Intestinal-pulmonary axis: a ‘Force For Good’ against respiratory viral infections

Abstract

Respiratory viral infections are a major global public health concern, and current antiviral therapies still have limitations. In recent years, research has revealed significant similarities between the immune systems of the gut and lungs, which interact through the complex physiological network known as the “gut-lung axis.” As one of the largest immune organs, the gut, along with the lungs, forms an inter-organ immune network, with strong parallels in innate immune mechanisms, such as the activation of pattern recognition receptors (PRRs). Furthermore, the gut microbiota influences antiviral immune responses in the lungs through mechanisms such as systemic transport of gut microbiota-derived metabolites, immune cell migration, and cytokine regulation. Studies have shown that gut dysbiosis can exacerbate the severity of respiratory infections and may impact the efficacy of antiviral therapies. This review discusses the synergistic role of the gut-lung axis in antiviral immunity against respiratory viruses and explores potential strategies for modulating the gut microbiota to mitigate respiratory viral infections. Future research should focus on the immune mechanisms of the gut-lung axis to drive the development of novel clinical treatment strategies.

Full text

Intestinal-pulmonary axis: a
‘Force For Good’against
respiratory viral infections
Jianing Zhu
1
, Zihang Huang
1
, Ying Lin
1
, Wenxu Zhu
1
,
Binbin Zeng
1
and Dong Tang
2,3,4,5,6,7
*
1
Clinical Medical College, Yangzhou University, Yangzhou, China,
2
Department of General Surgery,
Institute of General Surgery Northern Jiangsu People’s Hospital Affiliated to Yangzhou University,
Yangzhou, China,
3
Northern Jiangsu People’s Hospital, Yangzhou, China,
4
The Yangzhou Clinical
Medical College of Xuzhou Medical University, Yangzhou, China,
5
The Yangzhou School of Clinical
Medicine of Dalian Medical University, Yangzhou, China,
6
The Yangzhou School of Clinical Medicine
of Nanjing Medical University, Yangzhou, China,
7
Northern Jiangsu People’s Hospital, Clinical
Teaching Hospital of Medical School, Nanjing University, Yangzhou, China
Respiratory viral infections are a major global public health concern, and current
antiviral therapies still have limitations. In recent years, research has revealed
significant similarities between the immune systems of the gut and lungs, which
interact through the complex physiological network known as the “gut-lung
axis.”As one of the largest immune organs, the gut, along with the lungs, forms
an inter-organ immune network, with strong parallels in innate immune
mechanisms, such as the activation of pattern recognition receptors (PRRs).
Furthermore, the gut microbiota influences antiviral immune responses in the
lungs through mechanisms such as systemic transport of gut microbiota-derived
metabolites, immune cell migration, and cytokine regulation. Studies have shown
that gut dysbiosis can exacerbate the severity of respiratory infections and may
impact the efficacy of antiviral therapies. This review discusses the synergistic
role of the gut-lung axis in antiviral immunity against respiratory viruses and
explores potential strategies for modulating the gut microbiota to mitigate
respiratory viral infections. Future research should focus on the immune
mechanisms of the gut-lung axis to drive the development of novel clinical
treatment strategies.
KEYWORDS
respiratory viral infections, gut-lung immune axis, intestinal microbiota, systemic
transport of gut microbiota-derived metabolites, immune cell migration, immune
factor cycling
1 Introduction
Respiratory viruses primarily invade through the respiratory tract, where they can
proliferate extensively in the epithelial cells of the respiratory mucosa, causing localized
infections or leading to damage in other tissues and organs (1). Common viral families
include Orthomyxoviridae, Paramyxoviridae, and Coronaviridae, along with less common
Frontiers in Immunology frontiersin.org01
OPEN ACCESS
EDITED BY
Yongjian Wu,
The Fifth Affiliated Hospital of Sun Yat-sen
University, China
REVIEWED BY
Juandy Jo,
University of Pelita Harapan, Indonesia
Felipe Melo-Gonzalez,
Andres Bello University, Chile
*CORRESPONDENCE
Dong Tang
83392785@qq.com
RECEIVED 25 November 2024
ACCEPTED 28 February 2025
PUBLISHED 18 March 2025
CITATION
Zhu J, Huang Z, Lin Y, Zhu W, Zeng B
and Tang D (2025) Intestinal-pulmonary
axis: a ‘Force For Good’against
respiratory viral infections.
Front. Immunol. 16:1534241.
doi: 10.3389/fimmu.2025.1534241
COPYRIGHT
© 2025 Zhu, Huang, Lin, Zhu, Zeng and Tang.
This is an open-access article distributed under
the terms of the Creative Commons Attribution
License (CC BY). The use, distribution or
reproduction in other forums is permitted,
provided the original author(s) and the
copyright owner(s) are credited and that the
original publication in this journal is cited, in
accordance with accepted academic
practice. No use, distribution or reproduction
is permitted which does not comply with
these terms.
TYPE Review
PUBLISHED 18 March 2025
DOI 10.3389/fimmu.2025.1534241

families like Togaviridae and Picornaviridae. Respiratory viral
infections have long posed a significant public health challenge.
In 2015 alone, respiratory syncytial virus (RSV) infections led to
approximately 3.2 million hospitalizations and 59,600 deaths in
children under five globally (2). Additionally, influenza viruses
continue to impose a substantial global health burden, affecting
approximately 8% of adults and 25% of children each year (3).
While the mortality rate of seasonal influenza is generally low,
severe infections caused by certain influenza strains, such as H5N1
and H7N9, can have mortality rates of 50% or higher (4). Although
existing antiviral drugs and immunomodulatory therapies have
demonstrated efficacy in combating respiratory viral infections,
many such infections still lack specifictreatments(5,6), and
approved therapies often rely on synthetic drugs that can be
limited by side effects and the development of viral resistance (7,
8). There is an urgent need to identify new strategies for better
controlling respiratory viral infections.
Traditional research on the immune response to respiratory
viruses has primarily focused on the immune defenses of the
respiratory system itself. The lungs have distinct immune defense
mechanisms, including mucosal barriers, immune cells, and
immune molecules (9,10). However, recent studies have
increasingly demonstrated that immune signaling pathways
between the gut and respiratory system are interconnected. The
gut, the largest immune organ in the body, hosts a diverse
microbiota that interacts with the host’simmunesystemto
maintain immune homeostasis (11). Research has shown that
under certain pathological conditions, there is considerable
overlap in the types and functions of immune cells in the gut and
lungs, enabling coordinated responses to pathogen invasion
(12,13). Specific members of the gut microbiota are associated
with resistance to respiratory viral infections (14), and changes in
gut microbiota composition may affect susceptibility to respiratory
viruses and the progression of disease (15). This complex
biological and immunological interaction between the gut and
lungsisreferredtoasthe“gut-lung axis.”With an in-depth
understanding of the mechanism of action of the gut-lung axis in
the fight against respiratory viral infections, it is expected to
regulate the body’s immune function, enhance the resistance to
respiratory viral infections, and attenuate the inflammatory
response and pathological damage by intervening in the
interaction of the gut-lung axis, thus providing a new way of
thinking and a potential target for the prevention and treatment
of respiratory viral infections.
