K. Melby
b,t
,MarkNichter
b,u
, Sven Pettersson
b,v
, Hendrik Poinar
b,w
,
Tobias Rees
b,x
,CarolinaTropini
b,y,z
,LipingZhao
b,h
, and Tamara Giles-Vernick
b,aa,1
Edited by Lora V. Hooper, University of Texas Southwestern Medical Center, Dallas, TX, and approved December 14, 2020 (received for
review August 3, 2020)
The COVID-19 pandemic has the potential to affect the human microbiome in infected and uninfected
individuals, having a substantial impact on human health over the long term. This pandemic intersects with
a decades-long decline in microbial diversity and ancestral microbes due to hygiene, antibiotics, and urban
living (the hygiene hypothesis). High-risk groups succumbing to COVID-19 include those with preexisting
conditions, such as diabetes and obesity, which are also associated with microbiome abnormalities. Cur-
rent pandemic control measures and practices will have broad, uneven, and potentially long-term effects
for the human microbiome across the planet, given the implementation of physical separation, extensive
hygiene, travel barriers, and other measures that influence overall microbial loss and inability for reinocu-
lation. Although much remains uncertain or unknown about the virus and its consequences, implementing
pandemic control practices could significantly affect the microbiome. In this Perspective, we explore many
facets of COVID-19−induced societal changes and their possible effects on the microbiome, and discuss
current and future challenges regarding the interplay between this pandemic and the microbiome. Recent
recognition of the microbiome’s influence on human health makes it critical to consider both how the
microbiome, shaped by biosocial processes, affects susceptibility to the coronavirus and, conversely, how
COVID-19 disease and prevention measures may affect the microbiome. This knowledge may prove key in
prevention and treatment, and long-term biological and social outcomes of this pandemic.
COVID-19
|
microbiome
|
hygiene hypothesis
Humans are at a major crossroads of two major
biosocial processes affecting the microbes that col-
lectively inhabit us (our microbiome). The first process
is the continued loss of gut microbial diversity and
ancestral microbes among a large swath of the world’s
population. This loss of diversity has accelerated over
the past several decades, likely affecting the coexis-
tence between humans and our microbial residents
a
Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada;
b
Humans and the Microbiome Program, Canadian
Institute for Advanced Research, Toronto, ON M5G 1M1, Canada;
c
Department of Anthropology, Northwestern University, Evanston, IL 60208;
d
Manitoba Interdisciplinary Lactation Centre, Children’s Hospital Research Institute of Manitoba, Winnipeg, MB R3E 3P4, Canada;
e
Center for
Advanced Biotechnology and Medicine at Rutgers Biomedical and Health Sciences, Rutgers University, Piscataway, NJ 08854-8021;
f
Zoologisches
Institut, University of Kiel, 24118 Kiel, Germany;
g
Department of Pathology, University of California San Diego, La Jolla, CA 92093;
h
Department of
Biochemistry and Microbiology, Rutgers University, New Brunswick, NJ 08901;
i
Metagenopolis Unit, French National Institute for Agricultural
Research, 78350 Jouy-en-Josas, France;
j
Department of Immunology, Weizmann Institute of Science, Rehovot 761000, Israel;
k
Cancer-Microbiome
Division, Deutsches Krebsforschungszentrum, 69120 Heidelberg, Germany;
l
Technion Integrated Cancer Center, Department of Cell Biology and
Cancer Science, Technion−Israel Institute of Technology, Haifa 3525433, Israel;
m
Department of Biochemistry, McGill University, Montreal, QC H3G
1Y6, Canada;
n
Institute of Molecular Biology, University of Oregon, Eugene, OR 97403;
o
Centre National de la Recherche Scientifique, 75016 Paris,
France;
p
Laboratoire d’Anthropologie Sociale, Collège de France, 75005 Paris, France;
q
Department of Systems Biology, Irving Cancer Research
Center, Columbia University, New York, NY 10032;
r
Department of Obstetrics and Gynecology, Irving Cancer Research Center, Columbia University,
New York, NY 10032;
s
Pacific Biosciences Research Center, University of Hawai’i at Manoa, Honolulu, HI 96822;
t
Department of Anthropology,
University of Delaware, Newark, DE 19711;
u
Department of Anthropology, University of Arizona, Tucson, AZ 85721;
v
Lee Kong Chian School of
Medicine, Nanyang Technological University, 637715 Singapore;
w
Department of Anthropology, McMaster University, Hamilton, ON L8S 4M4,
Canada;
x
Transformations of the Human Program, Berggruen Institute, Los Angeles, CA 90013;
y
School of Biomedical Engineering, University of
British Columbia, Vancouver, BC V6T 1Z3, Canada;
z
Department of Microbiology & Immunology, University of British Columbia, Vancouver, BC V6T
1Z3, Canada; and
aa
Anthropology & Ecology of Disease Emergence, Institut Pasteur, 75015 Paris, France
Author contributions: B.B.F., K.R.A., M.A., M.J.B., T.C.G.B., H.C., M.G.D.-B., S.D.E., E.E., N.G.-Z., P.G., K.G., F.K., T.K., M.J.M.-N., M.K.M., M.N.,
S.P., H.P., T.R., C.T., L.Z., and T.G.-V. wrote the paper.
