REVIEW

C URRENT
OPINION Gut–lung crosstalk during critical illness
Sridesh Nath a, Georgios D. Kitsios a,b,c,
and Lieuwe D.J. Bos d,e,

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Purpose of review
Study of organ crosstalk in critical illness has uncovered complex biological communication between
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different organ systems, but the role of microbiota in organ crosstalk has received limited attention. We
highlight the emerging understanding of the gut--lung axis, and how the largest biomass of the human
body in the gut may affect lung physiology in critical illness.
Recent findings
Disruption of healthy gut microbial communities and replacement by disease-promoting pathogens
(pathobiome) generates a maladaptive transmitter of messages from the gut to the lungs, connected via the
portal venous and the mesenteric lymphatic systems. Gut barrier impairment allows for microbial
translocation (living organisms or cellular fragments) to the lungs. Host-microbiota interactions in the gut
mucosa can also impact lung physiology through microbial metabolite secretion or host-derived messengers
(hormones, cytokines or immune cells). Clinical examples like the prevention of ventilator-associated
pneumonia by selective decontamination of the digestive tract show that the gut--lung axis can be
manipulated therapeutically.
Summary
A growing body of evidence supports the pathophysiological relevance of the gut--lung axis, yet we are
only at the brink of understanding the therapeutic and prognostic relevance of the gut microbiome,
metabolites and host-microbe interactions in critical illness.
Keywords
critical illness, gut microbiome, gut--lung axis, pathobiome

INTRODUCTION nonhuman integral component of the human host,

Organ crosstalk, the complex biological communi-
cation between anatomically distant organs medi-
ated by various signaling factors, is essential for
dynamic maintenance of homeostasis. Maladjusted
inter-organ communication in critical illness can
amplify the systemic negative impact of single organ
dysfunction, beyond what is predicted from the
directly measured physiologic deficits of the failing
organ. For example, acute kidney injury can lead to
worse pulmonary dysfunction than what is expected
merely due to fluid retention, likely due to humoral/
cellular factors released or retained from the injured
kidneys and acting distally to the lungs [1]. Simi-
larly, our well intended interventions to restore or
replace homeostatic function in one organ system
may have unintended consequences in other distal
organs, because organ crosstalk occurs in complex
ways that are not easy to observe on the clinical
surface. Although extensive research has focused on
understanding organ crosstalk in critical illness,
involving physiologic, neurohormonal, metabolic
and immune mechanisms, more recent investiga-
tions have started to unravel the role of the
or the so-called forgotten organ of critical illness: the
human microbiome.
Matching human cells in nearly 1:1 ratio, an
estimated 39 trillion bacteria colonize the external
and internal surfaces of the human body, including
the skin, gastrointestinal, respiratory and urogenital
tract, yet the vast majority of bacterial biomass
resides in the gut and especially in the colon [2].
A growing body of research in the role of gut micro-
biota in health and disease has expanded the
a
Department of Medicine, Division of Pulmonary, Allergy and Critical
Care Medicine, bAcute Lung Injury Center of Excellence, cCenter for
Medicine and the Microbiome, University of Pittsburgh, Pittsburgh,
Pennsylvania, dIntensive Care and eLaboratory of Experimental Intensive
Care and Anesthesiology (LEICA), Amsterdam University Medical
Centers, location AMC, University of Amsterdam, Amsterdam, The
Netherlands
Correspondence to Lieuwe D.J. Bos, MD, PhD, Amsterdam UMC
location AMC, Intensive Care, Meibergdreef 9, 1105AZ Amsterdam,
The Netherlands. E-mail: l.d.bos@amsterdamumc.nl


These authors contributed equally to this work.
Curr Opin Crit Care 2023, 29:130–137
DOI:10.1097/MCC.0000000000001015

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KEY POINTS
 Gut microbial communities in critical illness show
decreased species diversity, loss of obligate anaerobes
and emergence of pathogenic species abundance,
collectively shaping the profile of a disease-
promoting pathobiome.