2Definition of the gut-lung axis
The lungs and gut both belong to the common mucosal immune
system (CMIS), serving as critical defense organs that protect the
body from pathogen invasion through both innate and adaptive
immune mechanisms. Research indicates that stimulation of one
organ can affect the immune responses of another, forming what is
referred to as the gut-lung cross-talk pathway (16,17), also known as
the gut-lung axis. Gut-Lung Axis refers to the complex network of
interactions between the gut and lungs through the nervous,
endocrine, and immune systems. This concept emphasizes the close
connection between two organs, particularly in terms of their roles in
inflammatory response and immune regulation. This connection
spans anatomical, microbiological, and immunological dimensions.
From an anatomical perspective, although the lungs and gut are
distant from each other, there are potential anatomical links that
reinforce the existence of the gut-lung axis. Current studies suggest
that communication along this axis may occur through the
bloodstream (18,19), lymphatic system (20), and neuroendocrine
pathways (21). Microbiologically, both the lungs and gut harbor
distinct microbial communities. The intestinal microbiota consists
mainly of Bacillota, Bacteroidota, Actinobacteria, etc., and is diverse
and abundant. The lung microbiota, on the other hand, is relatively
simple, consisting mainly of Pseudomonadota, Actinobacteria, etc.,
and its abundance is much lower than that of the intestinal tract
(22). The gut-lung axis encompasses interactions between host and
microbiota, as well as between different microbial communities,
playing a key role in maintaining host homeostasis and contributing
to disease progression. For instance, in patients with
bronchopulmonary dysplasia (BPD), the relative abundance of
Bacillota is significantly lower than the non-BPD group. At the
genus level, Clostridium sensu stricto 1 was sig nificantly lower in the
BPD group. However, Veillonella,Roseburia,Micrococcus,
Xanthomarina were significantly enriched in the BPD group. Gut
dysbiosis may contribute to BPD progression by altering immune
function and metabolism (23). From an immunological standpoint,
the lungs and intestines share many common immune cells, such as
tissue-resident memory T cells (TRMs) (24), Invariant natural killer
T (iNKT) (25), Mucosal-associated invariant T (MAIT) (26–28). In
addition, the microbiota in both the lungs and gut can influence the
development, maturation, and function of immune cells, thereby
regulating both local and systemic immune responses. Studies have
shown that gut microbiota can modulate immune cell composition
and function through the production of short-chain fatty acids
(SCFAs) and other metabolites (29). Supplementing specific gut
microbiota may help reestablish and restore the host’s immune
response (30).
3 Physiological basis of the gut-
lung axis
The high degree of conservation of respiratory virus-
recognizing receptors in intestinal and lung tissues, as well as the
remarkable similarity in the mechanisms of antiviral immune
response in these two organs, together form the molecular and
immunological basis of the gut-lung axis.
3.1 Similarities between the gut and lungs
in respiratory virus recognition receptors
The innate immune system serves as the first line of defense
against pathogen invasion, with receptors that can specifically
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recognize pathogen-associated molecular patterns (PAMPs)
(31,32). In mammals, the innate immune response is triggered
by host pattern recognition receptors (PRRs) that detect PAMPs.
When PRRs such as Toll-like receptors (TLRs) and RIG-I-like
receptors (RLRs) recognize PAMPs (33–35), they initiate signaling
pathways that activate the host cell’s defense mechanisms (36). This
recognition leads to cellular responses such as regulating
transcription factors essential for the production of interferons
(IFNs) and cytokines, increasing expression of MHC class II and
inducing expression of the costimulatory molecules CD40, CD80 and
CD86, aimed at neutralizing pathogens and activating other defense
mechanisms (37). Both the gut and lung immune systems harbor
similar virus recognition receptors, forming a critical component of
the host’sinnateimmunedefense.Table 1 summarizes in detail the
pulmonary and intestinal shared viral recognition receptors in
common respiratory viral infections.
3.1.1 The role of SARS-CoV-2 and ACE-2
receptors in the lungs and gut
The COVID-19 pandemic, caused by SARS-CoV-2, has
demonstrated high transmissibility and infectivity. The angiotensin-
converting enzyme 2 (ACE-2) receptor plays a crucial role in this
process, serving as the entry point for SARS-CoV-2 into cells, while
also contributing to the maintenance of lung and gut health (38).
SARS-CoV-2 invades host cells by binding to the ACE-2
receptor. Studies have shown that ACE-2 receptors are widely
distributed in alveolar cells, explaining the virus’s ability to cause
severe respiratory disease (39). Additionally, biopsies of the
stomach, duodenum, and rectum from infected patients have
revealed the presence of both SARS-CoV-2 and ACE-2 receptors
in gastrointestinal tissues (40–43), indicating that the gut is also a
potential site of viral entry (44–46). Following infection,
gastrointestinal symptoms such as nausea, vomiting, and diarrhea
may occur in addition to the common respiratory symptoms of
cough, shortness of breath, and loss of smell. Research has found
that up to half of COVID-19 patients report gastrointestinal
symptoms (47). SARS-CoV-2 invades host cells by binding its
spike glycoprotein (S protein) to ACE-2 receptors on the surface
of host cells (48–50). This invasion occurs not only in the lungs but
also in the gut. In vitro experiments have confirmed that SARS-
CoV-2 can efficiently enter and replicate in colonic epithelial cells
(51,52),This study demonstrates that ACE-2 receptors consistent
with the lung can also be expressed in the gut, providing binding
sites for viral infections.
In summary, the high expression of ACE-2 receptors in both the
respiratory and gastrointestinal systems provides a biological
explanation for the elevated infection rates of SARS-CoV-2 in
these two systems, revealing a similarity in the virus recognition
mechanisms of the gut and lungs.
3.1.2 The role of influenza virus and RLRs in the
lungs and gut
Influenza viruses, belonging to the Orthomyxoviridae family,
are classified based on specific combinations of their surface
proteins, hemagglutinin (HA) and neuraminidase (NA), with 18
HA and 11 NA subtypes identified so far (53). During infection, the
HA on the viral surface binds to sialic acid receptors on host cells,
allowing the virus to attach to target cells. Subsequently, through a
process mediated by clathrin-mediated endocytosis (CME), the
virus enters host cells via specific N-linked glycoproteins (54,55).
PRRs detect viral genetic material entering the cell, which in
turn initiates a series of signaling cascades to effectively inhibit viral
replication and remove the virus before the infection becomes
severe, protecting the organism from further aggression (56).
Among these PRRs, the RLR family—including RIG-I, MDA5,
and LGP2—plays a crucial role. Studies show that both RIG-I and
MDA5 are capable of recognizing RNA viruses in the epithelial cells
of the gut and lungs, detecting viral RNA in infected cells (57–59).
The activation of RIG-I is essential for the production of IFNs in
response to viruses such as paramyxoviruses, influenza viruses, and
Japanese encephalitis viruses (60,61), while MDA5 is particularly
important for detecting small RNA viruses (62,63).
TABLE 1 Generalization of viral recognition receptors shared by lung and intestine and similar immune mechanisms in common respiratory
viral infections.
Respiratory Viruses Shared Receptor Types Similar Signaling
Pathways Activated References
SARS-CoV-1
SARS-CoV-2 ACE-2 Angiotensin II →Ang (1-7) (80–82)
Flu Virus RLRs IFN ↑(57–59)
RSV TLRs MyD88↑TRIF↑
IFN ↑(76,83)
Adenovirus Coxsackievirus-Adenovirus
Receptor (CAR)
Leucocyte recruitment
tissue remodeling (84–86)
Human Metapneumovirus (HMPV) Acetylheparin Sulfate
Proteoglycan (HSPG) Integrin avb1↑(87)
Human Parainfluenza Virus (HPIV) Sialic Acid Virus attachment and entry into
host cells (88)
Human Microvirus B19 (B19V) Globotetraosylceramide (Gb4Cer) nonstructural (NS)1 protein↑(89,90)
A→B: metabolizes A into B.