The authors declare no competing interest.
This article is a PNAS Direct Submission.
Published under the PNAS license.
1
To whom correspondence may be addressed. Email: bfinlay@msl.ubc.ca or tamara.giles-vernick@pasteur.fr.
Published January 20, 2021.
PNAS 2021 Vol. 118 No. 6 e2010217118 https://doi.org/10.1073/pnas.2010217118
|
1of9
PERSPECTIVE
Downloaded at UNIVERSITY OF ARIZONA on January 20, 2021
and human health through the development of noncommunica-
ble diseases, including obesity, asthma, cardiovascular diseases,
and brain diseases (1). The second process, the COVID-19 pan-
demic, is occurring at a breakneck pace across the planet, with
diverse consequences for its populations. Large-scale pandemics
entail widespread pathogen transfer between individuals and dis-
ruption of human activity, and they presumably affect microbial
diversity and richness in infected and uninfected individuals. The
interaction of these two processes is of critical importance for the
collective human microbiome and, more broadly, for human health.
The model in Fig. 1 outlines the process by which microbial
diversity is lost. Gut microbial richness results from a balance of
the acquisition and the loss of microbial species. The original hy-
giene hypothesis, first framed by David Strachan (2), has evolved
into new, more complex and explicit hypotheses that capture
many of the processes that influence gut microbial establishment
and extinction (3, 4). The most recent versions maintain that mul-
tiple changes among some of the world’s populations have occa-
sioned a loss of microbial diversity, which has accelerated over the
last century because of many processes and practices: increased
urbanization; overuse of antibiotics and other medications; birth
and infant feeding practices; intensified hygienic practices that
disinfect bodies, homes, and workplaces; reduced diversity in
global diets (especially declining intake of dietary fiber and in-
creased consumption of processed foods); and widespread use
of tobacco, alcohol, and other drugs (5–7).
Reduced acquisition and increased depletion of microbes over
generations may lead to the extinction of microbial species
ancestrally associated with humans; species may be permanently
lost from the microbial pool unless reinoculation from other
sources occurs. First proposed by Blaser and Falkow (8) and inde-
pendently by Rook (9), this longer-term loss is known as the dis-
appearing microbiota hypothesis. Reduced microbial exposure
resulting from diverse social changes and associated increases
in host inflammation have been linked to rising rates of chronic
diseases, including obesity, diabetes, asthma, and various auto-
immune diseases (10). Disruption of the microbiome predisposes
us to multiple seemingly nontransmissible human diseases. Germ-
free animals, devoid of a microbiome, develop a high titer of IgE,
the antibody isotype associated with allergic inflammation (11);
loss of immune cells reacting to bacteria leads to severe allergic
inflammation (12). In humans, exposure to rural environments and
Fig. 1. A proposed model of how COVID-19 measures influence microbiota diversity during the lifetime of an individual. While some
environmental factors foster microbial diversity, others, such as intensive hygiene and antibiotics, negatively affect microbial diversity. COVID-19
measures prevent acquisition of microbiota diversity and accelerate microbiota loss.
2of9
|
PNAS Finlay et al.
https://doi.org/10.1073/pnas.2010217118 The hygiene hypothesis, the COVID pandemic, and consequences for the human
microbiome
Downloaded at UNIVERSITY OF ARIZONA on January 20, 2021
farm animals decreases the risk of allergy (13), whereas antibiotic
consumption during early age is associated with an increased risk
of developing allergic, autoimmune, and metabolic disease (4),
presumably by affecting the balance of acquisition and loss of
microbes. Notably, they may also heighten our susceptibility to
infectious disease, just as climate change, deforestation, factory
farms, and global connectivity intensify the likelihood of novel
infectious disease pandemics (14).
This process of microbial diversity loss is occurring unevenly
across the planet. Clean water, soap, and sanitation are not
equally distributed to all people; access to and use of antibiotics,
however, are widespread in low- and middle-income countries
(LMICs), constituting a “quick fix infrastructure,”even for the
poorest populations (15, 16). Moreover, multiple vulnerable
populations—urban residents, racial and ethnic minorities, mi-
grants, low-income earners (17)—disproportionately suffer from
certain chronic diseases linked to altered microbial functionality.
The COVID-19 pandemic itself is, of course, nested in a much
longer history of pandemics that have afflicted humankind. From
the Neolithic agricultural revolution, when larger human settle-
ments facilitated the circulation of pathogens between humans
and their domesticated animals, human history is punctuated with
the repeated suffering of large epidemics and their disruptive con-
sequences (18). Although notions of infection and practices of hy-
giene have varied across space and time, people have long used
certain practices to manage pandemics: fleeing endemic areas,
physical distancing, separating the sick from the healthy, andscape-
goating of certain groups, often the most vulnerable to falling ill
and dying. From the Black Death in the 14th century through small-
pox epidemics in the 18th century, cholera in the 19th century, and
the influenza pandemic of 1918–1919, pandemics have weighed
most heavily on the poor, migrants, and ethnic and racial minorities
(19). As with past pandemics, COVID-19 mirrors and exacerbates
existing inequalities, so that aging, poor, and chronically ill popu-
lations suffer much higher morbidity and mortality (20).
