Exposição à Microbiota Ambiental

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EDITORIAL
Exposure to environmental microbiota may modulate gut
microbial ecology and the immune system
© 2023 The Authors. Published by Elsevier Inc. on behalf of Society for Mucosal Immunology.
Mucosal Immunology (2023) 16:99–103: https://doi.org/10.1016/j.
mucimm.2023.03.001
Hitch et al.’s1 article “Microbiome-based interventions to modu-
late gut ecology and the immune system” provides an excellent
review of eight potential interventions: fecal microbiota trans-
plants; fecal filtrate transplants; diet; fermented foods; phage
therapy; and pre-, pro-, and post-biotics. One potential interven-
tion that was not reviewed by Hitch et al.1 was exposure to envi-
ronmental microbiota. Here we add to Hitch et al.’s1 review by
discussing how exposure to environmental microbiota may
modulate gut microbial ecology and immune function.
As outlined by Hitch et al.1, various sources of microbes influ-
ence our human microbiome (particularly via vertical transmis-
sion from mother to baby and via diet), and disruption of the
microbial ecosystem in humans may lead to disease. Similar to
fecal microbiota transplants, environmental exposure allows for
human interaction with a whole ecosystem of microbes, and
there is emerging evidence that the diversity of microbes in that
ecosystem, may influence the composition of human microbiota,
with consequences for immune function and health outcomes2.
The evidence base supporting such a relationship is in its infancy
with the first study in this area published in 20187; however,
exposure to the environmental microbiota, from both indoor
and outdoor environments, occurs constantly throughout the life
span, and appreciating its potential role is, therefore, important.
Humans have evolved in a microbe-rich environment, with
both pathogens and commensals modulating our gut micro-
biota and immune systems. The fact that we are susceptible to
infection from environmental pathogens has been known since
the advent of the germ theory of disease at the turn of the last
century, and the fact that our health depends on environmen-
tally acquired commensal microbes is now a burgeoning field
of discovery. Urbanization, land use change, and the associated
loss of biodiversity, as well as increased time spent indoors, have
reduced our exposure to the more biodiverse environmental
microbiota that we are adapted to. The “biodiversity hypothe-
sis,” an extension of the “hygiene hypothesis,” posits that this
reduced exposure to more diverse environmental microbiota
may be leading to unfavorable changes in human microbiomes
and therefore various diseases (e.g. autoimmune disorders, aller-
gies, and asthma)3. The biodiversity hypothesis was a theoretical
development, based on early epidemiological studies and ani-
mal work3. The early work to support this hypothesis was based
on comparisons of the microbiome of people living in different
areas, including across urban and biodiversity gradients, which
has also been further supported by observational animal evi-
dence2. Experimental animal and human studies have emerged
more recently, demonstrating the impact of environmental
Received: 31 January 2023 Revised: 26 February 2023 Accepted 2 Ma
Published online: 10 March 2023
microbiota exposure on the host microbiome2; thus, providing
evidence of the potential modulatory effect of environmental
microbiota on human gut microbiota and immune function.
In this Comment, as a supplement to Hitch et al.’s1 review of
interventions to modulate the gut microbiota and immune func-
tion, we ask “can exposure to environmental microbiota modu-
late the human gut microbiota and influence immune function?”
We focus on the human intervention studies, and readers who
are interested in the epidemiological and animal evidence relat-
ing to the impact of the environmental microbiota on host
microbiota are referred to a recent review of the literature2.
Regarding evidence from human intervention studies, there
are now several studies that have found that interacting with
the natural environment (e.g. touching soil and plant matter)
influences the skin, oral, nasal, and gut microbiome2. Here we
focus on the gut microbiome. The most compelling evidence
comes from studies with comparison groups4–8 and includes
both child and adult populations, which form the focus of this
discussion, and these studies are summarized in Table 1.
The interventions examined for their impact on the gut
microbiome and/or immune function include direct exposure
with a compost and soil mix7, playing in a sandpit that was
microbially enriched (including plant matter and commercial
gardening soils)6, and exposure to outdoor green spaces4,5
and green walls8; the last mentioned representing indirect expo-
sure to environmental microbiota.
Two of the studies examined the gut microbiome after cessa-
tion of the interventions; however, neither study found signifi-
cant differences between the intervention and control groups
at 14 days6, at 21 days7, and following cessation of the interven-
tion. These findings indicate that ongoing exposure may be
required or that the 14-day interventions were of insufficient
duration to drive long-term changes in the gut microbiota. In
addition, a recent study found that green walls in office spaces
may increase the diversity of the skin microbiome after 14 days
of exposure, and such changes were associated with the cyto-
kine transforming growth factor-beta messenger RNA expres-
sion from blood samples8, indicating a potential role of the
environmental microbiota in immune function. As there was
no direct contact with the green wall, these findings suggest
that the skin microbiome and immune function may relate to
exposure to the aerobiome associated with the treatments; how-
ever, no assessment of the aerobiome was conducted in this
study. Yet, this idea has support from a recent mouse study9,
where mice were exposed to an aerobiome of no soil, low diver-
sity soil, and high diversity soil, and following 7 weeks of expo-
sure, there were significant differences between the groups with
regard to the community composition of both the fecal and
cecal microbiome. The evidence regarding the potential effect
of the aerobiome on the gut microbiome and immune function
rch 2023
https://doi.org/10.1016/j.mucimm.2023.03.001
https://doi.org/10.1016/j.mucimm.2023.03.001
Table 1. Summary of the human intervention studies that investigate how exposure to different environmental microbiota may influence the gut microbiome and/or immune function.
