Research progress on comorbidity between gastrointestinal and pulmonary diseases from the perspective of the gut-lung axis

Abstract

The coexistence of gastrointestinal and respiratory diseases is a widespread phenomenon, featuring complex bidirectional interactions that seriously threaten human health and increase the difficulty of clinical management. The gut-lung axis is an emerging field in the study of organ-organ interactions in recent years, revealing the complex bidirectional regulatory network between gastrointestinal and respiratory diseases. The potential mechanisms of comorbidities of gastrointestinal and pulmonary diseases involve multiple interactions. This article systematically reviewed the significant role of the gut-lung axis in comorbidities of gastrointestinal and pulmonary diseases and discussed key dimensions such as the bidirectional regulatory mechanism of the gut-lung axis, the pathophysiological basis of comorbidities of gastrointestinal and pulmonary diseases, the clinical types of comorbidities, and intervention strategies. This has significant clinical translational value for optimizing the stratified management of complications of gastrointestinal and respiratory diseases and reducing the risk of acute exacerbation.

Key Words: Microbiota; Comorbidity mechanism; Lung diseases; Gastrointestinal diseases; Gut-lung axis

Core Tip: The gut-lung axis represents a bidirectional communication network that links the gastrointestinal and respiratory systems through microbial, immune, and metabolic pathways. This review synthesized recent advances in understanding how gut dysbiosis, microbial translocation, immune dysregulation, and epigenetic modifications contribute to gastrointestinal-pulmonary comorbidities. We highlighted key clinical phenotypes and explored emerging therapeutic strategies, including microbiota-targeted interventions, metabolite supplementation, and immune modulation. Future efforts should emphasize multi-omics integration, organoid-based models, and artificial intelligence-driven predictive analytics to advance precision medicine anchored in the gut-lung axis.

INTRODUCTION

Most research on the impact of the gut microbiome on disease has focused on intestinal disorders[1]. However, over the past decade numerous significant studies have demonstrated associations between the gut microbiota and diseases beyond the gut. For instance, the influence of the gut microbiota extends to distant sites such as the heart, lungs, brain, pancreas, and liver[2-6]. Specific microbes present in different microenvironments have been implicated in a range of disorders including autoimmune diseases, metabolic disorders, neurological diseases, and various cancers[7-10]. Moreover, diseases in these distant organs can in turn influence the composition of gut microbes, underscoring the bidirectional relationship between the gut and distant organs.

In the context of the lungs, this phenomenon is termed the gut-lung axis. The gut-lung axis represents an emerging research frontier, referring to the interactive system involving the gut microbiota, intestinal barrier function, and pulmonary immune responses[11]. This connection between the lungs and gut is mediated not only by direct neural and immune pathways but also by factors such as gut microbiota and metabolites achieved through the migration of gut microbes[12]. The bacterial composition and metabolites in the gut and lungs can modulate systemic and local immunity with specific microbial communities influencing the development of respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), and respiratory infections[13]. The concept of the gut-lung axis was first proposed by Pugin et al[14] in 1991 in which they systematically revealed that gut microbiota may cause pulmonary infections through bacterial ectopic migration. Currently, the gut-lung axis has become a hotspot in cross-organ microbiome research. Its “bidirectional communication” has been progressively demonstrated to play a crucial role in inflammation, infection, and tumorigenesis and has been incorporated into multiple international research initiatives[15,16]. This indicates that research into the comorbidity of gastrointestinal and respiratory diseases caused by gut-lung axis dysregulation has advanced from describing epidemiological patterns to investigating underlying mechanisms, attracting increasing attention from scholars.

The co-occurrence of gastrointestinal and pulmonary diseases is widespread[17-19]. For instance, the prevalence of inflammatory bowel disease (IBD) among patients with COPD is significantly higher than in the general population[20]. Approximately 85% of patients with COPD experience at least one gastrointestinal symptom[21], and intestinal permeability is elevated in patients with COPD compared with individuals without COPD[22]. COPD promotes IBD by causing damage to the intestinal mucosal structure[23]. Patients with IBD face a significantly increased risk of developing respiratory-related diseases after IBD diagnosis[13,24] with both lines of evidence indicating a “bidirectional exacerbation” relationship between pulmonary disease and intestinal symptoms.