The collision of the current pandemic with our decades-long
process of hygienic and accompanying microbial changes, and
the recent recognition of the importance of establishing and
maintaining a healthy microbiome, provides a unique opportunity
to explore, in real time, several key questions about humans and
their microbiomes (Table 1). This moment can provoke investiga-
tion of how social inequalities, the human microbiome, and risk
factors such as age or chronic disease affect susceptibility to the
most serious outcomes of severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) infection. It also allows examination
of how COVID-19 control measures interact with various human
practices and socioeconomic and ecological conditions that de-
termine and modify microbial composition, the stability of these
interrelations, and their capacity to establish or reestablish healthy
microbial composition.
In this Perspective, we explore, first, what we know about the
human microbiome’s influence on COVID-19, and then examine
in greater depth the current pandemic’s potential effects on the
human microbiome. We draw lessons from these intersecting pro-
cesses and identify critical questions that should be tackled simul-
taneously by biomedical and social sciences researchers and
public health actors for our near- and longer-term futures.
COVID-19 and the Microbiome
At this writing, we have little direct evidence of interactions be-
tween 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 pa-
thologies 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 en-
richment 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 mor-
tality rates (death/10
6
) in 122 countries have suggested that
inadequate sanitation and exposure to microbial diversity
(including Gram-negative bacteria) may be associated with re-
duced COVID-19−associated mortality in developing and under-
developed 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 con-
ditions, 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 cyto-
kines (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 micro-
biome composition. Might differences in gut microbiome and
associated immune cell programing influence individual host re-
sponses to SARS-CoV2 infection? Altering the microbiome com-
position through oral probiotics has been shown to alter the
course and severity of other respiratory infections, such as
influenza (33).
Finlay et al. PNAS
|
3of9
The hygiene hypothesis, the COVID pandemic, and consequences for the human
microbiome
https://doi.org/10.1073/pnas.2010217118
Downloaded at UNIVERSITY OF ARIZONA on January 20, 2021
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 epi-
thelial 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 pro-
biotics 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 mi-
crobial populations. More detailed knowledge of microbiota
changes during COVID-19 awaits further results.
Hygienic Measures during a Pandemic and Their Effects on
Microbiome Acquisition, Loss, and Reinoculation
“Hygiene”has long been associated with conditions and prac-
tices 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 coun-
tries, at individual and societal levels. Measures include deploy-
ment of personal protective equipment for health workers and
certain essential workers, extensive use of surgical masks, fre-
quent handwashing and application of hand sanitizer, and con-
tinuous 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 expo-
sure 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 micro-
biome is a crucial research question. If loss of microbiome diver-
sity 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 crit-
ically, 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 im-
mune 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 esti-
mated 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). More-
over, a recent investigation in 16 sub-Saharan African countries
found that the poorest households have serious difficulties gain-
ing 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
Table 1. Societal practices affected by COVID-19 response measures that impact the microbiome
Practice Pre-COVID COVID response measures
Consequence (and most
affected populations)
Further research and possible
recommendations
Hygiene Some wealthy populations:
loosening hygienic practices
Intensive disinfection and
hygiene in wealthy countries
Loss of microbial diversity How can we increase healthy
microbial exposure?
(outdoors, diet, etc.)
LMICs: access to clean water,
soap, sewage disposal
inaccessible or very uneven
Some in LMICs, but clean water,
soap, sewage disposal
remains inaccessible or very
uneven
May interact with food shortages
and antibiotics to lead to loss
of microbial diversity
Increase access to soap, clean
water, masks; long-term
investment in reliable sewage
systems
Food Uneven, with existence of
“double burden”(malnutrition
and obesity)
Mixed in wealthy countries:
some healthier eating, but
also rising risk of obesity from
high processed food
consumption, inactivity
Loss of microbial diversity Healthier, balanced food
assistance (increased fiber);
probiotics?
Uneven in LMICs, with significant
malnutrition, including
“double burden”(malnutrition
and obesity)
LMICs: food production
disrupted, with rising
malnutrition
Loss of microbial diversity (poor,
vulnerable populations)
Healthier, balanced and more
widespread food assistance
Antimicrobial use
(including
antibiotics)
High High Loss of microbial diversity Discourage antimicrobial use
when not needed
Social interaction
and mobility
Intensive Mixed Loss of microbial diversity,
particularly among elderly,
very young
Permit interactions within social
bubbles; allow outdoor access
in urban areas
4of9
|
PNAS Finlay et al.
https://doi.org/10.1073/pnas.2010217118 The hygiene hypothesis, the COVID pandemic, and consequences for the human
microbiome
Downloaded at UNIVERSITY OF ARIZONA on January 20, 2021
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 coun-
tries 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 pro-
posed 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 micro-
biomes across the globe, although its effects remain unknown.