Intervention type Study & study
design
Population
(sample size)
Intervention Comparison
intervention
Between-group comparisons
Gut microbiome Immune function
Samples taken &
parameters
investigated
Significant differences Samples taken &
parameters
investigated
Significant
differences
Rubbing hands in
soil/compost mix
Nurminen
et al.7
Comparative
study with
concurrent
controls
Healthy, urban-
dwelling adults
(n = 14; 7 per
group)
Rubbing hands in a
plant- and soil-
based compost.
Hands were rubbed
in the compost for
20 s before
breakfast, before
dinner/evening
snack, and before
bed. After rubbing
hands in the mix,
hands were washed
for 5 s with soap and
towel dried. The
intervention was for
14 d.
No intervention Fecal samples at
days 0, 14, and 35
Shannon diversity
index
Change in the Shannon diversity
index from days 0 to 14 was
significantly higher in the
intervention group than in the
control group
Not compared
between groups
Not compared
between groups
Microbially enriched
sand pit to play in
Roslund
et al.6
Randomized
controlled
trial
Children in
childcare
(n = 26; 13 per
group)
Microbially enriched
sandpit played in
twice daily for 20
min, over 14 d. The
sandpit was
available to play in
for a further 14 d.
The microbially
enriched sandpits
contained 1:1 sand
and a biodiverse
powder (composed
of deciduous leaf
litter, Sphagnum
moss, peat, 6
commercial
gardening soils, and
agricultural stack).
Placebo sandpit
played in twice dailyfor 20 min for each
session, over 14 d. The
sandpit was available
to play in for a further
14 d.
The placebo sand was
sand mixed with
blond peat (10:1)
Fecal samples at
days 0, 14, and 28
Richness; Shannon
diversity; and
Simpson diversity,
beta diversity
(operational
taxonomic units,
genus, order, family,
class, and phylum
levels)
At day 14, the proteobacterial
Simpson diversity was
significantly lower in the
intervention group, than in the
control group
Venous blood
samples at days 0
and 14
interleukin-17A and
interleukin-10
plasma
concentrations and
ratio.
Frequency of
regulatory T cells,
intracellular cytokine
expression in CD3 +
CD4 + memory T
cells, and
interleukin-2,
interleukin-21,
tumor necrosis
factor-α and
interferon-γ from
peripheral blood
mononuclear cell
samples
Change
ininterleukin-10
concentration and
interleukin-10:
interleukin-17A
ratio was
significantly
different between
the groups
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Table 1 (continued)
Intervention type Study & study
design
Population
(sample size)
Intervention Comparison
intervention
Between-group comparisons
Gut microbiome Immune function
Samples taken &
parameters
investigated
Significant differences Samples taken &
parameters
investigated
Significant
differences
Greening outdoor
spaces and
encouraging
interaction with
natural elements
Roslund
et al.4,5
Comparative
study with
concurrent
controls
Children in
childcare
(n = 39, 23 in
the
intervention
group and 16
in the control
group)
Greening
intervention where
plants, peat, sods,
and segments of the
forest floor were
added to the
outdoor playing
space and children
were encouraged to
interact with these
natural elements.
Intervention was for
up to 2 y.
No intervention Fecal samples at
days 0, 28, and year
1 (year 2 samples
were also collected
but n = 3 for the
intervention group
and n = 0 for the
control)
Operational
taxonomic units
richness; Shannon
diversity;
community
composition
(operational
taxonomic units,
genus, order, family,
class, and phylum
levels); composition
of Faecalibacterium
operational
taxonomic units;
beta diversity;
relative bacterial
abundance
At day 28, the community
composition and relative
abundance of Ruminococcaceae
were significantly different
between the two groups.
The relative abundance of
Clostridiales unclassified,
Ruminococcus2, and Dorea was
significantly different between
groups at both day 28 and year 1
in the per-protocol analysis but
not the intention-to-treat
analysis.
Not compared
between groups
Not compared
between groups
Green wall Soininen
et al.8
Randomized
controlled
trial
Healthy, urban
office workers
(n = 28; 11 in
the
experimental
and 17 in the
control group)
Green walls (of with
Philodendron
scandens, Dracaena
sp., and Asplenium
antiquum) in offices
for 14 d.
