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.

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).

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.

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 cells such as neutrophils, 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).

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 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-α and IFN-β) 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.

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 specific lysine residues on RIG-I. This form of 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 IKKϵ (111). These kinases, in turn, phosphorylate transcription factors such as IRF3 (interferon regulatory factor 3) and NF-κB, 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-α and IFN-β) 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.

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-α secretion 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 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-α (TNF-α)-induced MCP-1 expression through a GPR41/43-dependent pathway, inhibiting the phosphorylation of p38 and JNK, thereby indirectly suppressing the NF-κB 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 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-1β promoter, thereby inhibiting NF-κB-dependent gene expression. Additionally, it increases the expression of I-BABP in the intestine while reducing mRNA levels of interleukin-1β(IL-1β), interleukin-2 (IL-2), interleukin-6 (IL-6), TNF-α, and IFN-γ, 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).

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-κB, 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 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).

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 IFNα and IFNβ (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-α (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-α, IL-1β, 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’s cytokine profile, 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-α, 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 RegIIIγ), 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 RegIIIγ in 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).