Feeding Ourselves and Our Microbiome during a
Pandemic
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 in-
creased demand (43). The pandemic has thus profoundly trans-
formed 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 res-
taurant, caf ´e, and takeaway closures have also encouraged dietary
improvements through home cooking and reduced processed
food consumption in some locations and among some demo-
graphic 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 Organi-
zation expects that, for vulnerable groups facing these challenges,
COVID-related lockdowns, economic declines, and uneven re-
coveries will exacerbate hunger and malnutrition: These pop-
ulations simply will not have the income to gain access to food, or,
elsewhere, may have to rely on expensive packaged and pro-
cessed foods (43). Foods available through food banks and do-
nation 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 compo-
sition 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 to-
ward detrimental gut bacterial functions and potentially contrib-
uting 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 mi-
crobial 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 stom-
ach to the colon (51). Such markers are associated with lifelong
health problems, from susceptibility to further infection to psycho-
motor developmental delays. Moreover, a recent Lancet Com-
mission 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 Microbiomes
Social interactions, including mobility, are key contributors to gut
microbiota composition (53) and affect human health (Fig. 1).
What have been considered “noncommunicable diseases”(obe-
sity, 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, mo-
bility 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, ani-
mals, and goods to curtail infectious disease, quarantine first
emerged in Dubrovnik in the late 14th century. It eventually
comprised multiple measures (sanitary cordons, isolation, laza-
rettos, 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 yel-
low 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 night-
time 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
Finlay et al. PNAS
|
5of9
The hygiene hypothesis, the COVID pandemic, and consequences for the human
microbiome
https://doi.org/10.1073/pnas.2010217118
Downloaded at UNIVERSITY OF ARIZONA on January 20, 2021
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 la-
borers 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 in-
tersections 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 me-
diate the impacts on the microbiome?
COVID-19 restrictions to limit short-distance movements, re-
duced train and car travel, shuttered airports, and border closure
will limit diverse environmental exposures and likely impact hu-
man 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 re-
search question, but depends, in part, on implementation and
experiences of these restrictions. Implementation of these mea-
sures 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 preex-
isting microbiome diversity among different populations. Pop-
ulations 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 pastoral-
ists 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 experi-
enced rapid declines in microbial diversity (67, 68). How different
kinds of movement affect the microbiomes of different social
groups and populations merits additional attention.
Impacts of Hygiene on Microbiomes of the Young and the
Old
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.
Early Life/Infants. Birth and early infancy are critical periods for
microbiome establishment and development. Newborns are col-
onized by maternal microbes acquired during vaginal delivery and
through skin-to-skin contact, and their microbiomes are sup-
ported by prebiotic oligosaccharides and microbes provided in
breast milk (69). Research in model animals has shown that the
maternal immune system shapes the “healthy”microbiome of
early life, and that this strategy spans across the animal kingdom
(70). Moreover, a functionally and taxonomically diverse micro-
biome is key for infant immune system development. Yet, across
the planet, early life microbiomes are changing due to increased
antibiotics, Caesarean section rates, and formula feeding, and,
among wealthy populations, increased hygiene as well as indoor
and screen time. Being born by Caesarean section, for instance,
increases the risk of later allergy, asthma, and obesity rates (71)
through mechanisms that appear to be mediated, at least in part,
by microbiome dysbiosis during infancy.
The effects of COVID-19 among mothers on pregnancy out-
comes remain unclear, although vertical transmission in severe
cases has been reported (72–74). We know even less, however,
about how efforts to control COVID transmission affect an infant’s
microbiome during this critical developmental period. Altered
hospital, healthcare, and home care practices for infants and
children can interrupt the “seeding and feeding”of their micro-
biomes. These changes merit further investigation. Higher Cae-
sarean section rates may result from lower tolerance for
transmission risks (75), and more home births may be a conse-
quence of desires to avoid hospital exposure during the pan-
demic. Despite guidance from the WHO to support immediate
postpartum mother−infant contact and breastfeeding, including
for mothers with COVID-19 (using appropriate respiratory pre-
cautions), some hospitals have implemented infection prevention
and control policies that impose separation and discourage or
prohibit breastfeeding (76). Other jurisdictions are promoting
early hospital discharge for healthy dyads and suspending post-
partum home visits by public health nurses, thereby limiting lac-
tation support for new mothers. Although data are still emerging,
current evidence suggests that SARS-CoV2 transmission via
breastfeeding is unlikely (77). For nonbreastfed infants, formula
hoarding/shortages may also affect feeding practices.
At home, increased sanitization practices and limited social
interactions could reduce infant contact with “normal”environ-
mental microbes. Stress caused by the pandemic could alter the
maternal or caregiver microbiome, which could be transmitted to
the infant. Infants are falling behind in their regular vaccination
schedule, either because caregivers want to avoid health care
structures or because health services are overwhelmed (78). Some
families may avoid emergency rooms and health care visits, and
potentially not receive needed treatments, thereby affecting the
microbiome through, for instance, diarrheal or vaccine-preventable
diseases. Young children who normally attend school may be se-
questered at home, significantly decreasing their contacts with
6of9
|
PNAS Finlay et al.
https://doi.org/10.1073/pnas.2010217118 The hygiene hypothesis, the COVID pandemic, and consequences for the human
microbiome
Downloaded at UNIVERSITY OF ARIZONA on January 20, 2021
others. The state of the home (e.g., fastidious cleaning using dis-
infectants, part of an array of other cleaning practices), animal ex-
posure, and access to outdoors may also shape the child’s
microbiome. Conversely, it is possible that mothers working from
home may permit them to sustain breastfeeding longer than would
otherwise be possible, and some families may spend more time
outdoors or with pets, increasing contact with “healthy microbes.”