A↑: increased expression levels of A.
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RLRs, as RNA sensors localized in the cytoplasm, are
widespread in human cells, particularly in epithelial cells in direct
contact with the external environment, such as the gut and lungs.
Activation of RLR can stimulate an antiviral response by initiating
cellular autophagy, effectively inhibiting the process of viral
replication before it occurs (64). This early defense mechanism is
critical for halting viral spread and mitigating disease symptoms.
3.1.3 The role of RSV and TLRs in the lungs
and gut
RSV is a common virus, posing a significant health threat,
particularly to infants (65–67). TLRs, key components of the innate
immune system, recognize PAMPs and trigger immune responses
(68,69). Recent studies have increasingly focused on the role of RSV
and TLRs in regulating immune responses in both the lungs and
gut. As vital organs in the body, the immune balance of the lungs
and gut is crucial for overall health. RSV infection not only affects
the lungs but may also impact gut immunity, with TLRs serving as
critical mediators in this process.
Once RSV infects the lungs, it can influence gut immune
function via the bloodstream or neuroendocrine pathways. RSV
induces inflammation and recruits immune cells. Viral infection
damages the respiratory epithelium, releasing cytokines and
chemokines that attract immune cellssuchasneutrophils,
macrophages, and lymphocytes to the site of infection (70,71).
Furthermore, lung inflammation caused by RSV can lead to
systemic inflammatory response syndrome (72). This
inflammation may compromise the integrity of the gut barrier by
altering the expression of junction proteins in intestinal epithelial
cells (IECs) (73), allowing pathogens and toxins easier entry into the
body, which exacerbates inflammation and immune dysregulation
(74,75), ultimately affecting lung immune function.
The connection between TLRs in lung and gut immune
regulation involves several key aspects: First, TLRs in both organs
including TLR3, TLR4, TLR7/8 and TLR2/6 can recognize different
components of RSV and initiate immune responses (76). Second,
TLRs regulate the production of cytokines and chemokines (77,78),
affecting the recruitment and activation of immune cells, thereby
facilitating immune crosstalk between the lungs and gut. Finally,
TLRs modulate gut barrier function, controlling the entry of
pathogens and toxins into the bloodstream, which in turn
influences lung immune function (79).
3.2 Similarities in antiviral immune
mechanisms between the gut and lungs
In addition to their similarities in viral recognition mechanisms,
the gut and lungs exhibit highly consistent immune strategies in
response to viral invasion. Both rely on the expression of interferon-
stimulated genes (ISGs) and the ubiquitination pathway mediated
by TRIM25 to mount antiviral immune responses, effectively
defending against viral infections. This coordinated immune
action further underscores the critical role of the “gut-lung axis”
in antiviral immunity. Table 1 summarizes in detail the similar
immune mechanisms exhibited by the lungs and intestines in
common respiratory viral infections. Figure 1 lists two similar
immune pathways exhibited by the gut and lungs under common
respiratory virus infections.
3.2.1 ISGs and antiviral immunity
IFNs, as the first line of defense in antiviral immunity, play a key
role in inhibiting viral replication, promoting apoptosis, and
enhancing the activity of immune cells by inducing the
expression of ISGs. During infections in both the gut and lungs,
ISGs such as Janus kinase signal transducer and activator of
transcription (JAK-STAT) are significantly upregulated,
demonstrating the widespread applicability of these genes in
FIGURE 1
Human antiviral immune mechanism shared by the lungs and intestines, taking ISGs and TRIM25 antiviral immune mechanism as examples. As
shown in section (a), during the infection process of SARS-CoV-2 and influenza virus, etc., ISGs such as Janus kinase signal transduction and
transcription activators (JAK-STAT) are significantly upregulated, initiating a broad range of antiviral effects by ISGs. In section (b), RNA from RSV and
MERS-CoV, etc., triggers a conformational change in RIG-I, which TRIM25 binds to and oligomerizes, activating the MAVS to initiate the expression
of a series of antiviral genes. PAMPs, Pathogen-associated molecular patterns; IFN, Interleukin; IFNAR, Interleukin receptor.
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antiviral immunity across these two organs. Such mechanisms have
been implicated in both the SARS-CoV-2 and influenza virus
pathways of human infection (91,92).
Upon recognition of PAMPs, host cells rapidly produce and
secrete IFNs (93). IFNs, which regulate the host’s defense against
pathogens, are classified into Type I, II, and III, with Type I IFNs
(including IFN-aand IFN-b) being particularly critical in antiviral
responses (94). Type I IFNs bind to cell surface interferon receptors
(IFNAR), activating intracellular Janus kinases (JAKs) and signal
transducers and activators of transcription (STATs).
The activation of the JAK-STAT signaling pathway is a key step
in IFN signal transduction. When IFNs bind to IFNAR, JAKs are
recruited and phosphorylated, subsequently activating STATs.
Phosphorylated STATs form dimers that translocate to the
nucleus, binding to specific DNA sequences to initiate ISG
transcription (95). The expression of ISGs triggers broad antiviral
effects by inhibiting viral entry into cells and blocking viral
replication and assembly (96).
ISGs encode antiviral proteins such as Mx protein, protein
kinase R (PKR), and 2’,5’-oligoadenylate synthetase (OAS) (97–99),
which effectively suppress viral replication and transmission.
Additionally, ISGs participate in regulating the activation,
proliferation, and differentiation of immune cells, and they
promote inflammatory responses, thereby limiting pathogen
infection and spread on multiple fronts (100,101). Therefore, ISG
expression is a core component of the host’s defense mechanism
against pathogens, playing a vital role in maintaining the balance
between host and pathogen.
3.2.2 TRIM25-mediated ubiquitination pathway
and RIG-I antiviral signaling
TRIM25, as an E3 ubiquitin ligase, is able to activate RIG-I via
K63-strand ubiquitination, triggering the synthesis and secretion of
type I interferon and thus initiating an antiviral immune response
(102,103). Activation of this pathway significantly enhances host
antiviral immunity, which is one of the important mechanisms for
resisting the invasion of respiratory viruses such as RSV and Middle
East respiratory syndrome coronavirus (MERS-CoV) (102,104).
In antiviral innate immunity, RIG-I acts as a key RNA
deconjugating enzyme and plays an important role in recognizing
viral RNA (105). When viruses invade host cells and release their
RNAs, RIG-I specifically recognizes these “non-self”RNAs,
triggering a series of complex signaling cascades. Recognition of
viral RNAs by RIG-I leads to a conformational change, exposing the
hidden CARD domains(CARDs) (106,107), which provides a
binding site for TRIM25 recruitment. After TRIM25 recognizes
and binds to the CARDs of RIG-I (108), it acts as an E3 ubiquitin
ligase, which catalyzes the attachment of K63-linked ubiquitin
chains to specificlysineresiduesonRIG-I.Thisformof
ubiquitination does not target the protein for degradation but
instead modulates signal transduction (109), altering the
biochemical properties of RIG-I and promoting its
oligomerization. This oligomerization is crucial for the full
activation of RIG-I, enabling it to interact with the downstream
mitochondrial antiviral signaling protein (MAVS) (110).