Dysregulation of the gut-lung axis driven by gut microbiota imbalance is associated with poorer clinical outcomes in respiratory diseases. Conversely, acute exacerbations of pulmonary disease can also worsen intestinal symptoms[25]. Compared with monopathology, comorbid conditions typically yield poorer health outcomes[26,27]. For instance, among patients with COPD those with IBD exhibit higher mortality risk than those without IBD[28]. Furthermore, among patients with asthma those with concomitant gastroesophageal reflux disease (GORD) exhibit significantly increased risks of anxiety and depression compared with those without GORD[29,30]. Therefore, gaining a deeper understanding of the mechanisms underlying gastrointestinal-pulmonary disease comorbidity is critically important.

This review discussed the central role of the gut-lung axis in gastrointestinal and pulmonary disease comorbidity. We examined the bidirectional regulatory mechanisms of the gut-lung axis, the pathophysiological basis of gastrointestinal-pulmonary comorbidity, immunomodulation, microbial translocation and dysbiosis, clinical subtypes of comorbidities, and intervention strategies. This exploration further delineated the regulatory network and clinical translation pathways of the gut-lung axis as a pivotal hub in cross-organ pathophysiological connections, providing a foundation for early identification, precise classification, and personalized treatment of gastrointestinal-pulmonary comorbidities.

BIOLOGICAL BASIS AND BIDIRECTIONAL REGULATORY MECHANISMS OF THE GUT-LUNG AXIS

Anatomical and physiological connections of the gut-lung axis

Traditionally, the gut has been primarily regarded as a digestive organ while the lungs have been considered responsible for gas exchange and respiratory functions[31]. However, accumulating basic research evidence and epidemiological data in recent years have highlighted critical interactions between the gut microbiota and the lungs[32]. These interactions involve not only host-microbe relationships but also crosstalk between different microbial communities, influencing local and systemic immune responses as well as airway homeostasis. The gut-lung axis exerts its effects through both local regulatory mechanisms and long-distance effects, influencing the progression of respiratory diseases by modulating immune and inflammatory responses. This can compromise intestinal barrier integrity, which is associated with bacterial translocation, persistent inflammation, and pulmonary fibrosis[33-36].

Although the intestinal mucosa and pulmonary mucosa reside in distant organs, they exhibit high structural homology and close functional coordination in terms of immune mechanisms and microecological regulation. From an embryonic developmental perspective, the lungs and trachea develop from the foregut of the intestine while respiratory epithelial cells and membrane structures differentiate from the endoderm of the gastrula. The lungs share developmental homology with the colon and ileum in embryonic tissue formation[37]. Both the lungs and intestines are organs directly exposed to the external environment. They share a typical mucosal structure composed of epithelium and lamina propria, belonging to the common mucosal immune system. The secretion of secretory immunoglobulin A by both pulmonary and intestinal mucosae forms a crucial molecular biological basis for the “lung-gut axis”[38]. The mucosal immune network serves as a bridge connecting the lungs and intestines. The lungs and intestines can function as induction sites and effector sites, respectively, establishing a shared mucosal defense mechanism through mucosal lymphocyte homing[39].

The gastrointestinal vagus nerve serves as a core neural pathway connecting the intestines to the lungs. Through neural, endocrine, and immune mechanisms, it achieves remote regulation of pulmonary function[40]. Krzyzaniak et al[41] found that vagus nerve electrical stimulation significantly reduced post-burn pulmonary permeability and interleukin (IL)-6/IL-17 levels. Liu et al[42] demonstrated that short-chain fatty acids (SCFAs), metabolites of the lung microbiota, upregulate brainstem serotonin via the vagus nerve, indirectly inhibiting pulmonary calcitonin gene-related peptide release and airway inflammation. Activation of the gastrointestinal vagus nerve is often accompanied by reduced pulmonary neutrophil infiltration, thereby suppressing excessive inflammation[43]. Consequently, modulating vagal tone has been proposed as a potential therapeutic strategy for respiratory inflammatory diseases. However, the reliability and safety of this method needs to be carefully evaluated.