 The gut--lung axis is comprised of both microbial and
host-derived messengers, traveling from the gut to the
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lungs via the routes of the mesenteric lymphatic and the
portal venous system.
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 Impaired gut barrier integrity and increased
permeability allows for living gut microbes or their
cellular fragments to reach the lungs and populate the
lung microbiome or induce remote host innate
immune responses.
 Clinical studies show enrichment of the lung
microbiome with gut-origin bacteria in patients with
acute respiratory distress syndrome.
 The clinical success of selective decontamination
strategies of the digestive tract in reducing ventilator-
associated pneumonia and improving clinical outcomes
offers proof-of-concept evidence for the premise of
therapeutic manipulation of the gut--lung axis in
critical illness.
concept of ‘‘organ crosstalk’’ to also include the
direct and indirect effects of gut microbiota on distal
organ physiology (e.g. gut–brain, gut–lung or gut–
liver axis). In this review, we focus on the role of
the gut microbiome on pulmonary dysfunction in
critical illness and summarize recent evidence on
the proposed gut–lung axis.
GUT AND LUNG MICROBIOTA: DISTANT
BUT RELATED
Despite their common embryologic origin from the
foregut and their common pharyngeal passage, the
anatomic development of the respiratory and gas-
trointestinal tracts results in two environments
vastly different in their hospitality for microbiota.
The lungs are the unfriendly environment. The
healthy lower airways and airspaces are poor in
nutrient supply for bacteria and are continuously
patrolled by lung macrophages. This inhospitable
environment results in a low biomass yet diverse
community of bacteria originating from the oral
cavity. It is not entirely clear whether this low
microbial population density is resident in the
healthy lungs or continuously re-populated from
the upper respiratory tract, yet in each unit of time,
microbes are present and play important roles in
tuning resident innate and adaptive immune cells
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Gut--lung crosstalk during critical illness Nath et al.
[3]. On the other end of the ecological spectrum, we
have the microbe-friendly gut, generously sharing
the dietary nutrients ingested by the human host.
Progressively increasing in biomass and composi-
tional diversity along the gastrointestinal tract, gut
microbiota in the colon constitute an abundant,
diverse and metabolically active community of
mostly obligate anaerobic bacteria [4].
Despite its anatomical remoteness, a gut–lung
axis is strongly supported by experimental and clin-
ical evidence in health and disease (Fig. 1). The two
compartments are connected via the venous (sys-
temic and portal) and lymphatic circulations. Gut
microbiota can use these connecting routes to send
‘‘messages’’ to lung microbiota and human lung
cells either in direct ways, via microbial transloca-
tion and engraftment in the lungs, or mostly indi-
rect ways, involving a variety of microbial or host
‘‘messengers’’ (Fig. 1). Under this expansive gut–
lung crosstalk model, lung function can be impacted
by remote host-microbiota interactions in the gut,
even if gut microbes never breach the gut mucosa.
Although there is emerging data for inverse, lung-to-
gut influences on microbiota, we focus our evidence
synthesis on studies investigating the unidirectional
impact of the high biomass gut microbiome on lung
physiology in the context of critical illness, starting
by what is known on gut–lung crosstalk from
chronic lung disease.
GUT–LUNG AXIS IN CHRONIC LUNG
DISEASES
Human and animal model studies in chronic respi-
ratory diseases, such as allergies, asthma and chronic
obstructive pulmonary disease (COPD), have largely
shaped our understanding on the gut–lung axis.
Epidemiologic observations have linked early life
factors shaping the gut microbiome, such as mode
of delivery, lactation or antibiotic exposures, with
future development of atopic disease and asthma
[5]. Patients with COPD have distinct gut micro-
biome profiles from healthy controls, with plausible
causal mechanisms involving alternations of micro-
&
bial metabolism [6 ]. Clinical observations also
implicate translocation in severe COPD, as patients
with acute exacerbations have increased small intes-
tinal permeability, while plasma levels of 1,3-b-D-
glucan (BDG), a fungal cell-wall constituent, poten-
tially signifying translocating fungi from the gut),
correlate with lung matrix degradation markers and
&
worse lung function [7 ,8].
