Respiratory viral infections have historically been a leading cause of global morbidity and mortality, with outbreaks, epidemics, and pandemics affecting human populations throughout history. These infections account for approximately one-fifth of childhood deaths worldwide. Common respiratory viruses include adenovirus, enterovirus, metapneumovirus, rhinovirus, parainfluenza virus, influenza virus, coronavirus and respiratory syncytial virus (RSV) (Hodinka, 2016). Among these, coronaviruses, influenza viruses, and RSV are the most extensively studied. Coronaviruses are closely monitored due to their pandemic potential, influenza viruses are linked to pneumonia-related deaths, and RSV is the leading cause of hospitalizations due to respiratory infections in infants. Coronaviruses were first identified in chicken embryos in 1937. Interest in this family of viruses surged in the early 21st-century with the outbreaks of severe acute respiratory syndrome (SARS-CoV) in China and Middle East respiratory syndrome (MERS-CoV) in Saudi Arabia (Ludwig and Zarbock, 2020). More recently, the emergence of severe acute respiratory syndrome 2 (SARS-CoV-2) triggered the ongoing global pandemic Coronavirus disease 2019 (COVID-19), resulting in millions of infections and high mortality, especially among the elderly and individuals with comorbidities (Wiersinga et al., 2020). In addition to its health impact, the pandemic has had a profound impact on mental health and global economic stability. Meanwhile, seasonal influenza epidemics arise annually, causing between 290,000 and 645,000 death globally each year (Iuliano et al., 2018). RSV remains the leading cause of lower respiratory tract infections, such as bronchiolitis and pneumonia, especially in children under 1 year old with approximately 33 million cases and 3.4 million hospitalizations annually (Nair et al., 2010). Regardless of the specific viral pathogen, infected individuals typically present with mild to moderate symptoms, including fever, headache, fatigue, sore throat, cough, nasal congestion, and myalgia. Severe cases may progress to hypoxemia, pneumonia, hyperinflammation, sepsis, and multi-organ failure (Wiersinga et al., 2020). Notably, gastrointestinal (GI) symptoms, such as abdominal pain, nausea, diarrhea, and vomiting, are frequently observed, with prevalence depending on the virus and study population. For instance, diarrhea occurs in 4–25% of SARS-CoV-2 cases (Cheung et al., 2020; Guan et al., 2020), and in around 15% of influenza and RSV infections (Newman et al., 2023). These observations highlight a potential link between respiratory infections and alterations of the gut microbiota (GM). Furthermore, patients with inflammatory bowel disease frequently exhibit impaired lung function despite the absence of overt respiratory illness (Enaud et al., 2020; Zhou et al., 2021). Emerging evidence suggests that GM imbalance may increase susceptibility to respiratory viral infections (Enaud et al., 2020), while respiratory inflammation may in turn disrupt gut microbial composition (Xiao et al., 2023). This bidirectional communication between the respiratory tract and the gut is known as the “gut-lung axis.” In this review, we focus on the progression and severity of viral respiratory illnesses and their correlation with GM composition, with an emphasis on the immune-regulatory functions of the GM.

The gut–lung axis refers to the bidirectional interaction between the GI and respiratory systems, primarily mediated by the GM. The key mechanisms connecting the GI tract and lungs are presented in Figure 1. The GM is a highly complex and dynamic ecosystem comprising bacteria, archaea, eukaryotes, and viruses that have co-evolved with the host to establish mutually beneficial relationships. It comprises approximately 10¹³ microorganisms, a number comparable to that of human cells. Although it encompasses various microbial kingdoms, the community is dominated by bacteria, and the term “gut microbiota” usually refers to the bacterial component. The bacterial GM is predominantly composed of four phyla: Bacillota (Firmicutes), Bacteroidota (Bacteroidetes), Pseudomonadota (Proteobacteria), and Actinomycetota (Actinobacteria). Its diversity is shaped by intrinsic and extrinsic factors including age, environment, diet, lifestyle, and antibiotic use (Jandhyala et al., 2015). The GM plays an essential role in mucosal immune development and regulation, supporting both innate and adaptive immune responses. Approximately 70% of immune cells are found in the mucosa-associated lymphoid tissue (MALT), which is a critical network that connects mucosal immunity throughout the gut, lungs, and other surfaces (Enaud et al., 2020). The GM directly modulates immune responses, namely antiviral responses, by influencing neutrophil activity, Toll-like receptor (TLR) signaling, and the production of proinflammatory or regulatory cytokines. It also supports the differentiation of CD4 + T and CD8 + T cells into T helper (Th) 1, Th2, Th17, and regulatory T (Treg), as well as B cells via microbial-associated molecular patterns (MAMPs) such as peptidoglycan, lipopolysaccharides, and flagellin (Enaud et al., 2020; Baradaran et al., 2021). Moreover, GM-derived fermentation products, particularly short-chain fatty acids (SCFAs) such as butyrate, acetate, and propionate, which together represent 90–95% of total SCFAs, play a key role in shaping immune responses by binding to G-protein-coupled receptors on dendritic cells and promoting the release of cytokines such as TGF-β and retinoic acid. This process induces IgA class switching and the differentiation of B cells into IgA-secreting plasma cells. SCFAs also downregulate inflammatory cytokines such as TNF-α and strengthen intestinal barrier integrity (Baradaran et al., 2021; Li et al., 2022; Rastogi et al., 2022; Alswat, 2024). Finally, the GM plays a key role in maintaining intestinal and systemic immune homeostasis by limiting microbial translocation and producing antimicrobial peptides (Alswat, 2024).