Increasing evidence indicates that SCFAs, derived from the fermentation of indigestible foods by gut microbiota, represent the most prominent immunomodulatory metabolites in the gastrointestinal tract and the most thoroughly studied bacterial metabolites exerting their effects along the gut-lung axis[44]. The effects of microbiota-derived SCFAs extend beyond the intestinal lumen. SCFAs diffuse from the gut into the bloodstream, reaching the bone marrow where they promote hematopoiesis, thereby alleviating airway inflammation and maintaining pulmonary homeostasis[32]. Furthermore, since SCFAs produced in the gut can enter the circulation, these metabolites may exert direct effects on the lungs and may also be indirectly mediated by the pulmonary microbiota[45]. Compared with healthy individuals, patients with COPD exhibit lower fecal SCFA concentrations with COPD severity negatively correlated to SCFA levels[46]. This suggests that COPD may represent a downstream consequence of disrupted gut microbiota. Increasing SCFA concentrations and the abundance of beneficial gut microbiota through dietary fiber intake may represent one potential solution for mitigating COPD and its associated complications.

In summary, the gut-lung axis is not merely an anatomical notion, it is a trans-organ homeostatic system built from ontogenically related mucosal architectures, a common mucosal immune network, bidirectional immune-cell trafficking, neuroendocrine-immune multiroute signaling, and long-range control by microbial metabolites.

Core pathways of bidirectional regulation

Immune homeostasis depends on the microbiome, providing cues for the proper maturation and activation of the immune system, including microbial components and metabolites[47]. In humans environmental factors such as diet, antibiotic treatment, and stress can shift the gut microbiota toward reduced numbers of beneficial bacteria, accompanied by increased abundance of non-beneficial species[48]. The epithelial surfaces of the gastrointestinal and respiratory tracts are exposed to diverse microorganisms. Ingested microbes can enter both sites, and microbiota from the gastrointestinal tract can reach the lungs via respiration[13].

Current research is evaluating the impact of the gut microbiota on the lungs and the use of probiotics and prebiotics for preventing and treating acute and chronic pulmonary diseases. For example, a positive correlation exists between the presence of “beneficial” bacteria in the gut (such as Bifidobacterium longum) and lower asthma incidence[49]. Additionally, segmented filamentous bacteria in the gut stimulate pulmonary helper T cell 17 (Th17) cell responses and reduce Streptococcus pneumoniae infections and associated mortality[50].

Disruption of gut microbial composition and function, termed dysbiosis, compromises tissue and immune homeostasis and is associated with various inflammatory diseases both within and outside the gastrointestinal tract[51]. For instance, disruption of gut-lung crosstalk is linked to increased susceptibility to airway diseases and infections, including allergies[52]. The significance of the gut-lung axis is evident in patients with chronic gastrointestinal diseases and pulmonary disorders, such as irritable bowel syndrome and IBD, which exhibit a higher prevalence of pulmonary diseases[52-54]. Inflammatory mediators such as IL-17 and interferon-γ released from pulmonary infections or injuries can also reach the gut via the bloodstream or the gut-lung axis, compromising intestinal barrier integrity and disrupting microbiota homeostasis, thereby triggering or amplifying gut immune responses[55]. Compared with healthy individuals, dysbiosis of the gut microbiota is more commonly observed in patients with COPD[56]. Close monitoring of gut microbiota status holds dual value for diagnosing both gastrointestinal and pulmonary diseases.

Beyond bacterial components emerging evidence highlights the critical yet underappreciated role of the gut mycobiome in inter-kingdom microbial interactions and gut-lung axis signaling. Fungal communities, though less abundant than bacteria, produce unique metabolites and immunomodulatory signals that shape both intestinal and pulmonary immunity. The gut-lung fungal axis exerts its effects through multiple mechanisms. For instance, excessive proliferation of Candida albicans in the gut promotes the release of mannan-induced inflammatory mediators, exacerbating allergic airway inflammation[57].

PATHOLOGICAL MECHANISMS OF GASTROINTESTINAL AND PULMONARY DISEASE COMORBIDITY

Microbiota translocation and dysbiosis

The gut microbiota constitutes the largest microbial ecosystem in the human body, and its stability is crucial for maintaining intestinal barrier function and immune homeostasis. Under pathological conditions factors such as smoking, particulate matter exposure, or intestinal inflammation can disrupt the intestinal epithelial barrier, leading to microbial translocation and inducing or exacerbating pulmonary inflammatory responses[58-60]. For instance, exposure to cigarette smoke significantly reduces gut microbiota diversity, diminishes beneficial bacteria, and increases the proportion of Gram-negative bacteria. This, in turn, elevates serum lipopolysaccharide levels, activates alveolar macrophages, and induces the release of inflammatory mediators such as tumor necrosis factor-α (TNF-α) and IL-6, contributing to the development of diseases like COPD and acute respiratory distress syndrome (ARDS). PM2.5 exposure can also alter gut microbiota composition, reduce SCFA levels, and weaken their role in maintaining intestinal barrier function and anti-inflammatory effects, further promoting dysbiosis and systemic inflammation[61].

