REVIEW
Local barriers configure systemic communications
between the host and microbiota
Qiuhe Lu and Thaddeus S. Stappenbeck*
Associations between the dynamic community of microbes (the microbiota) and the host they colonize
appear to be vital for ensuring host health. Microbe-host communication is actively maintained across
physiological barriers of various body sites and is mediated by a range of bidirectional secreted proteins and
small molecules. So far, a range of“omics”methods have succeeded in revealing the multiplicity of
associations between members of a microbiota and a wide range of host processes and diseases. Although
these advances point to possibilities for treating disease, there has not been much translational success
thus far. We know little about which organisms are key contributors to host health, the importance of strain
differences, and the activitiesofmuchofthechemical“soup”that is produced by the microbiota. Adding
to this complexity are emerging hints of the role of interkingdom interactions between bacteria, phages,
protozoa, and/or fungi in regulating the microbiota-host interactions. Functional approaches, although
experimentally challenging, could be the next step to unlocking the power of the microbiota.
H
umans live in a microbe-dominated world.
Indeed, life on Earth shows substantial
evolutionary evidence of interdepen-
dency with microorganisms. Major drivers
of organismal interactions occur at tis-
sue barriers of host organs that interface with
the environment and the microbiota. The com-
position and function of the microbiota at
tissue barriers are influenced by many fac-
tors, including early-life microbial exposure,
host genetics, and dietary and lifestyle habits.
In turn, the microbiota in these locations af-
fect a wide array of systemic processes, includ-
ing metabolism, immunity, circadian rhythm,
and behaviors. For any organism in a natural
environment, a large array of factors are at
work, but urbanized humans experience an-
other level of inputs that range from ultra-
processed foods, irregular eating habits, and
high amounts of medication to shift work and
poor sleep hygiene, depleting the microbiota
and causing circadian rhythm disruption that
is linked with many chronic diseases ( 1 ).
Microbiome-related research has exploded
in the past two decades. The field is now
emerging from an initial phase of cataloging
microbial nucleic acid sequences and their
metabolic products. We have created vast
libraries of“multi-omics”data to mine for
natural products, patterns of microbial diver-
sity, and functional dynamics. An“omics ap-
proach”has been applied to nearly every organ
and disease occurring in humans, as well as
many other organismsand ecosystems. How-
ever, despite the huge research efforts and in-
vestment so far, our understanding is still too
incomplete to exploit the therapeutic potential
that the microbiota might offer.
How can we fill in the gaps in our under-
standing about host-microbiota relations? We
need to move from simply making associa-
tions of microbial taxa with host phenotypes
toward elucidating the mechanisms by which
specific microbes contribute to healthy host
physiology as well as disease. The challenge is
thatamicrobiotamaycontainrepresentatives
from every branch of the tree of life, including
bacteria, viruses, yeast, archaea, protozoa, and
helminths. Thus far, our understanding of
how these diverse microorganisms operate at
tissue barriers is sparse and selective. Our hope
is that emerging research will define the rules
that govern these complex host-microbe inter-
actions and establish new paradigms that ac-
celerate the development of evidence-based
therapeutics in this area.Defining host barriers
Mucosal surfaces interface with the environ-
ment and include several distinct habitats
where microbes interact with the host: oral
cavity, ocular structures, genitourinary tract,
upper and lower respiratory tract, skin, and
gut. By far, the largest population of these mi-
crobes is in the distal gastrointestinal tract,
where their amounts are similar to the abun-
dance of microbes found in topsoil during
summer months (up to 10% of wet weight
biomass). The microbial population ranges
widely over all other mucosal surfaces, span-
ning up to 13 orders of magnitude, but the
community composition varies between each
surfaceandcanbealteredduringdisease.
Mucosal barriers that prevent symbionts
from overwhelming their hosts include physi-
cal, chemical, and microbial components
(Fig. 1). The physical barrier is composed of
epithelial cells and closely associated immune
and stromal cells that are tailored for each
location. Epithelial tight junction proteins are
crucial for maintaining epithelial barrier in-
tegrity, and their function can be modulated
by microbes.We do know that the gut microbial product—
the short-chain fatty acid (SCFA) butyrate—
promotes barrier function by up-regulating
the expression of tight junction proteins ( 2 ).
Overlying the epithelium is a chemical bar-
rier that is composed of combinations of mucus
layers, secretory immunoglobulin A (SIgA) pro-
duced by local plasma cells, reactive oxygen
species, reactive nitrogen species, and a var-
iety of broad spectrum antimicrobial proteins
(a-defensins), all of which are designed to help
keep both symbionts and pathogens in check
( 3 , 4 ). Mucins are highly glycosylated polymeric
proteins that form a protective chemical
barrier (mucus) that can help segregate micro-
organisms and noxious substances from the
underlying epithelium ( 5 ). The intestines of
germ-free mice have an underdeveloped mucus
layer; here, symbionts not only stimulate the
production and secretion of mucus but also
promote its turnover in the lumen. The metab-
olites produced by the mucin-degrading bac-
teriaAkkermansia muciniphilainclude SCFAs
and sulfate that help maintain the gut lining
and promote barrier function ( 6 ). Another com-
mon bacterial symbiont,Enterococcus faecium,
secretes a peptidoglycan hydrolase (SagA) that
enhances intestinal epithelial barrier function
and pathogen tolerance. SagA activity gener-
ates small muropeptides that activate the host
nucleotide-binding oligomerization domain–
containing protein 2 (NOD2) signaling pathway
to modulate expression of barrier components
such as mucin 2, cryptdin 2, and the C-type
lectin Reg3 gamma (RegIIIg)( 7 , 8 ). SIgA in-
duced by symbionts at mucosal surfaces binds
to microbes and microbial products to prevent
their translocation across the epithelia, which
plays a key role in maintaining mucosal home-
ostasis and enforcing barrier function ( 4 ).
Perturbations of mucosal barriers associ-
ated with compositional changes to microbial
communities are loosely described as dysbio-
sis, a term that characterizes microbiomes with
low microbial diversity, depletion of potentially
beneficial microbes, and expansion of poten-
tially harmful microorganisms ( 9 ). Dysbiotic
microbial assemblages can exacerbate disrup-
tion of the mucosal barrier. Both infectious
diseases and chronic inflammatory disorders
feature dysbiosis, and altered microbiota and
mucosal disruption are observed in lung dis-
eases, such as asthma ( 10 ).
Germ-free mouse models have been adopted
experimentally to model humans with specif-
ic disease conditions. In a notable study, a
consortium of 11 IgA-targeted bacterial strains
cultured from an undernourished Malawian
child was sufficient to induce a diet-dependent
enteropathy in germ-free mice. The phenotype
was characterized by rapid disruption of the
intestinal epithelial barrier, weight loss, and
sepsis ( 11 ); this methodology has since become
foundational to the development of successfulTHE SYSTEMIC MICROBIOMELu et al., Science 376 , 950–955 (2022) 27 May 2022 1of6
Department of Inflammation and Immunity, Lerner Research
Institute, Cleveland Clinic, Cleveland, OH, USA.
*Corresponding author. Email: [email protected]