Once believed to be sterile, it is now recognized that the lungs host a microbiota, albeit with a much lower density than the gut. This community is thought to be transient and continuously replenished via inhalation, with subsequent clearance through mucociliary mechanisms. It predominantly comprises the same phyla as the GM, mainly Bacteroidota and Bacillota, with a density estimated at 10–100 bacteria per 1,000 human cells (Enaud et al., 2020; Rastogi et al., 2022; Marrella et al., 2024). Like the GM, the lung microbiota evolves with age, gaining diversity and functional capacity, and interacts closely with the host immune system. It thus contributes to immune surveillance, epithelial barrier maintenance, and protection against respiratory pathogens through crosstalk with resident immune cells (Marrella et al., 2024).

The gut and the lungs are connected by both direct and indirect pathways. Direct routes include the swallowing of infected sputum or the aspiration of gastroesophageal contents. Indirect communication is mediated by immune signaling and systemic dissemination of microbial metabolites, cytokines, and bacterial fragments (Enaud et al., 2020; Zhou et al., 2021; Baradaran et al., 2021). Components of the GM, such as SCFAs, have a central role. They can enter the bloodstream and modulate distant immune compartments, including the lungs. SCFAs exert anti-inflammatory effects by modulating immune cell migration and suppressing NF-κB activation pathways. SCFAs also promote hematopoiesis in the bone marrow and influence the immune microenvironment in the lungs by enhancing the generation of macrophage and dendritic cell precursors, followed by the seeding of the lungs with dendritic cells that exhibit high phagocytic activities (Trompette et al., 2014). SCFAs also dampen lung inflammation by reducing Th2 cell responses and stimulating Treg cell activity (Trompette et al., 2014). Ultimately, the GM plays a critical role in balancing immune tolerance toward commensal microorganisms while maintaining an effective immune response against invading pathogens. Studies have shown that antiviral responses of CD4 + and CD8 + T cells, as well as B cells are modulated by the GM. An imbalanced GM can disrupt cytokines release and impair dendritic cells migration in influenza-infected mice (Ahmadi Badi et al., 2021). Conversely, respiratory viral infections such as influenza have been shown to alter the GM by reducing microbial diversity and affecting SCFAs production, which may contribute to secondary pathogen overgrowth and inflammation (Enaud et al., 2020; Kalam and Balasubramaniam, 2024). Immune cells, cytokines, and microbial metabolites can thus travel via the blood and lymphatic systems from gut-associated lymphoid tissue (GALT) to bronchial-associated lymphoid tissue (BALT), reinforcing host defenses against respiratory infections (Enaud et al., 2020; Ahmadi Badi et al., 2021). Using a mouse model, Wang et al. demonstrated that lung-derived T cells infected by a respiratory virus can migrate to the small intestine and alter the GM through interferon-γ signaling. These effects may predispose to secondary enteric infections (Wang et al., 2014). Thus, gut dysbiosis may worsen respiratory illness severity, while lung infections can impair gut health, highlighting a bidirectional and dynamic gut–lung axis. Although the underlying mechanisms are not yet fully elucidated, this axis likely plays a central role in shaping disease presentation and outcome. This has prompted growing interest in understanding GM alterations during respiratory viral infections and their potential as therapeutic targets (Gu et al., 2020; Zuo et al., 2020; Tao et al., 2020; Wu et al., 2021; Khan et al., 2021; Li et al., 2021; Yeoh et al., 2021; Mazzarelli et al., 2021; Gaibani et al., 2021; Newsome et al., 2021; Cao et al., 2021; Hazan et al., 2022; Xu et al., 2022; Nagata et al., 2023; de Nies et al., 2023; Xu et al., 2021; Romani et al., 2022; Nashed et al., 2022; Suskun et al., 2022; Gutiérrez-Díaz et al., 2023; Qin et al., 2015; Gierse et al., 2021; Chen et al., 2023; Harding et al., 2020; Groves et al., 2018; Groves et al., 2020).

