Neutrophils are critical for host defense but become pathogenic in COPD due to sustained activation (38). In patients with COPD, neutrophil counts are significantly elevated in bronchoalveolar lavage fluid (BALF), sputum, and lung tissue, with numbers correlating with disease severity and exacerbation frequency (39). once activated, neutrophils release a repertoire of cytotoxic molecules, including reactive oxygen species (ROS), proteolytic enzymes (neutrophil elastase, matrix metalloproteinase-9 (MMP-9)), and neutrophil extracellular traps (NETs), which collectively drive tissue damage and emphysematous changes (40, 41). Notably, neutrophil dysfunction in COPD extends beyond hyperactivation: impaired phagocytosis and chemotaxis reduce their ability to clear pathogens, increasing susceptibility to infections and exacerbations (42, 43).

Gut-lung axis link: The hyperactive state of pulmonary neutrophils is systemically influenced by gut health. Circulating LPS derived from a dysbiotic gut can ‘prime’ neutrophils, lowering their activation threshold. Furthermore, the systemic deficit in gut-derived SCFAs removes a crucial brake on neutrophil chemotaxis and ROS production, thereby exacerbating their damaging potential in the lung (44–46).

Alveolar macrophages (AMs) are activated by cigarette smoke and microbial products. In COPD, there is a skewing toward pro-inflammatory M1 polarization, characterized by increased expression of inducible nitric oxide synthase (iNOS), TNF-α, IL-6, and IL-1β, which amplify inflammation and oxidative stress (47).M2 macrophages, associated with tissue repair, are also dysregulated (46, 48). Excessive or prolonged M2 activation can drives aberrant tissue remodeling via transforming growth factor-beta (TGF-β) and MMP-12, leading to airway fibrosis (49). Macrophage dysfunction in COPD is also marked by impaired efferocytosis—the clearance of apoptotic cells—which leads to the accumulation of necrotic debris and persistent inflammation (50).

Gut-lung axis link: The polarization state of pulmonary macrophages is susceptible to remote reprogramming by gut metabolites. Butyrate and other SCFAs are potent inducers of an anti-inflammatory and pro-resolutive phenotype in macrophages, primarily through HDAC inhibition (10). The systemic SCFA deficiency characteristic of COPD thus cripples a key signal that would otherwise help temper M1-driven inflammation and promote tissue repair in the lung.

Adaptive immune responses mediated by T cells are central to COPD pathogenesis, CD8⁺ T cells are particularly abundant in the lungs of patients with COPD, contributing to alveolar epithelial cell death and emphysema severity (51). CD4⁺ T cells in COPD are polarized toward pro-inflammatory Th1 and Th17 phenotypes, with reduced anti-inflammatory T regulatory (Treg) cells, creating a Th17/Treg imbalance that perpetuates inflammation (52). Treg cells, which suppress immune responses, are numerically and functionally deficient in COPD, failing to constrain Th1 and Th17 activity.

Gut-lung axis link: The systemic deficit of SCFAs, particularly butyrate, impairs the epigenetic programming of Treg differentiation in the gut and their subsequent trafficking to the lung. Concurrently, gut dysbiosis can promote the priming and expansion of Th17 cells, which then migrate to the pulmonary environment, exacerbating inflammation (53).

DCs are professional antigen-presenting cells that link innate and adaptive immunity by capturing and presenting antigens to naive T cells, thereby initiating T cell differentiation. In COPD, DC function is dysregulated, leading to inappropriate T cell activation and polarization (54). Airway DCs in COPD exhibit an activated phenotype, expressing increased levels of costimulatory molecules (CD40, CD80, CD86) and pro-inflammatory cytokines (IL-6, IL-12, TNF-α), which promote Th1 and Th17 differentiation (55). This activation is triggered by cigarette smoke components, microbial products (e.g., LPS), and epithelial-derived cytokines such as thymic stromal lymphopoietin (TSLP) and IL-33.

Gut-lung axis link: The constant low-grade influx of microbial products (e.g., LPS) from a leaky gut provides a persistent stimulus for DC activation. Moreover, microbial metabolites can shape the development and function of both DCs and MDSCs in the bone marrow, illustrating how the gut microbiota can systemically modulate the very origin and priming of these critical innate immune cells (45).

MDSCs are a heterogeneous population of immature myeloid cells with potent immunosuppressive activity, which are increasingly recognized as players in COPD pathogenesis (56). MDSCs accumulate in the peripheral blood and BALF of COPD patients, with their numbers correlating with disease severity and exacerbation risk. These cells suppress T cell proliferation and function via arginase-1, inducible iNOS, and ROS, creating an immunosuppressive microenvironment that impairs pathogen clearance and promotes chronic inflammation (57). While MDSCs initially act to limit excessive immune responses, their sustained activation in COPD leads to immune paralysis, increasing susceptibility to bacterial and viral infections. MDSCs also contribute to inflammation by secreting pro-inflammatory cytokines such as IL-6 and TNF-α, which amplify neutrophil and macrophage activation. Moreover, MDSCs promote angiogenesis and fibrosis via vascular endothelial growth factor (VEGF) and TGF-β secretion, contributing to airway remodeling (58).

Gut-lung axis link: The expansion and activation of MDSCs in COPD can be fueled by gut dysbiosis. The translocation of microbial products like LPS into the circulation may activate TLR4/NF-κB signaling in myeloid progenitors, promoting MDSC differentiation and recruitment to the lung.