One major unanswered question concerns the long-term im-
pact of COVID-19 infection on the early life microbiome. Infant
and childhood mortality due to COVID-19 is extremely low, but
the effects of asymptomatic carriage on the infant microbiome
are unknown.
Later Life/Elderly. The most recent statistics on the first wave of
SARS-CoV2 infection indicate that the vast majority of severe
COVID-19 cases occur in the elderly, with people over age 70
accounting for >90% of mortality (79). Although higher mortality
might result from generally frail health status or living in
transmission-prone settings, the microbiome decreases in diver-
sity among the elderly (80) and may play a potential role in
COVID-19 severity and mortality. Most chronic diseases associ-
ated with aging have some link to the microbiome (81).
COVID-19 has dramatically affected the care, mobility, and
social interactions of elder populations. Hospitalized seniors or
those living in institutional settings have experienced limited or no
contact with family members, with consequences for their mental
and physical health. Seniors may have greater anxiety and fear for
their own health during this pandemic, but must simultaneously
cope with the absence of social support and physical and emo-
tional connection, for their own and others’health. Isolation from
family members is generally associated with poor prognosis (82).
This isolation is not only social but has important sensorial
dimensions—just as important at the end of life as it is in the
beginning. Anthropologists have emphasized the importance of
touch, which may have critical implications for reinoculation of
missing microbes from younger to older generations (83).
Are relatively high rates of COVID-19 disease and severity
among people living in institutionalized settings due primarily to
viral exposure, or could there be microbiome-mediated risk? Such
investigation should explore whether the elderly living in institu-
tionalized settings have a more impoverished microbiome com-
pared to those living at home with extended families. A host of
factors shape aging people’s microbiome: dietary differences;
institutional use of sanitizing products; different social exchange
of microbiome with similarly aged people in institutions compared
to younger people (e.g., grandchildren at home); and multiple
medicine use, including antibiotics and other antimicrobials to
manage preexisting chronic illnesses (84).
The microbiomes of aging people are also influenced by
communal interactions, leading us to wonder whether the se-
questering of care for the elderly and chronically ill have created
the conditions that facilitate viral transmission. Residing in vari-
ously sized built environments, the elderly interact with coresi-
dents suffering from comorbidities and engaging in high
medication use, as well as care providers. Does this form of
community dysbiosis contribute to high rates of mortality in care
homes, especially if there is little exposure to healthy family
members, the outdoors, and a healthy diet?
Elsewhere in low-income countries, where the elderly more
likely live in multigenerational households, we also wonder what
impact varied social contacts and interactions might have on their
microbiomes and on COVID-19 infection. Would these interactions
outweigh other chronic health conditions, including low nutritional
status (85)? At present, we do not have sufficient data to answer
these important questions.
The Communal Microbiome
COVID-19 sharpens our focus on how preventive health practices,
such as antimicrobial use, may have collateral damage on a col-
lective 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 di-
minish collective microbial diversity, increasing dysbiosis in micro-
bial function, altered immune function, and, possibly, chronic
inflammation. An insult to the microbiome through, for instance,
antibiotic use, compounded by an already depleted collective mi-
crobial 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 rela-
tion 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 conse-
quences 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 trans-
mission 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 trans-
mission; we hypothesize that these measures could also sustain
microbial variability (87, 88). Our knowledge of COVID-19 and the
Finlay et al. PNAS
|
7of9
The hygiene hypothesis, the COVID pandemic, and consequences for the human
microbiome
https://doi.org/10.1073/pnas.2010217118
Downloaded at UNIVERSITY OF ARIZONA on January 20, 2021
microbiome is incomplete, and we have only begun to explore
their interactions. Nevertheless, these suggested measures and
practices could prevent COVID transmission, simultaneously re-
duce the negative impacts of pandemic control measures on
human microbiomes, and, potentially, offer important health
benefits for future generations.
Conclusion
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 re-
covery. These insights and new measures will provide a platform
to improve our management of the next pandemic disruption.
Data Availability. All study data are included in the article.
1B. B. Finlay; CIFAR Humans; Microbiome, Are noncommunicable diseases communicable? Science 367, 250–251 (2020).
2D. P. Strachan, Hay fever, hygiene, and household size. BMJ 299, 1259–1260 (1989).
3M. Scudellari, News feature: Cleaning up the hygiene hypothesis. Proc. Natl. Acad. Sci. U.S.A. 114, 1433–1436 (2017).
4L. T. Stiemsma, L. A. Reynolds, S. E. Turvey, B. B. Finlay, The hygiene hypothesis: Current perspectives and future therapies. ImmunoTargets Ther. 4, 143–157
(2015).
5Q. Le Bastard et al., Systematic review: Human gut dysbiosis induced by non-antibiotic prescription medications. Aliment. Pharmacol. Ther. 47, 332–345 (2018).
6J. L. Sonnenburg, E. D. Sonnenburg, Vulnerability of the industrialized microbiota. Science 366, eaaw9255 (2019).
7N. A. Bokulich et al., Antibiotics, birth mode, and diet shape microbiome maturation during early life. Sci. Transl. Med. 8, 343ra382 (2016).
8M. J. Blaser, S. Falkow, What are the consequences of the disappearing human microbiota? Nat. Rev. Microbiol. 7, 887–894 (2009).