MAVS serves as the central node in antiviral signal
transduction, activating several kinases, including TBK1 and
IKKe(111). These kinases, in turn, phosphorylate transcription
factors such as IRF3 (interferon regulatory factor 3) and NF-kB,
driving them into their active states (112). Once activated, these
transcription factors translocate into the nucleus and initiate the
expression of a suite of antiviral genes, including type I interferons
(IFN-aand IFN-b) and pro-inflammatory cytokines (113).
IFNs propagate between infected and neighboring cells in an
autocrine and paracrine manner, amplifying antiviral signals
through the JAK-STAT signaling pathway, inhibiting viral
replication, and inducing the expression of a range of antiviral
proteins in host cells. Thus, the TRIM25-mediated ubiquitination
pathway and the RIG-I antiviral pathway are a complex and
sophisticated regulatory network that ensures that the host is able
to rapidly and efficiently initiate an immune response against
viral infection.
4 Immunological linkage mechanisms
between the gut and the lungs
In recent years, a growing body of research has highlighted the
close relationship between the gut and the lungs in terms of
immune mechanisms and functions. Pulmonary diseases are often
accompanied by intestinal damage, and conversely, intestinal
diseases can also trigger pathological changes in the lungs. For
example, influenza virus infection can cause gastrointestinal
symptoms such as vomiting and diarrhea (114), HMPV can
modulate intestinal adaptive immunity despite the absence of
viral expression in the gut (115). Moreover, patients with
inflammatory bowel disease (IBD) frequently develop respiratory
diseases such as asthma and chronic obstructive pulmonary disease
(COPD) (116). This bidirectional relationship underscores the
significance of the “gut-lung axis.”This section further explores
these mechanisms in the context of the gut-lung axis and their
impact on respiratory viral infections.
4.1 Migration of intestinal microbiota
It is well known that the human body harbors a vast array of
microorganisms, including bacteria, fungi, viruses, and archaea.
Among these, the gut microbiota is the most densely populated,
primarily consisting of species such as Bifidobacterium,
Lactobacillus, and Escherichia coli (117). As a crucial component
of the intestinal barrier, the gut microbiota plays an essential role in
digesting food, synthesizing vitamins, regulating the immune
system, and defending against pathogens (118).
Although the microbiota of the gut and lungs are distributed in
different anatomical locations, they are closely linked through the
“gut-lung axis.”The translocation of microbiota is one of the key
mechanisms underlying this connection. In 2023, a study by
Jayanth Kumar Narayana et al. found that in stable
bronchiectasis, the microbiota community exhibited significant
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gut-lung interactions. The translocation of bacteria between the gut
and lungs may be associated with increased overall severity of
bronchiectasis, suggesting that microbial migration between these
organs is related to the disease (119). Studies have shown that some
microbiota can migrate to other organs and tissues, such as the
brain (120), muscles (121), and lungs. This migration can influence
local tissues and may even trigger systemic inflammatory responses,
further exacerbating disease progression. Acute respiratory distress
syndrome (ARDS) is an acute and diffuse pulmonary inflammation
and a common cause of respiratory failure, often secondary to
various respiratory viral infections, such as influenza A virus (IAV).
In 2016, Robert P. Dickson and colleagues conducted sequencing
of bacterial communities in bronchoalveolar lavage (BAL)
specimens from ARDS patients and found that certain
Bacteroides operational taxonomic units (OTUs) absent in
healthy lungs were highly consistent with those found in four
anaerobic genera from the gut, and these were associated with the
severity of acute systemic inflammation (122). Similarly, in 2023,
Dusanka Popovic et al. used the fungus A. fumigatus to induce
pulmonary inflammation and discovered that the disruption of
pulmonary homeostasis facilitated the migration of new bacterial
species to the lungs, with 41.8% of the bacteria also present in fecal
samples, indicating a degree of gut microbiota translocation to the
lungs (123). These findings support the existence of the “gut-lung
axis”and suggest a bidirectional relationship between lung
inflammation and gut microbiota dysbiosis.
4.2 Regulatory role of intestinal microbiota
More and more studies have proved that microbiota can not
only migrate directly to target organ to play an immune role, but
also regulate the immune function of the body through a variety of
ways, such as systemic transport of gut microbiota-derived
metabolites, immune cell migration, and cytokine cycling
(Figure 2). 2022, Xiaowu Baiet al. found that cigarette smoke can
directly lead to the disruption of the intestinal microbiota of the
mouse, which can lead to the impairment of the intestinal barrier
and enhance the expression of oncogenic signals and pro-
inflammatory genes (124). This suggests that the disruption of
intestinal microbiota may be the starting point for the regulation of
immune function by intestinal microbiota. Similarly, IAV, COVID-
19 and other respiratory viruses also showed disturbances in the
intestinal microbiota (114,125), which provides a target for us to
further investigate the role of intestinal microbiota regulation in the
context of respiratory virus infection.
4.2.1 Systemic transport of gut microbiota-
derived metabolites
Metabolites produced by the gut microbiota, such as SCFAs and
secondary bile acids, can influence distant organs, including the
pulmonary immune environment, via the bloodstream, thereby
enhancing the efficiency of antiviral immune responses. This
systemic transport of gut microbiota-derived metabolites not only
alters the host’s energy metabolism but also regulates immune
responses, bolstering the host’s resistance to respiratory viral
infections. The alterations may be associated with changes in the
host’s defense mechanisms driven by microbial metabolites. For
instance, a study by Michael C. Abt et al. in 2012 demonstrated that
the responsiveness of macrophages to type I and II IFNs was
impaired in ABX-treated mice, which consequently reduced their
ability to control viral replication. This finding indicates that
commensal bacteria influence the activation threshold of widely
utilized innate antiviral pathways, such as the IFN signaling
pathway (126). Similarly, a study published in 2023 by Junling
Niu et al. revealed that the acetate produced by Bifidobacterium
pseudolongum NjM1 promotes the interaction between NLRP3 and
the MAVS by binding to the GPR43 receptor on the host cell
surface. This interaction subsequently activates the TBK1/IRF3
pathway, driving the production of type I IFNs (127). Table 2
summarizes in detail the immune impact exerted by several
common microbial metabolites in the fight against respiratory
viral infections.
SCFAs, the primary metabolites generated by the fermentation
of dietary fiber by gut microbiota, play a pivotal role in maintaining
epithelial barriers and programming immune cells under
homeostatic conditions. Butyrate, in particular, inhibits histone
deacetylases (HDACs) through various pathways, thereby
enhancing the expression of anti-inflammatory genes (128).