Impaired intestinal barrier function can lead to the translocation of gut microbiota and their metabolites to the lungs, inducing or exacerbating pulmonary diseases[61,62]. For instance, in models of acute lung injury or ARDS, gut-derived bacteria can accumulate in the lungs, altering the pulmonary microbiome structure and further amplifying inflammatory responses[62]. Gut microbiota dysbiosis and barrier disruption mark the onset of gut-lung axis dysfunction. Microbiota translocation not only directly activates pulmonary immune responses but also remotely modulates inflammatory states in the lungs via metabolic byproducts, representing a key mechanism underlying gastrointestinal-pulmonary disease comorbidity.

Association between gut microbiota and pulmonary diseases

Based on existing research, dysbiosis of the gut microbiome is significantly associated with the onset and progression of certain pulmonary diseases as summarized in Table 1[62-65].

Table 1 Association between the gut microbiome and several common lung diseases.

Diseases	Details	Ref.
COPD	Fecal microbiological profiles were analyzed using 16S rRNA gene sequencing. The results showed a distinct difference in the bacterial community composition between the AECOPD, COPD, and healthy control groups. The COPD and AECOPD groups had higher levels of Firmicutes but lower levels of Bacteroidetes compared with the healthy control group at the phylum level. At the genus level, there was an increased abundance of Lachnoclostridium, Alistipes, Streptococcus, and Prevotella in patients with COPD and AECOPD. Increasing levels of Lachnoclostridium and Prevotella may indicate an acute exacerbation of COPD	[62]
Asthma	Gut microbial species and metabolites primarily SCFAs may either worsen or reduce airway inflammation by regulating the balance of Th1/Th2 and other immune mediators	[63]
ARDS	The major characteristic of the intestinal flora in patients with ARDS/CAP was higher abundances of Gram-negative bacteria than normal controls. The gut microbiota derived from patients with ARDS/CAP promoted neuroinflammation and behavioral dysfunction in mice. Mice who underwent fecal transplant from patients with ARDS/CAP had increased systemic LPS, systemic inflammation, and increased colonic barrier permeability	[64]
VAP	The fungal genus Alternaria spp. is associated with the occurrence of VAP. The composition of the gut microbiota differs between patients who are critically ill patients and subsequently develop VAP and those who do not	[65]

AECOPD: Acute exacerbation of chronic obstructive pulmonary disease; CAP: Community-acquired pneumonia; COPD: Chronic obstructive pulmonary disease; SCFAs: Short-chain fatty acids; Th1: Helper T cell 1; ARDS: Acute respiratory distress syndrome; LPS: Lipopolysaccharide; VAP: Ventilator-associated pneumonia.

Imbalance in immune regulation

The gut microbiota plays a central role in the development and regulation of the immune system, particularly in maintaining the balance of T cell subsets such as regulatory T cells (Treg) and Th17 cells. Dysbiosis can disrupt this equilibrium, inducing immune dysregulation and subsequently affecting the pulmonary immune microenvironment[66-68]. Studies indicate that gut microbiota disruption suppresses Treg cell differentiation while promoting Th17 cell expansion, leading to elevated proinflammatory factors like IL-17 and IL-6. These factors can migrate via the bloodstream to the lungs, activate local immune cells, and induce neutrophil infiltration and lung tissue damage[69].

In bronchopulmonary dysplasia models, perinatal antibiotic exposure disrupts the gut microbiota, downregulates immune-related gene expression, and induces marked inflammatory and fibrotic changes in lung tissue[70]. Additionally, gut microbiota metabolites such as SCFAs and Tryptophan (Trp) metabolites can regulate immune processes including alveolar macrophage polarization and T cell differentiation by activating signaling pathways like AhR and G Protein-Coupled Receptors, thereby maintaining pulmonary immune homeostasis[71-73]. The gut microbiota participates in sustaining pulmonary immune homeostasis by modulating Treg/Th17 balance, immune cell differentiation, and cytokine networks. Microbiota dysbiosis-induced immune imbalance represents one of the core mechanisms mediating comorbidity through the gut-lung axis.