9G. A. Rook, Hygiene and other early childhood influences on the subsequent function of the immune system. Dig. Dis. 29, 144–153 (2011).
10 T. W. Buford, (Dis)trust your gut: The gut microbiome in age-related inflammation, health, and disease. Microbiome 5, 80 (2017).
11 J. Cahenzli, Y. Köller, M. Wyss, M. B. Geuking, K. D. McCoy, Intestinal microbial diversity during early-life colonization shapes long-term IgE levels. Cell Host
Microbe 14, 559–570 (2013).
12 C. Ohnmacht et al., MUCOSAL IMMUNOLOGY. The microbiota regulates type 2 immunity through RORγt
+
T cells. Science 349, 989–993 (2015).
13 S. Illi et al.; GABRIELA Study Group, Protection from childhood asthma and allergy in Alpine farm environments—The GABRIEL Advanced Studies. J. Allergy Clin.
Immunol. 129, 1470–7.e6 (2012).
14 A. A. Aguirre, Changing patterns of emerging zoonotic diseases in wildlife, domestic animals, and humans linked to biodiversity loss and globalization. ILAR J. 58,
315–318 (2017).
15 L. Denyer Willis, C. Chandler, Quick fix for care, productivity, hygiene and inequality: Reframing the entrenched problem of antibiotic overuse. BMJ Glob. Health
4, e001590 (2019).
16 T. Giles-Vernick, L. Bainilago, M. Fofana, P. Bata, M. Vray, Home care of children with diarrhea in Bangui’s therapeutic landscape (Central African Republic). Qual.
Health Res. 26, 164–175 (2016).
17 D. R. Williams, S. A. Mohammed, J. Leavell, C. Collins, Race, socioeconomic status, and health: Complexities, ongoing challenges, and research opportunities.
Ann. N. Y. Acad. Sci. 1186,69–101 (2010).
18 J. L. A. J. Webb, The Guts of the Matter: A Global History of Human Waste and Infectious Intestinal Disease (Studies in Environmental History, Cambridge
University Press, Cambridge, United Kingdom, 2019).
19 L. Wade, An unequal blow. Science 368, 700–703 (2020).
20. A. D. Napier, E. F. Fischer, The culture of health and sickness. Le Monde Diplomatique, 4 July 2020. https://mondediplo.com/2020/07/04uganda. Accessed 4
July 2020.
21 F. Trottein, H. Sokol, Potential causes and consequences of gastrointestinal disorders during a SARS-CoV-2 infection. Cell Rep. 32, 107915 (2020).
22 Z. Raisi-Estabragh et al., Greater risk of severe COVID-19 in Black, Asian and minority ethnic populations is not explained by cardiometabolic, socioeconomic or
behavioural factors, or by 25(OH)-vitamin D status: Study of 1326 cases from the UK biobank. J. Public Health 42, 451–460 (2020).
23 T. Zuo et al., Alterations in gut microbiota of patients with COVID-19 during time of hospitalization. Gastroenterology 159, 944–955.e8 (2020).
24 F. Scaldaferri et al., The thrilling journey of SARS-CoV-2 into the intestine: From pathogenesis to future clinical implications. Inflamm. Bowel Dis. 26, 1306–1314
(2020).
25 M. M. Lamers et al., SARS-CoV-2 productively infects human gut enterocytes. Science 369,50–54 (2020).
26 J. Zhou et al., Infection of bat and human intestinal organoids by SARS-CoV-2. Nat. Med. 26, 1077–1083 (2020).
27 P. Kumar, B. Chander, COVID 19 mortality: Probable role of microbiome to explain disparity. Med. Hypotheses 144, 110209 (2020).
28 J. Zhang et al., Risk factors for disease severity, unimprovement, and mortality in COVID-19 patients in Wuhan, China. Clin. Microbiol. Infect. 26, 767–772 (2020).
29 T. Jeyakumar, N. Beauchemin, P. Gros, Impact of the microbiome on the human genome. Trends Parasitol. 35, 809–821 (2019).
30 Y.Yang et al., Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome. medRxiv:
2020.03.02.20029975 (6 March 2020).
31 B.Diao et al., Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19). medRxiv:2020.02.18.20024364 (20 February
2020).
32 A. Park, A. Iwasaki, I. Type, Type I and type III interferons—Induction, signaling, evasion, and application to combat COVID-19. Cell Host Microbe 27,870–878
(2020).
33 J. W. Y. Mak, F. K. L. Chan, S. C. Ng, Probiotics and COVID-19: One size does not fit all. Lancet Gastroenterol. Hepatol. 5, 644–645 (2020).
34 R. Vandegrift et al., Cleanliness in context: Reconciling hygiene with a modern microbial perspective. Microbiome 5, 76 (2017).
35 T. Hodgetts et al., The microbiome and its publics: A participatory approach for engaging publics with the microbiome and its implications for health and hygiene.
EMBO Rep.,19, e45786 (2018).
36 World Health Organization, 1 in 3 people globally do not have access to safe drinking water. https://www.who.int/news/item/18-06-2019-1-in-3-people-globally-
do-not-have-access-to-safe-drinking-water-unicef-who. Accessed 29 July 2020.
37 S. S. Jiwani, D. A. Antiporta, Inequalities in access to water and soap matter for the COVID-19 response in sub-Saharan Africa. Int. J. Equity Health 19, 82 (2020).