The most thoroughly studied mechanism of the
gut–lung axis involves the microbial metabolites
short-chain fatty acids (SCFAs), such as propionate
or butyrate [9]. Production of SCFA in the gut
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 Gastrointestinal system
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FIGURE 1. A schematic summary of the connecting routes and the possible messengers constituting the gut--lung axis in critical
illness. The two compartments are anatomically connected via the venous and lymphatic circulations. Gut barrier disruption due to
ischemia or inflammatory tissue injury in critical illness can allow for translocation of gut microbiota (mostly bacteria or fungi), which
can travel via the venous or lymphatic route and engraft in the lungs, generating a gut-microbiota enriched lung microbiome. Apart
from this prototypical scenario of a microbial gut--lung axis, gut microbiota can affect lung physiology even when the connecting
routes are sterile from living organisms. Cellular fragments from killed microbes (e.g. cell-wall constituents, such as
Lipopolysaccharide or b-D-glucan for bacteria and fungi, respectively or nucleic acids, such as cell-free DNA) or metabolites released
by living bacteria (such as short-chain fatty acids) may reach the lungs and stimulate innate or adaptive immune responses. In an
expanded conceptual model of the gut--lung axis, the two organs can interact even when there is no breach of the intestinal mucosa
by living organisms or microbial components. Host--microbiota interactions in the intestinal mucosa can result in release of damage-
associated molecular patterns (DAMPs, e.g. cell-free human DNA from injured intestinal cells), extracellular vesicles, cytokines,
hormones or even migrating immune cells, which can all reach the lungs and act as host messengers of the host-microbiome
interactions confined within the gut. DAMPs, damage-associated molecular patterns.

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depends entirely on bacteria. Dietary fiber that is
unfermentable by the host is metabolized by fer-
menting bacteria in the colon to produce SCFAs.
Diets high in fiber and low in animal protein and
fat further enrich fiber-fermenting bacteria and con-
sequently SCFA production. SCFAs serve as a fuel for
colonic epithelia cells, thereby improving barrier
function and mucosal integrity, but also act as impor-
tant immunomodulatory molecules. SCFAs modu-
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late allergic and asthma responses by promoting
dendritic cell maturation in the bone marrow in ways
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that such dendritic cells are ineffective at driving TH2
cell responses when they migrate to the airways [10].
Pilot clinical studies on asthma patients have shown
the benefit of inulin supplementation (a soluble fiber
which is fermented by intestinal microbes leading to
SCFA production) in reducing airway inflammation
and exhaled nitric oxide levels [11].
Such gut-derived coordination of adaptive
immune responses requires repeated host–micro-
biota interactions to impact systemic responses
and the immunophenotype of lung resident cells,
as the result of a complex and time-consuming
process. Despite their relevance in chronic respira-
tory diseases, such mechanisms may not operate
similarly in critical illness, which can happen
acutely and evolve rapidly, with innate immune
responses mostly at play. We will next review the
available clinical and mechanistic evidence of gut–
lung axis and its impact on innate immunity and
lung function in critical illness syndromes.
GUT MICROBIOME IN CRITICAL ILLNESS –
A FAST COLLAPSE AND A DEFECTIVE
RECONSTRUCTION
Critical illness has been associated with rapid, seis-
mic changes in gut microbial communities [12].