Inflammatory and metabolic dysregulation

Metabolites produced by gut microbiota not only act as immunomodulators but also serve as key regulators of inflammatory signaling pathways. Dysbiosis can lead to sustained activation of inflammatory signaling cascades, triggering systemic metabolic dysregulation such as insulin resistance, hyperglycemia, and lipid metabolism abnormalities. These metabolic abnormalities, in turn, exacerbate pulmonary inflammation and injury[74]. For instance, SCFAs exert potent anti-inflammatory effects by activating G Protein-Coupled Receptors signaling and inhibiting histone deacetylase activity[75,76]. Dysbiosis reduces SCFA levels, weakening their inhibitory effect on inflammatory pathways like nuclear factor kappa-B and promoting sustained release of inflammatory mediators such as IL-1β and TNF-α, thereby forming an inflammatory cascade[77-79]. In disease models like bronchopulmonary dysplasia and COPD, impaired glucose metabolism is closely associated with pulmonary vascular remodeling and alveolar structural destruction, suggesting a crucial role for metabolic dysregulation in pulmonary structural remodeling[80,81].

Butyrate derived from the gut microbiota promotes the production of proresolving mediators by alveolar macrophages, accelerating inflammation resolution. Oral sodium butyrate administration alleviates acute exacerbations in COPD mice[82,83]. The gut microbiota participates in the onset and progression of pulmonary inflammation by regulating inflammatory signaling pathways and metabolic homeostasis. The inflammatory cascade and metabolic dysregulation induced by dysbiosis form a crucial bridge in the gut-lung axis-mediated comorbidity. Therefore, supplementing the gut microbiota or its metabolites may represent an effective therapeutic strategy for treating inflammation-related pulmonary diseases.

CLINICAL PATTERNS AND DIAGNOSTIC CHALLENGES IN GASTROINTESTINAL AND PULMONARY COMORBIDITIES

Clinical patterns of gastrointestinal and pulmonary comorbidities

Based on existing research, the primary clinical patterns of gastrointestinal and pulmonary disease comorbidity from the gut-lung axis perspective have been preliminarily categorized as follows: Asthma and GORD[84-87]; COPD and IBD[88]; acute pancreatitis and ARDS[89]; and chronic bacterial pneumonia and antibiotic-associated diarrhea[90].

A nationwide cohort study from Denmark indicated an increased risk of obstructive pulmonary disease in IBD[24]. Smoking and genetics are common risk factors for both conditions. Dysbiosis of the gut microbiota can cause inflammatory cells circulating in the body to migrate to the lungs. Multiple studies indicate that the incidence of ARDS among hospitalized patients with severe acute pancreatitis ranges from 18.6% to 46.6%[91,92]. Severe acute pancreatitis leads to the release of trypsin and phospholipase A2 into the bloodstream, which directly digest pulmonary surfactant and induce alveolar collapse[93]. Massive release of TNF-α, IL-6, IL-8, and platelet-activating factor increases pulmonary capillary permeability, leading to neutrophil accumulation in the lungs[94]. Disruption of the intestinal barrier causes bacterial translocation or endotoxin migration, elevating circulating lipopolysaccharides and reactivating alveolar macrophages, forming a “second hit”[95]. Tissue factor release forms microthrombi, exacerbating ventilation-perfusion mismatch[96]. Compared with patients with acute pancreatitis alone, those concurrently suffering from acute pancreatitis and ARDS exhibit higher mechanical ventilation requirements, longer intensive care unit stays, increased mortality rates, and impaired long-term pulmonary function[91]. Patients with bacterial pneumonia receiving antibiotic therapy exhibit a high incidence of antibiotic-associated diarrhea, and combined drug regimens can elevate this risk[97,98]. Antibiotics disrupt the intestinal anaerobic microbiota, impairing bile acid deconjugation and reducing SCFAs, leading to osmotic or secretory diarrhea.

Treatment challenges in gastrointestinal and pulmonary disease comorbidities

Despite the identification of numerous gastrointestinal-pulmonary disease comorbidities, significant diagnostic and therapeutic challenges persist in this interdisciplinary field. Although the concept of the gut-lung axis has been proposed, its specific immune pathways and the mechanisms of action involving microbial metabolites remain incompletely elucidated, making it difficult to precisely identify therapeutic targets.