38 T. M. Rawson, D. Ming, R. Ahmad, L. S. P. Moore, A. H. Holmes, Antimicrobial use, drug-resistant infections and COVID-19. Nat. Rev. Microbiol. 18,409–410
(2020).
39 A. Desclaux, La mondialisation des infox et ses effets sur la sant ´e en Afrique: L’exemple de la chloroquine. The Conversation, 19 March 2020. https://
theconversation.com/la-mondialisation-des-infox-et-ses-effets-sur-la-sante-en-afrique-lexemple-de-la-chloroquine-134108. Accessed 14 June 2020.
8of9
|
PNAS Finlay et al.
https://doi.org/10.1073/pnas.2010217118 The hygiene hypothesis, the COVID pandemic, and consequences for the human
microbiome
Downloaded at UNIVERSITY OF ARIZONA on January 20, 2021
40 P. M. Abena et al., Chloroquine and hydroxychloroquine for the prevention or treatment of COVID-19 in Africa: Caution for inappropriate off-label use in
healthcare settings. Am. J. Trop. Med. Hyg. 102, 1184–1188 (2020).
41 A. Belayneh, Off-label use of chloroquine and hydroxychloroquine for COVID-19 treatment in Africa against WHO recommendation. Res. Rep. Trop. Med. 11,
61–72 (2020).
42 L. Maier, et al., Extensive impact of non-antibiotic drugs on human gut bacteria. Nature 555, 623–628 (2018).
43 C. M. Galanakis, The food systems in the era of the coronavirus (COVID-19) pandemic crisis. Foods 9, 523 (2020).
44 J. E. Hobbs, Food supply chains during the COVID-19 pandemic. Canadian J. Agric. Econ. 68,171–176 (2020).
45 A. Zarrinpar, A. Chaix, S. Yooseph, S. Panda, Diet and feeding pattern affect the diurnal dynamics of the gut microbiome. Cell Metab. 20, 1006–1017 (2014).
46 A. G. Rundle, Y. Park, J. B. Herbstman, E. W. Kinsey, Y. C. Wang, COVID-19-related school closings and risk of weight gain among children. Obesity (Silver Spring)
28, 1008–1009 (2020).
47 L. Di Renzo et al., Eating habits and lifestyle changes during COVID-19 lockdown: An Italian survey. J. Transl. Med. 18, 229 (2020).
48 M. M. Ippolito et al., Food insecurity and diabetes self-management among food pantry clients. Public Health Nutr. 20, 183–189 (2017).
49 M. Levy, A. A. Kolodziejczyk, C. A. Thaiss, E. Elinav, Dysbiosis and the immune system. Nat. Rev. Immunol. 17,219–232 (2017).
50 C. Rodr´
ıguez-P ´erez et al., Changes in dietary behaviours during the COVID-19 outbreak confinement in the Spanish COVIDiet study. Nutrients 12, 1730 (2020).
51 P. Vonaesch et al.; Afribiota Investigators, Stunted childhood growth is associated with decompartmentalization of the gastrointestinal tract and overgrowth of
oropharyngeal taxa. Proc. Natl. Acad. Sci. U.S.A. 115, E8489–E8498 (2018).
52 B. M. Popkin, C. Corvalan, L. M. Grummer-Strawn, Dynamics of the double burden of malnutrition and the changing nutrition reality. Lancet 395,65–74 (2020).
53 C. Pasquaretta, T. G ´omez-Moracho, P. Heeb, M. Lihoreau, Exploring interactions between the gut microbiota and social behavior through nutrition. Genes (Basel)
9, 534 (2018).
54 E. Tognotti, Lessons from the history of quarantine, from plague to influenza A. Emerg. Infect. Dis. 19, 254–259 (2013).
55 I. L. Brito et al., Transmission of human-associated microbiota along family and social networks. Nat. Microbiol. 4,964–971 (2019).
56 H. Mortas
¸, S. Bilici, T. Karakan, The circadian disruption of night work alters gut microbiota consistent with elevated risk for future metabolic and gastrointestinal
pathology. Chronobiol. Int. 37, 1067–1081 (2020).
57 S. Malan-Muller et al., The gut microbiome and mental health: Implications for anxiety- and trauma-related disorders. OMICS 22,90–107 (2018).
58 C. Wenham, J. Smith, R. Morgan; Gender and COVID-19 Working Group, COVID-19: The gendered impacts of the outbreak. Lancet 395, 846–848 (2020).
59 J. W. Dyal et al., COVID-19 among workers in meat and poultry processing facilities - 19 states, April 2020. MMWR Morb. Mortal. Wkly. Rep. 69,557−561 (2020).
60 J. Corburn et al., Slum health: Arresting COVID-19 and improving well-being in urban informal settlements. J. Urban Health 97, 348–357 (2020).
61 D. Hawkins, Differential occupational risk for COVID-19 and other infection exposure according to race and ethnicity. Am. J. Ind. Med. 63, 817–820 (2020).