These changes include decreased species diversity,
loss of obligate anaerobes, emergence of Proteobac-
terial and other pathogenic species abundance,
which collectively shape the profile of a disease-
promoting pathobiome replacing the healthy gut
&&
microbiome [13 ]. The drivers of the microbiome
collapse and its maladaptive replacement by a path-
obiome are numerous, including inter-individual
variability in microbiome resilience, immune status,
gut perfusion/oxygenation and permeability, as well
as critical care interventions, such as antibiotics,
opioids, proton pump inhibitors and nutritional
management (tube feedings, total parenteral nutri-
&&
tion) [14 ,15]. Although no commonly agreed def-
inition or diagnostic test exist for detection of a gut
pathobiome or broadly-defined gut dysbiosis,
altered microbiota profiles in critically-ill patients
are predictive of secondary infections including
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Gut--lung crosstalk during critical illness Nath et al.
bacteremia, Clostridioides difficile colitis and nosoco-
&&
mial pneumonia [16 ,17]. A pathobiome is then the
necessary (but perhaps not sufficient) condition for
a maladaptive gut–lung axis in critical illness.
EMPIRICAL EVIDENCE INDICATIVE OF
GUT–LUNG AXIS IN CRITICAL ILLNESS
Culture-based surveys in mechanically ventilated
patients have shown that pharyngeal or intestinal
colonization with gram-negative bacteria predicts
subsequent ventilator-associated pneumonias
&
(VAP) [18 ,19]. Such epidemiologic observations
provided the rationale for preventive decontamina-
tion strategies, such as oral care with chlorhexidine
rinses, or the more aggressive options of selective
decontamination of the digestive tract (SDD) and
selective oropharyngeal decontamination (SOD)
with nonabsorbable antibiotics against Gram-nega-
&& && &&
tive bacteria, yeasts, and S. aureus [20 ,21 ,22 ].
SDD avoids the use of antibiotics with anaerobic
coverage, with the aim of eliminating gut-derived
pathogens while preserving commensal anaerobes.
Head-to-head comparison has shown SDD to be
superior to SOD in reducing VAP incidence and
improving clinical outcomes including mortality.
Empiric administration of antianaerobic antibiotics
in critically ill patients was recently shown to be
associated with decreased overall survival, increased
risk of VAP, and enrichment by pathogenic Enter-
obacteriaceae in gut microbial communities and
&&
respiratory cultures diagnostic of VAP [23 ]. This
randomized and observational evidence defies con-
ventional thinking that VAP mostly develops due to
contiguous spread of upper respiratory tract patho-
gens into the lower respiratory tract and highlights
the gut as a probable pool of pathogens for secon-
&&
dary infections in the ICU [21 ]. We will next
review how gut microbiota may escape the confine-
ments of their anatomical compartment.
THE ROUTE FROM THE GUT TO THE
LUNGS
The two major routes connecting the gut to the lungs
are the portal venous and the mesenteric lymphatic
system (Fig. 1). The portal venous system drains
venous blood from the digestive tract into the liver,
the major site for clearance of gut-derived microbial
fragments, such as endotoxin, or even translocated
bacteria. Kupffer cells, the liver resident macro-
phages, have highly efficient phagocytic capacity
compared to alveolar and interstitial macrophages
[24], and effectively scavenge the translocating
microbial burden. However, the capacity of this filter-
ing system can be exceeded (e.g. by excessive
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 Gastrointestinal system
bacterial translocation, Kupffer cell dysfunction) or
by-passed (such as in porto-systemic shunts in
patients with cirrhosis), allowing for translocating
microbes or microbial products to reach the lungs
[25,26].
The mesenteric lymphatic system facilitates
absorption of fluid and nutrients from the gut, trans-
porting lymph to the superior mesenteric lymph
duct and finally the thoracic duct. The thoracic duct
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enters the systemic (blood) circulation at the junc-
tion of the left subclavian and internal jugular veins,
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draining into the right atrium and then directly into
&&
the pulmonary circulation [27,28 ]. Hence, the
lungs are the first organs to be exposed to mesenteric
lymph and its contents. Mechanistic studies in ani-
mal models have highlighted the relevance of the
mesenteric lymphatic system in the gut–lung axis.