Butyrate indirectly promotes the differentiation of effector T cells
(Teff) by increasing the acetylation levels of histone H3K9 in
chromatin. Additionally, by blocking the deacetylation of the
promoter regions of exhaustion-related genes (such as PD-1 and
TIM-3), butyrate inhibits the exhausted phenotype of CD8
+
T cells
in chronic immune responses. At the metabolic level, butyrate can
reshape the energy metabolism of CD8
+
T cells, supporting cell
survival in a low-glucose microenvironment and restricting the
excessive activation of Teff and inflammatory damage (129). Wei
Wang and colleagues found that butyrate induces transcriptional
changes via HDAC inhibition, ultimately reducing the expression of
cFLIP and IL-10, thereby activating the NLRP3 inflammasome to
trigger pro-inflammatory processes (130). Additionally, butyrate
regulates the number and function of effector cells such as
regulatory T cell (Treg), T helper cells 1 (Th1), and T helper cells
17 (Th17) (131), helping to maintain immune balance, reduce
inflammation, and preserve gut homeostasis. Propionate primarily
modulates immune responses via the GPR43 receptor, suppressing
IL-12 and TNF-asecretion in dendritic cells while promoting the
expansion of gut-homing Tregs, thereby reinforcing a localized
anti-inflammatory microenvironment (132). Additionally,
propionate induces macrophage polarization toward an M2 anti-
inflammatory phenotype through HDAC inhibition (133).Acetate,
acting as a ligand for GPR43/GPR41, enhances IgA secretion by
activating systemic transport of gut microbiota-derived metabolites
(e.g., upregulated glycolysis) in B cells, thereby strengthening
mucosallayer pathogen clearance (134). It also mitigates
inflammatory damage to the epithelial barrier by suppressing
neutrophil chemotactic factors (CXCL1/CXCL2) (135). SCFAs
bidirectionally regulate the efficiency of memory formation and
the persistence of immune responses in antigen-activated CD8
+
T
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cells through G protein-coupled receptors (GPCRs) and
monocarboxylate transporters (MCTs/SMCTs). In the GPCR
pathway, SCFAs bind to GPR41/GPR43 to activate AMPK and
inhibit mTORC1, thereby promoting the shift of CD8
+
T cells
toward a memory precursor phenotype driven by oxidative
phosphorylation (OXPHOS) and fatty acid oxidation (FAO),
which is accompanied by enhanced mitochondrial biogenesis and
fatty acid uptake. Meanwhile, the influx of SCFAs mediated by
MCTs/SMCTs reinforces metabolic adaptation by inhibiting
HDAC activity and synergistically amplifying OXPHOS metabolic
advantages through GPCR signaling (136). For instance, SCFAs in
renal cells reduce tumor necrosis factor-a(TNF-a)-induced MCP-
1 expression through a GPR41/43-dependent pathway, inhibiting
the phosphorylation of p38 and JNK, thereby indirectly suppressing
the NF-kB pathway and mitigating inflammation (137). Although
the precise mechanisms of this inhibition vary across different cells
and tissues, they all involve regulating immune responses, reducing
inflammation, and improving disease states. Therefore, SCFAs
possess potent anti-inflammatory properties.
Secondary bile acids, which are metabolites of bile acids by the
gut microbiota, have been shown to play an essential role in
regulating immune responses in both the lungs and the gut.
Farnesoid X receptor (FXR) and G-protein-coupled bile acid
receptor 5 (TGR5) are two important bile acid receptors that are
key to regulating gut inflammation and suppressing the pro-
inflammatory responses of macrophages. FXR primarily
influences the gut environment by regulating bile acid
metabolism, with its high expression in the gut and liver making
FIGURE 2
Specific manifestations of lung and intestinal immune correlations. Lung and intestinal immune relevance is manifested in four main areas: Migration
of gut bacteria, immune cell migration,cytokine recycling and systemic transport of gut microbiota-derived metabolites. HDAC, histone
deacetylases; GPCRS, G protein-coupled receptors;SCFAS, short-chain fatty acids; TGRS, traditional gender roles; FXR, Farnesoid X receptor ;SABs,
Secondary bile acids.
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it crucial for maintaining intestinal homeostasis. Activation of FXR
can suppress inflammation, protect the intestinal barrier, fight
bacterial infections, and reduce oxidative stress (138). For
example, FXR activation stabilizes the binding of the corepressor
NCoR at the IL-1bpromoter, thereby inhibiting NF-kB-dependent
gene expression. Additionally, it increases the expression of I-BABP
in the intestine while reducing mRNA levels of interleukin-1b(IL-
1b), interleukin-2 (IL-2), interleukin-6 (IL-6), TNF-a, and IFN-g,
thereby alleviating disease severity (139). TGR5, a cell surface
receptor, responds to stimulation by secondary bile acids and
plays a role by directly suppressing the pro-inflammatory
responses of macrophages. Specifically, TGR5 deficiency
exacerbates inflammation, whereas TGR5 activation inhibits
NLRP3 inflammatory vesicle activation and M1-type macrophage
polarization (140). It has been shown that activation of the bile acid-
TGR5 axis prevents influenza virus infection or inhibits the
inflammatory response following influenza virus infection (141).
Similar to the gut, microbial metabolites in the lung also exert
significant impacts on the host immune system. A study by Jingli Li
et al. in 2020 demonstrated that exposure to PM2.5 significantly
altered the richness, evenness, and composition of the lung
microbiota, and disrupted the levels of pulmonary metabolites
such as valine, acetate, and fumarate. These changes not only
affect normal energy metabolism in the host but also predispose
to inflammation in distant organs (142).
4.2.2 Immune cell migration
The gut contains 70-80% of the body’s immune cells, which play
critical roles in maintaining gut homeostasis, defending against
pathogens, and preserving mucosal barrier function. For example,
group 3 innate lymphoid cells (ILC3s) secrete cytokines such as IL-
22 to enhance intestinal barrier integrity and exert anti-
inflammatory effects (151). Macrophages, on the other hand,
contribute to post-inflammatory recovery through key signaling
pathways such as NF-kB, JAK/STAT, and PI3K/AKT, as well as
specific microRNAs like miR-155 and miR-29 (152).
In the gut, there is a complex regulatory and supportive
relationship between the immune system and the gut microbiota.
Under the stimulation of gut microbes, immune cells can become
activated and exert immunosurveillance functions throughout the
body. A study by Seohyun Byun et al. in 2024 demonstrated that
colonic Tregs, induced by microbiota, exhibit strong suppressive
abilities and higher IL-10 levels, further supporting the wide-ranging
regulatory role of gut microbiota in immune function (153). Recent
studies have revealed that gut microbiota metabolites can migrate to
the lungs, interact with GPCRs on the surface of alveolar
macrophages (AMs), and activate the AMPK-mTOR signaling
axis, thereby enhancing the metabolic adaptability and antiviral
response capacity of AMs. Additionally, microbial signals can
strengthen the rapid recognition and phagocytic clearance of
influenza virus by AMs through the TLR-MyD88 pathway. These
findings indicate that the gut microbiota can enable AMs to control
viral replication and suppress excessive inflammation in the early
stages of infection (154). Moreover, SCFAs can inhibit the
differentiation of Ly6C
+
monocytes into an inflammatory
phenotype and promote their differentiation into patrolling
monocytes with tissue repair functions, thereby maintaining the
local replenishment pool of AMs (155). As early as 1979, John
Bienenstock hypothesized based on experimental results that the
mucosal immune system might function as a system-wide “organ,”
with immune cells in various mucosal tissues interacting with one
another. Since the gut and lungs both belong to the CMIS, gut
microbiota can influence pulmonary immunity through the “gut-
lung axis”by promoting immune cell migration (156). Immune cell
migration mainly occurs via two pathways: the lymphatic system
and the bloodstream. First, immune cells activated by gut microbiota
TABLE 2 Immune effects of different microbial metabolites in the fight against respiratory viral infections.