Gastrointestinal bleeding, diarrhea, cough, and dyspnea frequently co-occur in patients in the intensive care unit or who are elderly, but symptom overlap complicates disease prioritization. It is more challenging when therapeutic anti-TNF-α biologics for IBD reactivate latent tuberculosis, exacerbating pulmonary infection. Conversely, long-term inhaled corticosteroids in patients with COPD elevate the risk of Clostridium difficile infection[99]. Furthermore, physicians across different departments often prioritize different disease aspects. For instance, pulmonologists rarely assess intestinal symptoms[100,101] while gastroenterologists may overlook chronic cough or airway obstruction[102,103]. Establishing large-scale multi-omics cohorts, developing cross-organ risk prediction algorithms, and conducting adaptive platform trials targeting gut-lung synchronous endpoint are essential to overcome the current fragmented treatment paradigm focused solely on single-disease management.

INTERVENTION STRATEGIES FOR COMORBIDITIES AND CLINICAL TRANSLATION

Interventions targeting the microbiota

Regulating the gut microbiota to indirectly improve pulmonary disease phenotypes represents one of the most promising translational directions. In a COPD mouse model, fecal microbiota transplantation significantly reduced alveolar destruction and inflammatory cell infiltration, suggesting its potential application in advanced COPD[99]. Influenza infection causes damage to the lung and intestinal tissues, disrupts the intestinal microbiota and metabolites, and affects the Th17/Treg balance. Antibiotic treatment exacerbates these symptoms. Supplementation of tryptophan and Lactobacillus improves lung and intestinal health[104]. Moreover, alterations in pulmonary and intestinal Trp metabolites correlate strongly with pulmonary microbiota dysbiosis, demonstrating optimal discriminatory power for diagnosing and grading neonatal ARDS[105]. These findings reveal that Trp and its intestinal derivatives can remotely regulate the pulmonary immune microenvironment via the gut-lung axis, influencing inflammation severity and tissue repair. However, clinical translation remains constrained by critical challenges including donor standardization and long-term safety evaluation.

Metabolite supplementation

Oral sustained-release butyrate capsules improve Forced Expiratory Volume in 1 second and 6-minute walk distance in patients with COPD; related phase II trials are ongoing[44]. Metabolite supplementation is emerging as a promising therapeutic approach for gastrointestinal and pulmonary comorbidities. It is important to note that the clinical translation of such effects is likely influenced by a multitude of host and environmental factors beyond a single metabolite.

Nutrition and lifestyle intervention

A high-fiber diet has demonstrated potential in improving symptoms among patients with coronavirus disease 2019[106]. The Mediterranean dietary pattern is significantly associated with reduced frequency of COPD exacerbations, potentially achieved by decreasing gut proinflammatory bacteria abundance[107]. Among smokers, smoking cessation combined with inulin supplementation reverses gut dysbiosis and lowers airway IL-8 levels[108,109]. Dietary lifestyle interventions centered on high-fiber intake, Mediterranean-style eating, smoking cessation, and prebiotic supplementation can achieve cross-organ regulation of pulmonary inflammation and susceptibility to infection by reshaping the gut microbiota. This offers a safe, feasible, and cost-effective clinical pathway for non-pharmacological adjunctive therapy in chronic respiratory diseases and respiratory infections. These associations while promising highlight the need to consider the multifaceted nature of disease progression in which diet is one interacting component among genetic, immunological, and comorbid factors.

Drug repositioning

Rifaximin, as a gut-targeted antibiotic, reduces the gut Lipopolysaccharide-producing bacterial load and lowers systemic inflammatory markers in patients with COPD[110]. Curcumin reduces the risk of IL-6 storms in patients with coronavirus disease 2019 by inhibiting the nuclear factor kappa-B pathway while modulating gut microbiota composition to increase Faecalibacterium abundance[111-113]. It is recommended to develop targeted microbiota regulation strategies based on microbial profiles. Drugs like rifaximin and curcumin exert multifaceted effects through the gut-lung axis, providing a new microbiota-dependent mechanism for drug repurposing. This suggests that future clinical applications could screen for beneficiary populations based on gut microbiota, enabling low-cost, high-efficiency drug utilization. We present these strategies in Figure 1.

Figure 1  Intervention strategies for the co-occurrence of gastrointestinal and respiratory system diseases.