For example, in murine models of acute respiratory
distress syndrome (ARDS) and traumatic/hemorrha-
gic shock with severe abdominal infection, ligation
of gut lymph vessels or drainage of gut lymph fluid
prevented lung injury [29]. Although both the
venous and lymphatic system are possible conduits
in a gut–lung axis, the relative contributions of each
route in different syndromes or phases of critical
illness are not well defined.
TRANSLOCATION OF GUT MICROBES
In multiorgan failure during critical illness, the gut
may fail not only in its primary mission of nutrient
absorption, but also in maintaining barrier integrity,
i.e. sealing the host circulation from the abundant
&&
microbiome in the intestinal lumen [30,31 ]. Many
factors can lead to intestinal barrier damage and
increased permeability [32,33], including mesen-
teric hypoperfusion, increased intra-abdominal
pressure, hypoxemia, inflammation, microcircula-
tory disturbances, as well as nutritional deprivation
with reduced SCFA production, which serve as fuel
for colonic epithelia. On the luminal surface,
decreased production, altered composition or
increased degradation of the glycoprotein mucus
allows bacteria to adhere to the epithelial surface
&&
[31 ]. At the epithelial level, the physical barrier is
compromised by increased apoptosis of intestinal
epithelial cells, impaired renewal due to diminished
proliferation and migration, and altered expression
and regulation of tight junction proteins, cumula-
tively creating a permeable, inefficient physical bar-
&&
rier [31 ]. Such host physiologic derangements
coupled by proliferation of disease-promoting bac-
teria and/or induction of virulence in commensals
&&
organisms [13 ] can lead to translocation of living
organisms to either the venous circulation and/or
the mesenteric lymphatic system.
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Although, gut translocation is a biologically
highly plausible and experimentally reproducible
phenomenon, documenting and quantifying gut
microbial translocation in the human host is a rather
challenging task. First, accessing the portal venous or
mesenteric lymphatic systems for biospecimen acquis-
ition are extremely invasive and technically challeng-
ing procedures, effectively infeasible for clinical care or
large-scale clinical research [34,35]. Even if the optimal
samples were available (e.g. portal venous blood or
mesenteric lymph), detection of bacteria with conven-
tional microbiologic cultures is likely insensitive, as
many of the translocating organisms may be difficult
to grow anaerobic bacteria [36], whereas the ultra-
sensitive culture-independent microbiota sequencing
approaches (e.g. 16S rRNA gene amplification) are
vulnerable to contamination risks. Lastly, transloca-
tion is likely an episodic and not a steady phenom-
enon, and intermittent sampling can miss it. For
example, in experimental shock models, gut perme-
ability and mesenteric lymph toxicity peaked in the
immediate hours following shock, hence subsequent
assessment of blood or mesenteric lymph may fail to
detect translocating bacteria [37]. Thus, the ability to
study translocation in the critically ill host in practical
and reproducible ways is limited, and we have to rely
on surrogate metrics, such as paired microbiome anal-
ysis of gut and blood samples as well as comparing
lung and gut microbiota for emergent similarities
during critical illness. Recent research in coronavirus
disease 2019 (COVID-19) has provided proof-of-con-
cept evidence for gut translocation. In mouse models,
severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) infection induced gut dysbiosis and
altered barrier permeability, whereas paired analysis
of gut and blood samples from antibiotic-treated
COVID-19 patients revealed proliferation of patho-
genic bacterial genera in the gut, as well as increased
risk of bloodstream infections by such pathogenic
&&
microbiota [38 ]. Additionally human studies in
patients with ARDS have shown that the lung micro-
biome is enriched with gut-associated bacteria, which
may have engrafted in the lungs following the venous
or lymphatic route, and not via oropharyngeal aspira-
&& &
tion [39 ,40 ]. Similarly, in murine models of sepsis,
the lung microbiome was enriched with bacteria
found in the murine gut such as members of the
Bacteroidales order, Enterococcus and Lachnospiraceae
&& &
species [39 ,40 ].