Metabolite Primary Sources Impact References
Butyrate Dietary fiber fermentation by
anaerobic bacteria Enhances barrier via GPR109A/AMPK; induces Treg via HDAC inhibition. (129)
Propionate Dietary fiber fermentation by
anaerobic bacteria Suppresses DC inflammation; promotes M2 macrophage polarization. (132,133)
Acetate Dietary fiber fermentation by
anaerobic bacteria Boosts IgA via B-cell glycolysis; inhibits neutrophil chemotaxis. (134,135)
Bile Acids Metabolism of bile acids by
gut microbes
Modulation of intestinal inflammation and reduction of macrophage pro-
inflammatory responses via FXR and TGR5 receptors (138,143)
Indoles Gut bacteria metabolize tryptophan Reduction of pro-inflammatory cytokines through aromatic hydrocarbon receptor
(AhR) regulation of intestinal barrier integrity and immunomodulation (144–146)
Lactic Acid Lactobacillus fermentation produces Regulates the intestinal internal environment, reduces the inflammatory response
and promotes the expression of anti-inflammatory cytokines (147)
LPS Gram-negative bacteria Activation of TLR4 receptor triggers a strong pro-inflammatory response leading
to immunopathology (148)
TMAO Enterobacteriaceae lead to inflammation (149)
Phenylacetyl
Glutamine (PAGln)
Christensenellaceae and
other microbiota Significantly reduces inflammatory mediators (150)
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travel through the lymphatic system into the thoracic duct and then
enter the bloodstream, spreading throughout the body, including the
lungs (157). Second, gut microbiota can stimulate intestinal immune
cells to release specific chemokines (such as CCL20) (158), which
guide immune cells to migrate to the lungs, aiding in strengthening
pulmonary immune defense. In the lungs, these immune cells
enhance local immune responses, helping to fend off respiratory
viral infections.
Similar to the gut, immune cells in the lung also exhibit
migration to the intestine. For instance, a study by Ruane D et al.
found that pulmonary CD103
+
and CD24
+
CD11b
+
dendritic cells
(DCs) induce IgA class-switch recombination (CSR) in B cells via T
cell-dependent or -independent pathways. This process promotes
the migration of B cells to the intestine, where they exert protective
effects (159).
4.2.3 Cytokine circulation
In response to infection, immune cells release cytokines, which
are crucial signaling molecules. For example, upon activation by
enteric pathogens such as Staphylococcus aureus and Toxoplasma
gondii, plasmacytoid dendritic cells (pDCs) can produce a variety of
cytokines, including IFNaand IFNb(160). The PAMPs expressed
by pathogens are recognized by PRRs expressed by IECs, which
trigger immune responses by inducing various pro-inflammatory
cytokines, chemokines, and type I interferons. This process further
activates B and T lymphocytes to initiate humoral immunity (161).
Meanwhile, the gut microbiota can influence the host’s cytokine
profile through various mechanisms, thereby regulating immune
responses in distant tissues (162). In particular, cytokine circulation
in the gut-lung axis is considered a key factor in maintaining
immune coordination between the two organs.
Gut microbiota can regulate immune function by influencing
cytokine production through several pathways. For example,
microbial metabolites, such as secondary bile acids, can guide the
differentiation of monocytes, reducing the secretion of IL-12 and
TNF-a(163). Additionally, microbe-associated molecular patterns
(MAMPs), which are conserved molecular structures in bacteria,
fungi, and viruses, can interact with PRRs, maintaining gut
homeostasis. For instance, TLR4 recognizes lipopolysaccharide
(LPS) from Gram-negative bacteria, triggering an inflammatory
response and inducing the production of cytokines such as TNF-a,
IL-1b, and IL-6 (164).
The effect of cytokines is not confined to the local area; they can
spread throughout the body via the bloodstream. For example, in
pulmonary diseases such as COPD and pulmonary fibrosis,
circulating cytokines induce systemic inflammatory responses and
immune regulation abnormalities (165,166). Conversely, cytokine
circulation can help the body defend against invading pathogens. A
study by Chen Jiayi et al. in 2019 proposed that during influenza
virus infection, gut microbiota influence IL-22 production, which
enhances the integrity of the pulmonary mucosal barrier and
reduces viral invasion (167). In cases of lung infection, gut
microbiota can modulate the host’scytokineprofile, thereby
enhancing antiviral defenses in the lungs.
Disruption of the gut microbiota can lead to increased levels of
pro-inflammatory cytokines such as IL-6 and TNF-a, while the
production of anti-inflammatory cytokines like IL-10 may decrease.
This imbalance, transmitted through the bloodstream, can affect the
lungs.During influenza virus infection, dysbiosis of the intestinal
microbiota leads to elevated levels of pro-inflammatory cytokines,
which exacerbate the inflammatory response in the lungs and affect
the host’s immune response to influenza virus (168). Therefore,
maintaining a healthy balance of gut microbiota is crucial for
preventing and managing respiratory viral infections. Similarly, a
study by Liu et al. demonstrated that pulmonary-derived IL-22 can
promote the expression of antimicrobial peptides (such as RegIIIg),
thereby altering the composition of the gut microbiota (169).
Following RSV infection, an imbalance of Th17/Treg cells occurs
in the lungs of mice, leading to excessive release of IL-22 in
pulmonary tissues. This IL-22 enters the systemic circulation,
stimulating the expression of RegIIIgin the gut. This process
impairs the development of Th17/Treg cells in the gut, ultimately
resulting in intestinal immune damage and disruption of the gut
microbiota. These findings highlight that the gut-lung axis is a
bidirectional pathway (169).
5 Regulatory role of the gut-lung axis
in different respiratory viral infections
In a healthy state, the gut-lung axis maintains immune balance
between the gut and lungs, ensuring normal function in both
organs. However, in pathological conditions such as gut
microbiota dysbiosis, viral infections, or heightened inflammatory
responses, the balance of the gut-lung axis can be disrupted. This
imbalance can lead to excessive or insufficient immune responses in
the lungs, increasing the risk of respiratory viral infections or
exacerbating their severity, potentially even affecting treatment
outcomes (170).
Research has shown that during the early stages of respiratory
viral infections, the gut microbiota and its metabolites can rapidly
activate the host’s innate immune system, providing initial antiviral
defense, regulating pulmonary inflammation, and influencing the
early course of infection (171). Additionally, if the gut barrier is
compromised early in infection, the translocation of endotoxins and
microbes may exacerbate pulmonary inflammation, worsening the
prognosis (172). In the later stages of infection, the gut microbiota
plays a continuous role in regulating the host’schronic
inflammatory response. Dysbiosis in the gut-lung axis can lead to
long-term imbalances, resulting in chronic lung diseases or
aggravating pre-existing conditions. Late-stage infections are often
accompanied by multi-organ damage and systemic inflammation,
where microbial imbalance in the gut can further intensify this
systemic inflammatory response. This exacerbation, through the
transmission of inflammatory mediators and metabolites, can
impact other organs, including the lungs (173,174). The immune
regulatory functions of the gut-lung axis vary across different
respiratory viral infections.
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5.1 Regulatory role of the gut-lung axis in
influenza virus infection
The World Health Organization estimates that approximately 1
billion people worldwide are infected with the influenza virus each
year, resulting in 3 to 5 million severe cases and 290,000 to 650,000
deaths. Among these, the IAV is highly transmissible, spreads
rapidly, and exhibits a high mutation rate, having caused multiple
global pandemics throughout history.
Research by Wang et al. demonstrated that H1N1 influenza
virus (PR8 strain) infection induces gut immune damage by altering
the composition of the intestinal microbiota. The CCL25-CCR9 axis
mediates the recruitment of lung-derived effector CD4
+
T cells into
the small intestine and contributes to microbiota composition
changes during influenza infection. These lung-derived CD4
+
T
cells, through the secretion of IFN-g,influence both the microbiota
and intestinal injury. Moreover, in conjunction with IL-15
produced by the microbiota, they promote the polarization of
resident Th17 cells. Notably, a deficiency in IL-17A mitigates the
immune damage induced by influenza in the small intestine (175).