62 J. A. Gilbert, B. Stephens, Microbiology of the built environment. Nat. Rev. Microbiol. 16,661–670 (2018).
63 A. S. Wilson et al., Diet and the human gut microbiome: An international review. Dig. Dis. Sci. 65,723–740 (2020).
64 J. C. Clemente et al., The microbiome of uncontacted Amerindians. Sci. Adv. 1, e1500183 (2015).
65 E. Mosites et al., Microbiome sharing between children, livestock and household surfaces in western Kenya. PLoS One 12, e0171017 (2017).
66 E. D. Sonnenburg et al., Diet-induced extinctions in the gut microbiota compound over generations. Nature 529, 212–215 (2016).
67 A. F. Voor in ‘t holt et al., Acquisition of multidrug-resistant Enterobacterales during international travel: A systematic review of clinical and microbiological
characteristics and meta-analyses of risk factors. Antimicrobial Resis. Infect. Control 9, 71 (2020).
68 P. Vangay et al., US immigration westernizes the human gut microbiome. Cell Host Microbe 175, 962–972 (2018).
69 K. Fehr et al., Breastmilk feeding practices are associated with the co-occurrence of bacteria in mothers’milk and the infant gut: The CHILD Cohort Study. Cell
Host Microbe 28, 285–297.e4 (2020).
70 O. Furman et al., Stochasticity constrained by deterministic effects of diet and age drive rumen microbiome assembly dynamics. Nat. Commun. 11, 1904 (2020).
71 O. E. Keag, J. E. Norman, S. J. Stock, Long-term risks and benefits associated with cesarean delivery for mother, baby, and subsequent pregnancies: Systematic
review and meta-analysis. PLoS Med. 15, e1002494 (2018).
72 J. Juan et al., Effect of coronavirus disease 2019 (COVID-19) on maternal, perinatal and neonatal outcome: Systematic review. Ultrasound Obstet. Gynecol. 56,
15–27 (2020).
73 R. W. Alberca, N. Z. Pereira, L. M. D. S. Oliveira, S. C. Gozzi-Silva, M. N. Sato, Pregnancy, viral infection, and COVID-19. Front. Immunol. 11, 1672 (2020).
74 R. R. Galang et al., Severe coronavirus infections in pregnancy: A systematic review. Obstet. Gynecol. 136, 262–272 (2020).
75 H. Qi et al., Safe delivery for pregnancies affected by COVID-19. BJOG 127, 927–929 (2020).
76 C. Tomori, K. Gribble, A. E. L. Palmquist, M.-T. Ververs, M. S. Gross, When separation is not the answer: Breastfeeding mothers and infants affected byCOVID-19.
Maternal Child Nutrition 16, e13033 (2020).
77 M. H. Tun et al.; CHILD Study Investigators, Postnatal exposure to household disinfectants, infant gut microbiota and subsequent risk of overweight in children.
CMAJ 190, E1097–E1107 (2018).
78 C. A. Bramer et al., Decline in child vaccination coverage during the COVID-19 pandemic—Michigan Care Improvement Registry, May 2016-May 2020. MMWR
Morb. Mortal. Wkly. Rep. 69, 630–631 (2020).
79 X. Li et al., Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan. J. Allergy Clin. Immunol. 146, 110–118 (2020).
80 B. Bana, F. Cabreiro, The microbiome and aging. Annu. Rev. Genet. 53, 239–261 (2019).
81 H. J. Zapata, V. J. Quagliarello, The microbiota and microbiome in aging: Potential implications in health and age-related diseases. J. Am. Geriatr. Soc. 63,
776–781 (2015).
82 J. Holt-Lunstad, T. B. Smith, M. Baker, T. Harris, D. Stephenson, Loneliness and social isolation as risk factors for mortality: A meta-analytic review. Perspect.
Psychol. Sci. 10, 227–237 (2015).
83 P. W. Geissler, R. Prince, The Land Is Dying: Contingency, Creativity and Conflict in Western Kenya (Berghahn, Oxford, United Kingdom, 2010).
84 N. Salazar, L. Vald ´es-Varela, S. Gonz ´alez, M. Gueimonde, C. G. de Los Reyes-Gavil ´an, Nutrition and the gut microbiome in the elderly. Gut Microbes 8,82–97
(2017).
85 S. Shahar, D. Vanoh, A. F. Mat Ludin, D. K. A. Singh, T. A. Hamid, Factors associated with poor socioeconomic status among Malaysian older adults: An analysis
according to urban and rural settings. BMC Public Health 19, 549 (2019).
86 E. T. Miller, R. Svanbäck, B. J. M. Bohannan, Microbiomes as metacommunities: Understanding host-associated microbes through metacommunity ecology.
Trends Ecol. Evol. 33, 926–935 (2018).
87 M. Brauer, F. B. Bennitt, J. D. Stanaway, Global access to handwashing: Implications for COVID-19 contro l in low-income countries. Environ. Health Perspect. 128,
057005 (2020).
88 J. Y. Maillard et al., Reducing antibiotic prescribing and addressing the global problem of antibiotic resistance by targeted hygiene in the home and everyday life
settings: A position paper. Am. J. Infect. Control 48, 1090–1099 (2020).
Finlay et al. PNAS
|
9of9
The hygiene hypothesis, the COVID pandemic, and consequences for the human
microbiome
https://doi.org/10.1073/pnas.2010217118
Downloaded at UNIVERSITY OF ARIZONA on January 20, 2021