TRANSLOCATION OF MICROBIAL
COMPONENTS AND METABOLITES
Apart from living microbes, their cellular constituents
or metabolic products may also travel along the gut–
lung routes and influence host biology. Pathogen-
Volume 29  Number 2  April 2023

associated molecular patterns (PAMPs) [41], including
bacterial or fungal cell wall components, lipoproteins,
carbohydrates, nucleic acids etc., represent signals
recognized by pattern recognition receptors on
immune cells, particularly macrophages, leading to
cell activation and release of inflammatory mediators.
The prototypical PAMP is lipopolysaccharide (LPS),
the endotoxin found on the outer cell wall of gram-
negative bacteria, which causes increased neutrophil
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migration, higher myeloperoxidase activity, and cyto-
kine levels in the lungs leading to epithelial cell dam-
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age and permeability alveolar edema [42,43]. Among
critically ill patients without evidence of invasive
fungal infection, plasma levels of the fungal PAMP
BDG were significantly associated with the marker of
intestinal permeability intestinal fatty acid binding
protein-2, the hyper-inflammatory subphenotype of
systemic host responses, higher mortality and longer
times for liberation from mechanical ventilation
& &&
[7 ,44 ]. Such studies provide indirect evidence of
the role of gut-origin circulating PAMPs on lung phys-
iology and outcomes.
In contrast to gut derived PAMPs, microbial
metabolites, such as SCFAs, bile acids and desamino-
tyrosine can have beneficial effects on lung immun-
ity. There is evidence that gut derived SCFAs help in
lung clearance of bacteria, modulated by down-
stream effects of G protein-coupled receptor 43
(GPR43)- and Late Endosomal/Lysosomal Adaptor,
MAPK And MTOR Activator 2 (LAMTOR2)-depend-
ent signaling pathways. Activation of GPR43 leads
to increased production of reactive oxygen species,
activation of inflammasome and increased phagocy-
&
tosis during bacterial pneumonia [45 ]. Similarly,
LAMTOR2-dependent signal pathway promotes
&
macrophage elimination of K. pneumoniae [46 ]. Con-
versely, in murine models of antibiotic-induced dys-
biosis with decreased SCFA production, inoculation
with Respiratory Syncytial Virus results in less effec-
tive immune response and viral clearance in lungs
&
[47 ]. In COVID-19 patients upon admission to the
ICU, reduced levels of fecal microbial metabolites,
such as secondary bile acids and desaminotyrosine,
were predictive of more severe respiratory failure and
mortality, with postulated impact on T- regulatory
(Treg) cell development and interferon-I signaling
&&
[48 ]. The demonstrated protective roles of microbial
metabolites, such as SCFAs and bile acids, suggest
that the optimal gut–lung interaction is not only
about preventing a pathobiome, but also promoting
a healthy gut microbiome.
GUT–MUCOSA INTERACTIONS
Following intestinal injury during local or systemic
stress, mesenteric lymph or portal venous blood can
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Gut--lung crosstalk during critical illness Nath et al.
transport not only microbial, but also gut-derived,
host mediators to the pulmonary circulation. Such
host-derived messengers of the gut–lung axis include
damage-associated molecular patterns (DAMPs),
such as cellular fragments of dying cells, cell-free
nuclear or mitochondrial DNA, histones, ATP etc.,
which can trigger sterile inflammatory responses.
Furthermore, other host molecules influenced by
gut microbiota interactions, such as gut-derived hor-
mones (e.g. incretins), extracellular vesicles and cyto-
kines can also exert immunomodulatory and
&&
vascular permeability effects in the lungs [28 ,41].