No intervention Not examined Not examined Venous blood
samples at days 0,
14 and 28
interleukin
-17A and
interleukin-10
plasma
concentrations and
ratio
transforming growth
factor-β1 protein
plasma
concentration
(unclear if this refers
to the active or
inactive form)
The change from
days 0-28 was
different between
the groups for
transforming
growth factor-β1
concentration
Notes: the results reported here do not include changes over time per group, nor correlations between microbiome and immune function.
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J. Stanhope and P. Weinstein
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is in its infancy and establishing such a relationship in humans
will be challenging, owing to the current limitations of investi-
gating the microbiome of low biomass samples.
Our existing understanding of how environmental pathogens
infect humans, and the preliminary evidence published to date
suggests that exposure to environmental microbiota may influ-
ence host microbiota, immune function, and health outcomes;
however, more evidence, with fewer potential biases, is required.
To date, there are relatively few human studies that include com-
parison groups, and even these studies have a range of potential
methodological biases. For example, allocation bias in two of the
studies4,5,7, not isolating the microbiome exposure from other
elements of the interventions (e.g. seeing natural elements)4,5,8,
and the relatively short-term nature of the interventions6–8 and
follow-up periods following the cessation of the intervention4–8.
The sample sizes in all studies were also relatively small. Further-
more, the microbiome analyses to date have focused on rela-
tively high-order taxa, often lack clarity regarding DNA
extraction and sequencing techniques and bioinformatics, and
do not account for the compositional nature of the microbiome
when comparing relative abundance. More comprehensive
assessments of immune function are also required. However,
although these shortcomings may impact our understanding of
how the gut microbiota are influenced by environmental micro-
biota exposures, the studies provide preliminary evidence that
these exposures might change the human gut microbiota and
immune function—the focus of this paper.
There remain many questions regarding dosage, duration of
treatment, and the persistence of changes after the intervention
has ceased, but answers to inform the evidence base are
expected with the growth of research in this area. The general-
izability of the findings must also be considered when determin-
ing how these findings may apply beyond the scenarios
investigated. For example, all human studies with comparison
groups have been conducted in Finland with healthy partici-
pants. Although the observational evidence suggests that envi-
ronmental microbiota exposure influences the gut microbiota,
the generalizability of such interventions to modulate the gut
microbiota is less clear, owing to potential differences in the
makeup of the exposure environment, and behavioral differ-
ences in the exposed population (e.g. time spent indoors, diet,
and physical activity). We also do not yet have data regarding
how the environmental microbiota might affect the gut ecology
and immune function of people with poorer health. One poten-
tial concern regarding exposure to the environmental micro-
biota as a tool to modulate the gut microbiota is safety.
Although we are always in contact with the environmental
microbiota, it is critical that when suggesting changes to this
exposure we are mindful of potentially increasing infection risk
(e.g. pathogens in the environment), particularly for clinical pop-
ulations or people with compromised immune systems.
Several approaches may be undertaken to improve exposure
to more diverse environmental microbiota. These approaches
may include behavior changes (e.g. soil rubs, gardening, and
more time outdoors in greenspace) or optimizing the environ-
mental microbiota in the spaces where people spend their time.
For instance, in outdoor environments greater vegetation diver-
sity is associated with more diverse soil microbial diversity and
more diverse aerobiomes2, whereas in indoor environments
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the environmental microbiota may be changed through archi-
tectural design features, including windows to allow for sunlight
and ventilation, manipulating humidity and temperature, and
reducing indoor pollutants10. Furthermore, more targeted
approaches, including microbially inoculated paints and tiles,
are emerging as strategies that may modulate the environmen-
tal microbiota (and therefore human microbiota) in environ-
ments where green space exposure per se is not possible (e.g.
border biosecurity, submarine, or space travel). Environmental
microbiome exposure interventions could be used alongside
other microbiome-based interventions for synergies that may
enhance and/or prolong any benefits. For example, the fre-
quency of fecal microbiota transplant administration could
potentially be reduced if exposure to more diverse environmen-
tal microbiota prolongs their efficacy.We conclude that exposure to environmental microbiota may
alter human microbiota and immune function and should be
included when discussing potential microbiome-based interven-
tions. Research in this area is in its infancy, and additional
research is required to better understand the types and dosages
of exposures, the generalizability of findings across populations,
and ensure the safety of such interventions.
AUTHOR CONTRIBUTIONS
JS and PW both conceived and drafted the manuscript.
DECLARATIONS OF COMPETING INTEREST
The authors have no competing interests to declare.
ACKNOWLEDGMENTS
We thank the reviewers and editors for their valuable feedback on the Comment.
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J. Stanhope and P. Weinstein
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Mucosal Immunology (2023) 16:99–103
Jessica Stanhope
School of Allied Health Science and Practice, The University of
Adelaide, Adelaide, Australia
✉ email: jessica.stanhope@adelaide.edu.au (J. Stanhope)
Philip Weinstein
School of Public Health, The University of Adelaide, Adelaide,
Australia
www.elsevier.com
mailto:jessica.stanhope@adelaide.edu.au