Intestinal dysbiosis can exacerbate respiratory viral infections by influencing viral entry mechanisms, modulating immune responses, and worsening disease severity.

Vaccination is one of the most effective public health tools for preventing infectious diseases, saving an estimated 2–3 million lives each year (Lynn et al., 2022; Gonçalves et al., 2022). However, the efficacy of vaccine can vary significantly from person to person, with factors such as age, geography, and GM composition influencing the immune response. The relationship between the GM and vaccine response is bidirectional: vaccines can alter GM composition, while the GM, in turn, affects vaccine efficacy and side effects. For example, individuals in low- to middle-income countries, as well as infants and the elderly, often exhibit weaker responses to vaccines than other groups (Lynn et al., 2022). Several studies have demonstrated associations between GM composition and vaccine immunogenicity in the context of SARS-CoV-2. In immunocompetent individuals, high abundances of Bifidobacterium adolescentis and Roseburia faecis have been linked to stronger neutralizing antibody responses. Similarly, in immunocompromised individuals, Bilophila, Alistipes, and Butyricicoccus were positively correlated with antibody titers. In contrast, elevated levels of Streptococcus and Parabacteroides were associated with weaker serological responses (Ng et al., 2022; Alexander et al., 2023). Furthermore, individuals with higher levels of SCFAs, which play a key role in B cell metabolism and antibody production, tend to exhibit enhanced immune responses to vaccination. SCFAs fuel oxidative phosphorylation, glycolysis, and fatty acid synthesis in immune cells, thereby supporting efficient humoral immunity (Lynn et al., 2022; Alexander et al., 2023). GM composition also appears to influence the adverse effects experienced following vaccination. Individuals who reported fewer side effects after vaccination showed an increase in Prevotella copri and two Megamonas species, which are believed to have anti-inflammatory properties (Ng et al., 2022). Conversely, vaccines may also induce transient disruptions in gut microbial homeostasis. For example, SARS-CoV-2 vaccination has been linked to a temporary decrease in alpha diversity, and shifts in microbial composition, such as a decrease in Bacteroidota and Pseudomonadota, and an increase in Bacillota (Jiao et al., 2022; Tang et al., 2022). These changes include an increase in beneficial taxa such as Faecalibacterium, Bifidobacterium, Lachnospira, Roseburia, Anaerostipes hadrus, Ruminococcus torques, and Oscillibacter, alongside a decrease in Bacteroides and Blautia (Jiao et al., 2022; Tang et al., 2022). These findings highlight the potential for targeted modulation of the GM to enhance vaccine efficacy. Strategies to optimize vaccine-induced protection, particularly in vulnerable populations such as the elderly, infants, and immunocompromised patients, could include prebiotics, probiotics, or dietary interventions aimed at supporting beneficial microbial communities.