The gut–lung axis can be influenced not only by
circulating host molecules, but also by migrating
immune cells. An important example involves the
interaction between segmented filamentous bacte-
ria (SFB) and mucosal immune responses. T-helper
17 (Th17) and T-regulatory (Treg) cells are fre-
quently found at barrier surfaces such as intestinal
mucosa, lungs and skin where they function to
protect the host from pathogenic microorganisms
and to restrain excessive effector T-cell responses,
&&
respectively [49 ]. Tregs contribute to the resolu-
tion phase of ARDS, while Th17 cells can cause
systemic inflammation by producing interleukin
(IL)-17, which is elevated in patients with sepsis-
related ARDS [50]. Additionally, higher Th17 to Treg
cell ratio in the systemic circulation is associated
with poorer prognosis in ARDS [51]. SFB are com-
mensal organisms in the gut, promoting develop-
ment of Th17 cells locally for enhanced resistance to
&&
intestinal pathogens [11,49 ]. Similarly, SFB can
regulate the CD4þ T-cell polarization into the
Th17 pathway, which when overexpressed can exac-
erbate pulmonary fungal infections and autoim-
mune lung conditions. This plausible pathway
linking systemic T cell responses in ARDS and sepsis
with gut microbiota represents another dimension
of the gut–lung axis that may be amenable to ther-
apeutic manipulation [52].
CONCLUSION – THE ROAD TOWARDS
THERAPEUTIC MANIPULATION OF THE
GUT–LUNG AXIS
The vascular routes connecting the gut and lungs,
along with evidence from epidemiologic observa-
tions, clinical studies and animal model experi-
ments provide compelling evidence supporting
the presence and function of a gut–lung axis in
critical illness. However, we are far from sufficient
understanding of the driving principles to confi-
dently intervene with the gut–lung axis. Even
though clinical interventions targeting an improve-
ment in composition and function of the gut micro-
biome to reduce lung injury and inflammation may
www.co-criticalcare.com 135
 Gastrointestinal system
seem a logical next step, many of the underlying
mechanisms need to be further clarified before we
can make educated decisions on who to target with
what intervention.
In order to establish the direction of gut–lung
interaction, we will require investigation with tech-
niques such as paired metagenomic comparisons of
gut and lung microbiota and the use of labeled
‘tracer’ bacteria in gnotobiotic animals. Further-
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more, secondary analysis of randomized controlled
trials or instrumental variable analyses with gut-
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targeted interventions could further enhance our
understanding of the direction of effect. Addition-
ally, to elucidate the route and the most relevant
messengers, animal models are likely required due
to the difficulty in sampling portal and lymphatic
systems in critically ill patients. We should also not
only focus on the bacterial kingdom, but remain
aware that trans-kingdom interactions are likely
important [53].
A common issue in critical care practice is the
extensive use of often empiric, broad-spectrum
antibiotics. Recent retrospective research in crit-
ically ill patients has shown that use of antianaero-
bic antibiotics is associated with decreased overall
survival and increased risk of VAP, with detectable
impact on gut microbial communities and lower
&&
respiratory tract microbiology [23 ]. Such research
shows that even when governed by principles of
targeting and stewardship, clinical choices on anti-
biotics from different classes are undertaken with
limited appreciation of their off-target effects on
the gut microbiome.
Overall, our understanding of the gut–lung axis
has significantly increased over the recent years.
Once the secrets of this relationship are unlocked,
it may provide novel treatment strategies and can
shape our choices in antimicrobial treatment strat-
egies. Translational research is needed to improve
our understanding of the gut–lung axis as well as
methods of reinstatement of symbiosis.
Acknowledgements
None.
Financial support and sponsorship
Lieuwe D.J. Bos receives research funding from Amster-
dam UMC., Longfonds, ERS, ZonMW and the Innova-
tive Medicine Initiative. Dr Kitsios receives funding
support from the National Institutes of Health: K23-
HL139987 and R03-HL162655.
Conflicts of interest
Dr Kitsios has received research funding from Karius, Inc.
The remaining authors have no conflicts of interest.
136 www.co-criticalcare.com
Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
REFERENCES AND RECOMMENDED
READING
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