During viral infection, the gut microbiota can influence
pulmonary inflammation by modulating the host’simmune
response. Certain probiotics, such as Lactobacillus, have been
shown to enhance the host’s antiviral immunity and reduce
influenza virus-induced lung inflammation. For instance,
Lactobacillus rhamnosus CRL1505 has been found to mitigate
lung inflammation caused by the influenza virus by modulating
TLR3-mediated inflammatory responses in the lungs. This
probiotic also lowers lung damage and mortality by inhibiting
virus-induced inflammation-coagulation interactions (176).
Additionally, Lactobacillus plantarum DK119, when administered
intranasally or orally, significantly reduced body weight loss and
viral load in H1N1 influenza A virus-infected mice (177), providing
scientific evidence for the potential of probiotics as natural
antiviral agents.
Influenza virus infection often triggers excessive activation of the
host’s immune system, leading to the release of large quantities of
pro-inflammatory cytokines, such as through sustained activation of
the NF-kB signaling pathway. This excessive inflammatory response
isakeyfeatureofsevereinfluenza pneumonia (178). Ichinohe et al.
found that the symbiotic microbiota regulates respiratory mucosal
immunity through appropriate activation of the inflammasome.
Local or distal injection of TLR ligands can rescue immune
deficiencies in antibiotic-treated mice. The products of the
symbiotic microbiota may trigger various PRRs, stimulating the
release of factors from local or systemic leukocytes, supporting the
steady-state production of pro–IL-1b,pro–IL-18, and NLR proteins,
thereby priming signal 1 for inflammasome-dependent cytokine
activation. After H1N1 influenza virus (PR8 strain) infection,
inflammasome activation leads to the migration of DCs from the
lungs to the draining lymph nodes and initiates T cell activation
(179). Moreover, metabolic interactions between the gut and lungs
may influence the progression of influenza virus infection by
regulating pathways like glycolysis (180).
5.2 Regulatory role of the gut-lung axis in
RSV infection
RSV is a single-stranded, negative-sense RNA virus and a
significant pathogen of lower respiratory tract infections,
especially in infants and immunocompromised individuals. Severe
cases can lead to bronchiolitis or pneumonia. Studies have shown
that the gut microbiota plays a critical role in modulating immune
responses to RSV infection, and dysbiosis of the gut microbiome is
closely related to the pathogenesis of RSV infection.
Studies have demonstrated that RSV infection not only
significantly alters the diversity and abundance of the gut
microbiota but also induces intestinal immune damage (169). In
mouse models of RSV infection, research has found a decrease in
beneficial bacteria and an increase in opportunistic pathogens
(181–183). The populations of key bacterial groups in the gut
microbiota, such as Lactobacillus and Bifidobacterium, undergo
significant changes, which in turn affect pulmonary immune
responses and inflammation levels. RSV infection increases the
expression of specific immune-regulatory cells and cytokines in the
gut, which may help control viral replication and the inflammatory
response in the lungs. For example, RSV infection leads to an initial
increase, followed by a decline, in the mRNA levels of ROR-gtand
Foxp3 in both the lungs and gut (169). These genes are closely related
to the differentiation and function of Tregs and Th17 cells (184,185),
which play crucial roles in maintaining immune balance and
regulating lung inflammatory responses (169,186). During
infection, the expression of pro-inflammatory cytokines and
chemokines, such as TNF-a, IL-6, and IFN-g, increases in the gut,
which may help inhibit viral replication and alleviate lung
inflammation (187). Chemokine ligand 4 (CXCL4) inhibits RSV
replication by binding to heparan sulfate, the primary RSV
receptor, thereby blocking viral attachment (188). Additionally,
RSV infection activates the host IFN-I signaling pathway, inducing
the expression of ISGs such as MX1 and OAS1, which suppress viral
replication (189). Moreover, metabolites play a significant role in
immune regulation within the gut-lung axis. Acetate has been
demonstrated to protect mice from RSV infection in an IFNAR-
dependent manner. Through IFNAR mediation, the activation of
GPCRs such as GPR43 in alveolar epithelial cells reduces virus-
induced cytotoxicity and enhances antiviral effects via the IFN-b
response (190). Thus, by modulating the gut microbiota or targeting
specific immune pathways within the gut-lung axis, it may be possible
to improve airway inflammation and lung damage caused by RSV
infection, thereby influencing the prognosis (191–193).
5.3 Regulatory role of the gut-lung axis in
SARS-CoV-2 infection
SARS-CoV-2, a positive-sense single-stranded RNA virus, is a
novel respiratory pathogen that has caused the global COVID-19
pandemic, leading to a significant public health burden worldwide.
Recent studies have revealed the critical role of the gut-lung axis in
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regulating immune responses during SARS-CoV-2 infection,
primarily through its systemic immune modulation function.
Studies indicate that the gut microbiota can influence the
expression of ACE-2, the primary receptor that mediates SARS-
CoV-2 entry into host cells. ACE-2 plays a pivotal role in regulating
inflammation and viral entry (194), and its expression is closely
linked to the composition of the gut microbiota (195,196). For
instance, Bacteroides spp. can downregulate ACE-2 expression in
the colonic epithelium, reducing viral binding efficiency (195).
Dysbiosis of the gut microbiota has been observed in COVID-19
patients, potentially increasing susceptibility to the virus by
upregulating ACE-2 expression (195–197).
The common reduction in gut microbiota diversity observed in
COVID-19 patients also includes a decrease in anti-inflammatory
bacterial genera, such as Faecalibacterium prausnitzii,andan
enrichment of opportunistic pathogens, such as Clostridium
ramosum and Enterococcus (194,195). This dysbiosis can
exacerbate lung injury through various mechanisms, including a
decrease in SCFAs production, which impairs M2 polarization of
AMs and inhibits the secretion of anti-inflammatory cytokine IL-10
(195,198); increased intestinal permeability, allowing PAMPs to
enter the circulation and trigger a systemic “cytokine storm”(194);
and dysregulation of hematopoietic function in the bone marrow,
promoting an increase in Ly6C
+
inflammatory monocytes and
exacerbating lung tissue damage (195).
Moreover, further evidence from the newly developed humanized
ACE-2 knock-in (hACE2-KI) mouse model suggests that changes in
the gut microbiota during SARS-CoV-2 infection through the lung-
gut axis may mitigate excessive inflammatory responses. An increase
in certain bacterial genera, such as Lachnospiraceae_NK4A136_group
and unclassified_f_Lachnospiraceae, may help alleviate the overactive
inflammation induced by SARS-CoV-2 infection. Conversely, an
increase in Staphylococcus species in fecal samples may indicate
bacterial migration from the gut to the lungs, potentially triggering
secondary infections in the lung-gut axis (199).
6 Potential applications of the gut-
lung axis in antiviral therapy
Numerous studies have shown that the gut-pulmonary axis can
be a potential target for anti-respiratory viral infection therapy, and
there are an increasing number of antiviral therapeutic regimens
with the primary goal of modulating the immune function of the
lungs and intestines, such as physician’s bacilli, dietary
modification, and antiviral drug interventions. Figure 3
summarizes several clinically used anti-respiratory viral infection
therapeutic regimens targeting the gut-lung axis and their main
roles, which are described in detail below.