Due to strong association between intestinal dysbiosis and disease progression in respiratory viral infections, various strategies have been suggested to restore microbial balance and improve clinical outcomes. Among these, the use of prebiotics and probiotics, for both prophylactic and therapeutic purposes, has gained considerable attention. Probiotics exert their effects through both direct and indirect mechanisms. Directly, they can trap viruses, inhibit replication, and produce antiviral compounds such as bacteriocins. Indirectly, they modulate the host immune response by enhancing the production of interleukins, IgA, and by improving the function of CD4 + and CD8 + T cells and natural killer cells. Certain strains have also been shown to promote the growth of beneficial taxa such as Faecalibacterium prausnitzii, Akkermansia, and Lactobacillus. Importantly, these effects are strain-specific and are not limited to live bacteria. Even non-viable probiotics or bacterial components such as polysaccharides can exert immunomodulatory properties (Mirzaei et al., 2021; Shinde et al., 2020). Preclinical and clinical studies suggest that probiotics may help prevent upper respiratory tract infections, reduce symptom duration, and modulate inflammatory responses (Mirzaei et al., 2021), though results remain inconsistent across studies (Lehtoranta et al., 2014). A recent meta-analysis of 18 trials involving patients with SARS-CoV-2 infection showed that probiotics, primarily Bifidobacterium and Lactobacillus strains, were associated with reduced mortality, shorter hospital stays, faster recovery, and lower rates of clinical deterioration, whether administered alone or in combination with standard therapy (Sohail et al., 2023). However, the heterogeneity of probiotic formulations, dosing regimens, and study populations, along with variations in study quality, limits the generalizability of these findings. Large-scale randomized controlled trials are needed to establish consistent efficacy and optimal protocols. Moreover, the current evidence base does not support the use of probiotics in the prevention of SARS-CoV-2 infection, highlighting the need to define their optimal indications (Sohail et al., 2023). Certain probiotic-derived compounds, such as those from Lactobacillus plantarum, have demonstrated in silico the ability to prevent SARS-CoV-2 from entering into host cells (Batista et al., 2023; Anwar et al., 2020). Probiotics have also shown promise as vaccine adjuvants or delivery vectors, enhancing seroconversion and strengthening immune responses to respiratory virus vaccines (Gonçalves et al., 2022). However, to realize their full therapeutic potential, it is essential to standardize the choice of bacterial strains, dosage, and administration protocols across studies. In summary, prebiotics and probiotics are promising adjuvant strategies for preventing and treating respiratory viral illnesses. While still in the experimental phase, their use may complement traditional therapies and support host immune defenses, especially in populations with known dysbiosis or impaired vaccine responses.

Respiratory viral infections such those caused by SARS-CoV-2, influenza, and RSV have systemic effects that extend well beyond the lungs. One of the most significant effects is the disruption of GM composition, which may persist even after recovery. The gut-lung axis plays a central role in this bidirectional relationship: pulmonary infections can disturb the gut microbial balance, while gut dysbiosis can, in turn, exacerbate the disease (Enaud et al., 2020; Zhou et al., 2021). These alterations are primarily characterized by a decrease in beneficial, including SCFA-producing bacteria, and an increase in opportunistic pathogens, which contribute to intestinal permeability and systemic inflammation (Zuo et al., 2020; Gaibani et al., 2021; Nagata et al., 2023; Qin et al., 2015; Harding et al., 2020). Although there is no direct evidence linking gut dysbiosis to GI symptoms during respiratory infections, GM composition appears to be a key factor in modulating disease progression and severity. This can potentially increase individuals’ susceptibility to coinfections and the onset of NCDs, and may contribute to the development of neuropsychiatric symptoms. GM imbalances following these infections can trigger a proinflammatory state, leading to increased gut permeability and subsequent GI manifestations reported in patients (Hussain et al., 2021). The consequences of intestinal dysbiosis extend beyond GI symptoms, to influence immune responses, viral entry, and extrapulmonary complications, thereby worsening disease severity. Given the significant roles of GM, therapeutic strategies aiming at restoring microbial balance could provide a new way of preventing and managing these infections. Although probiotics and prebiotics have shown promise in enhancing antiviral immunity, standardized and large-scale confirmatory studies are needed to ensure consistent outcomes (Mirzaei et al., 2021; Shinde et al., 2020; Sohail et al., 2023). While these strategies are still experimental, they demonstrate the potential of microbiome-targeted interventions in respiratory viral infections. Furthermore, microbiota composition has been linked to immune responses to vaccines, with for instance Bifidobacterium and Roseburia enhancing antibody production (Ng et al., 2022; Alexander et al., 2023). Therefore, microbiota-targeted interventions could optimize vaccine responses. Overall, the GM emerges as a key player in the pathogenesis of viral infections such as COVID-19, influenza, and RSV, influencing not only disease severity, but also recovery and vaccine responses. Future research should focus on longitudinal assessments of microbiota alterations and host-microbiota interactions, as well as the development of targeted microbiome-based therapies to mitigate the impact of viral respiratory infections. Gaining deeper insight into these complex relationships may open new approaches in personalized medicine, optimizing immune resilience, and improving clinical outcomes.