Comorbidity between gastrointestinal and pulmonary diseases may lead to misdiagnosis due to overlapping symptoms. Certain pulmonary disease medications cause damage to the gastrointestinal mucosa, exacerbating comorbid symptoms through the gut-lung axis[114-116]. Clinical management faces significant challenges due to individual heterogeneity, lack of biomarkers, regulatory gaps, and difficulties in multisystem integration[16,44,117].

CHALLENGES AND FUTURE DIRECTIONS

Limitations of existing research

Although a growing body of research supports the notion that gut microbiota can influence lung diseases via the gut-lung axis, direct evidence is lacking to establish whether microbial migration constitutes a causal relationship. Most studies remain at the correlational level, making it difficult to rule out confounding factors or reverse causality. For instance, some investigations in patients with ARDS or bronchiectasis have identified gut-derived bacterial genera enriched in the lungs, suggesting potential microbial migration, yet it remains unclear whether this serves as a driving factor in disease development[118]. Furthermore, whether the microbial migration observed in animal models applies to humans requires further validation.

Current intervention studies on the gut-lung axis primarily focus on probiotics, prebiotics, or fecal microbiota transplantation. However, the optimal timing for intervention, target microbial populations, and suitable populations remain unclear[119]. For instance, in chronic lung diseases like COPD or asthma, gut microbiota dysbiosis often occurs during the early stages or acute exacerbations of the disease. There is no unified standard on whether interventions should be implemented during the predisease phase, stable phase, or acute phase[120,121]. Furthermore, different disease phenotypes may correspond to distinct microbial profiles. Precisely identifying key bacterial genera and developing personalized intervention strategies remain significant challenges in current research.

Future directions and prospects for clinical translation

Future research should integrate multi-omics technologies such as metagenomics, metabolomics, and transcriptomics to systematically elucidate the specific mechanisms by which the gut microbiota influence pulmonary diseases through metabolic products and immune regulatory pathways. For instance, previous studies using metagenomic sequencing have identified potential causal relationships between specific gut bacterial genera and pulmonary embolism risk[122], suggesting that multi-omics data can be leveraged to identify potential intervention targets.

Existing animal models are largely confined to specific bacterial strains or single time points, making it difficult to simulate the complex microbiota-host interactions observed in humans. Future efforts should focus on developing more humanized models, such as human microbiota-colonized mice and organ-on-a-chip systems[123-126], combined with dynamic sampling techniques. This approach will enable the simulation of the temporal relationship between microbiota changes and pulmonary immune responses across different disease stages, thereby providing stronger evidence for causal inference.

The application prospects of artificial intelligence and machine learning algorithms in microbiome data analysis are vast. By constructing disease-microbiome association maps and integrating clinical phenotype data, early prediction of pulmonary disease risk and personalized intervention strategies can be achieved[127,128]. For instance, bidirectional causal analysis based on Mendelian randomization methods has been employed to uncover potential causal chains linking gut microbiota to eight respiratory diseases, providing genetic evidence for clinical translation[129,130].

The gut-lung axis, serving as a vital bridge linking intestinal and pulmonary diseases, has achieved preliminary breakthroughs at the mechanistic level. However, challenges remain in causal inference and intervention strategies. Through technological integration, model optimization, and algorithm-driven approaches, future efforts are expected to advance its translation from basic research to precision medicine clinical applications. This holds promise for overcoming the limitations of traditional single-organ therapies, enabling integrated early warning, classification, and personalized regulation of gastrointestinal and respiratory comorbidities.

CONCLUSION

The gut-lung axis reveals the mechanisms of gastrointestinal and pulmonary comorbidities through multidimensional perspectives including shared immunity, the microbiome, and its metabolites, laying the foundation for cross-organ precision medicine. Current limitations include single-organ therapies, crude microbiome interventions, and the absence of biomarkers. Furthermore, most current evidence stems from cross-sectional studies or animal models, leaving insufficient robust evidence to establish causal relationships in specific clinical contexts or to determine optimal timing and targets for interventions. Research on the gut-lung axis is at a pivotal juncture, transitioning from mechanism exploration toward precision medicine. By focusing on generating robust evidence within specific clinical scenarios and developing targeted intervention tools and predictive models, we can overcome the limitations of current single organ diagnostics and therapies. This approach holds promise for achieving early warning, precise classification, and coordinated management of gastrointestinal-pulmonary comorbidities.

ACKNOWLEDGEMENTS

We appreciate the constructive comments provided by the anonymous reviewers to greatly improve the quality of this manuscript.