6.1 The use of probiotics and prebiotics
Probiotics and prebiotics, as effective tools for modulating the gut
microbiota, have been extensively studied. By increasing the number of
beneficial bacteria or providing the nutrients required for their growth,
FIGURE 3
Anti-respiratory viral infection therapies targeting the gut-pulmonary axis. Probiotics can regulate intestinal immune cells, modulate cytokines,
improve intestinal microbiota balance, and regulate intestinal microbiota metabolites; fecal transplants can reprogram lung macrophages on one
hand, and restore intestinal microbiota balance on the other; pharmacological interventions (including TCM and western medicine) can regulate
antiviral immune functions in the lungs and intestines; and increased intake of dietary fibers can promote the production of SCFAs, enhance
intestinal antiviral immunity.
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they can regulate the intestinal immune environment, thereby
influencing the antiviral immune response in the lungs.
Bifidobacterium,Lactobacillus rhamnosus,andLactobacillus
plantarum have shown significant effects in modulating excessive
inflammatory responses. In vitro studies have demonstrated that
probiotics can reduce the release of pro-inflammatory cytokines,
prevent excessive activation of the NLRP3 inflammasome, mitigate
inflammation, and reduce the risk of lung fibrosis caused by
COVID-19 (200). Bifidobacterium can also enhance neutrophil
phagocytic activity and (201), together with Lactobacillus
rhamnosus, modulate T cell responses, improve gut microbiota
balance, promote the production of antibodies such as IgA and IgG,
and boost immunity against influenza viruses (202). Lactobacillus
not only exerts its effects through antimicrobial mechanisms but
also by modulating immune responses along the gut-lung axis,
restoring the microbial balance between the gut and lungs, thereby
alleviating symptoms such as ARDS induced by SARS-CoV-2 (200).
Studies have also found that the intake of probiotics significantly
prevents and mitigates respiratory viral infections. For example, the
consumption of appropriate amounts of Lactobacillus plantarum and
Lactobacillus paracasei in adults has been shown to shorten the
duration of the common cold, relieve symptoms, and enhance the
immune response to influenza vaccination (203). Prebiotics, such as
inulin and fructo-oligosaccharides, improve lung health indirectly by
promoting the production of SCFAs, strengthening the gut barrier
function, and reducing inflammatory responses.
6.2 Dietary regulation and
microbiota transplantation
Dietary regulation, through the adjustment of fiber, fat,
polyphenols, and other components in the diet, directly influences
the composition and function of the gut microbiota, thereby enhancing
antiviral immune responses. For example, increasing dietary fiber
intake not only promotes the production of SCFAs but also
strengthens antiviral immunity. In traditional Chinese medicine
(TCM), the concept of “the gut and lungs sharing a common origin”
suggests a close connection between intestinal health and respiratory
diseases, implying that gut health has a potential link to respiratory
conditions, This aligns with the modern medical concept of the “gut-
lung axis”(204). Based on this foundation, certain Chinese medicines,
such as Qinbai Qingfei Concentrated Pill and Xuanfei Baidu Formula,
have been used to alleviate pulmonary inflammation and modulate
immune responses, exhibiting bidirectional regulatory effects on the
gut-lung axis. These treatments not only reduce lung inflammation but
also restore systemic immune balance by modulating the gut
microbiota (205).
Fecal microbiota transplantation (FMT), an emerging microbial
transplantation technology, has also shown preliminary potential in
treating respiratory viral infections through regulation of the gut-
lung axis. FMT can restore gut microbiota balance, reduce lung
inflammation, and enhance antiviral immunity. Research has
demonstrated that FMT can reprogram lung macrophages,
improving their efficacy in combating respiratory viruses (154).
6.3 Drug intervention and regulation of gut
microbial metabolites
Certain antiviral drugs not only act directly on viruses but also
indirectly modulate the host immune response by affecting the gut
microbiota. Studies have shown that influenza virus infection can
lead to gut microbiota imbalance, while rifaximin, a non-absorbable
antibiotic, significantly increases the abundance of Lactobacillus
and Bifidobacterium, restoring gut microbial balance. It also reduces
tissue damage by strengthening lung and intestinal barrier
function (206).
Moreover, promoting the production of SCFAs or related
metabolites, such as indole-3-propionic acid (IPA), has shown
great potential in antiviral therapy. Research indicates that
specific probiotic mixtures can reverse gut dysbiosis caused by
RSV infection and significantly increase SCFA levels. The
elevation of SCFAs enhances the antiviral capabilities of immune
cells in the lungs via the gut-lung axis, thereby boosting antiviral
immune responses (191). In another study, mice infected with IAV
treated with probiotics exhibited a marked increase in butyrate
levels, a reduction in viral load, and an enhanced immune response
(207). This suggests that promoting SCFA production could be a
key therapeutic strategy in mitigating viral infections through the
gut-lung axis. Additionally, supplementation with metabolites such
as IPA has been shown to reduce influenza viral load and alleviate
both pulmonary and systemic inflammation. Therefore, therapies
aimed at boosting the production of SCFAs and IPA may represent
promising approaches for preventing and treating respiratory viral
infections in the future (208).
7 Conclusion and perspectives
Despite increasing research highlighting the critical role of the
gut-lung axis in various respiratory viral infections, there remain
several limitations. First, the precise molecular mechanisms and their
interactions are not yet fully understood, particularly concerning the
role of SCFAs in pulmonary immune regulation, where variability
persists (209). Second, in clinical diagnosis and treatment, it remains
challenging to accurately determine whether a disease is linked to
dysregulation of the gut-lung axis, and the effectiveness and
applicability of related interventions require further clinical
validation. Additionally, constructing experimental models that
accurately reflect human conditions poses technical challenges, and
existing models may diverge from real-world scenarios, potentially
affecting the accuracy of research findings (210,211).
Looking ahead, future research should focus on elucidating how
the gut microbiota modulates pulmonary immune responses
through specific molecular pathways. The integration of multi-
omics technologies, such as single-cell sequencing, metabolomics,
and proteomics, will help uncover the key molecules and signaling
pathways within the gut-lung axis. Identifying functional microbial
strains related to pulmonary immune regulation, along with in-
depth studies using gene-editing technologies, will advance
personalized therapeutic strategies. As research progresses,
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personalized antiviral therapies based on the gut-lung axis are likely to
achieve breakthroughs. Moreover, the roles of other inter-organ axes,
such as the gut-brain, gut-liver, and lung-brain axes, in respiratory viral
infections also warrant further exploration. By integrating these complex
networks, future research will provide a more comprehensive theoretical
foundation for the prevention and treatment of viral infections.
Author contributions
JZ: Writing –original draft. ZH: Writing –original draft. YL:
Writing –original draft. WZ: Writing –original draft. BZ: Writing –
original draft. DT: Writing –review & editing.
Funding
The author(s) declare that financial support was received for the
research and/or publication of this article.This work was supported
by grants from the Graduate Research- Innovation Project in Jiangsu
province (SJCX22_1816), the Graduate Research and Practice
Innovation Plan of Graduate Education Innovation Project in
Jiangsu Province (No. SJCX211644), Social development project of
key R & D plan of Jiangsu Provincial Department of science and
technology (BE2022773), and Hospital level management project of
Subei People’s Hospital YYGL202228, the Social Development-
Health Care Project of Yangzhou, Jiangsu Province (No.
YZ2021075), and the Jiangsu Students’Platform for Innovation
and Entrepreneurship Training Program (202411117030Z).
Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.
Generative AI statement
The author(s) declare that no Generative AI was used in the
creation of this manuscript.
Publisher’s note
All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed or
endorsed by the publisher.
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