SCFAs-acetate, propionate, and butyrate-are the primary metabolites produced by fermentation of dietary fiber by gut bacteria, and their levels are significantly reduced in COPD patients (59). SCFAs exert profound effects on pulmonary immune cells via G protein-coupled receptors (GPR41, GPR43) and histone deacetylase (HDAC) inhibition. Butyrate, a potent HDAC inhibitor, promotes Treg differentiation, thereby restoring the Th17/Treg balance (60). Propionate and acetate activate GPR41 and GPR43 on macrophages, inhibiting M1 polarization and promoting M2-mediated tissue repair. Additionally, SCFAs reduce neutrophil chemotaxis and ROS production, limiting tissue damage (61).

Tryptophan metabolites, including indole-3-acetic acid (IAA) regulate pulmonary immunity (62). IAA, produced by Lactobacillus species, inhibits pro-inflammatory cytokine production, while kynurenines activate the aryl hydrocarbon receptor (AhR) on T cells, promoting Treg differentiation and IL-22 secretion, which enhances epithelial barrier integrity (63). In COPD, depletion of tryptophan-metabolizing bacteria leads to reduced IAA and kynurenine levels, impairing AhR signaling (64). Bile acids, modified by gut bacteria, also contribute to gut-lung axis signaling. Tauroursodeoxycholic acid (TUDCA), a secondary bile acid, inhibits NLRP3 inflammasome activation in macrophages, but can also impair neutrophil function, increasing infection risk (13, 19, 65).

The gut is a major site of immune cell development, and gut-derived immune cells traffic to the lung via the systemic circulation (66, 67). In COPD, gut dysbiosis alters this trafficking: depletion of beneficial bacteria reduces Treg migration to the lung, while expansion of pathogenic species increases Th17 and CD8⁺ T cell trafficking (9).

The intestinal epithelial barrier prevents microbial translocation and maintains immune homeostasis, and gut dysbiosis impairs this barrier by reducing tight junction proteins (e.g., occludin, claudin) and increasing permeability. In COPD, increased gut permeability leads to translocation of LPS and other microbial products into the systemic circulation, where they activate TLR4/NF-κB signaling in pulmonary immune cells, amplifying inflammation (20). Beneficial gut bacteria, such as Bifidobacterium and Lactobacillus, strengthen the intestinal barrier; their depletion in COPD exacerbates microbial translocation and pulmonary inflammation (68).

Gut microbiota regulates key inflammatory signaling pathways in pulmonary immune cells, including the TLR4/NF-κB and NLRP3 inflammasome pathways (45). TLR4/NF-κB signaling is activated by LPS and other microbial products, leading to the transcription of pro-inflammatory genes. In COPD, gut dysbiosis and increased intestinal permeability are thought to promote the translocation of microbial products such as LPS into circulation, which can sustain systemic and pulmonary inflammation via pathways including NF-κB activation in macrophages and neutrophils, which perpetuates cytokine production and tissue damage (69). Beneficial bacteria, such as Bacteroidetes, inhibit TLR4/NF-κB signaling by secreting polysaccharide A (PSA), which activates TLR2 and suppresses NF-κB translocation, a unique immunomodulatory mechanism. The NLRP3 inflammasome, a multiprotein complex that activates caspase-1 and IL-1β secretion, is also regulated by gut microbiota. In COPD, increased gut permeability leads to activation of the NLRP3 inflammasome in macrophages, enhancing IL-1β production and inflammation (23, 70). SCFAs and bile acids inhibit NLRP3 activation, and their reduced levels in COPD contribute to inflammasome hyperactivation. Additionally, gut bacteria such as Akkermansia muciniphila reduce NLRP3 activation by modulating gut barrier function, highlighting the potential of microbiota-based interventions to target inflammatory pathways (71).

scfas, primarily acetate, propionate, and butyrate, are produced by bacterial fermentation of dietary fibers. They exert pleiotropic effects via two primary, interconnected mechanisms:

Gut microbes metabolize dietary tryptophan into ligands for the aryl hydrocarbon receptor (AhR). AhR activation in CD4⁺ T-cells promotes their differentiation into Tregs while suppressing Th17 development, mitigating Th17/Treg imbalance (73, 74). The kynurenine pathway of tryptophan metabolism also generates AhR ligands. Bile acids, upon modification by gut bacteria, become potent signaling molecules. TUDCA, a secondary bile acid, exerts complex effects in COPD. It has been demonstrated to suppress the NLRP3 inflammasome activation in macrophages, thereby reducing the cleavage and release of pro-inflammatory IL-1β (75). However, in a paradoxical role, TUDCA can also impair AMP-activated protein kinase (AMPK) signaling in neutrophils. This disruption cripples their phagocytic capacity and oxidative burst, increasing susceptibility to secondary bacterial infections, such as those caused by Pseudomonas aeruginosa (76), a common pathogen in COPD exacerbations.

Deaminotyrosine (DAT), another microbiota-derived metabolite, enhances type I interferon signaling and protects against viral infections, which are major triggers of COPD exacerbations (77). Table 2 summarizes key microbial metabolites in gut-lung communication.

Moving beyond bacteria, pioneering research has identified gut-resident protozoa as key modulators of pulmonary immunity. Colonization of the gut by the rodent-specific commensal Tritrichomonas musculis (T.mu) triggers the activation and S1P-dependent migration of inflammatory type 2 innate lymphoid cells (iILC2s) from the gut to the lungs, where they produce type 2 cytokines, driving eosinophil accumulation (83). It is crucial to note that T. musculis is a rodent-specific commensal. While this discovery unveils a novel eukaryotic component of the gut-lung axis, the direct translation to human COPD is not yet established. This highlights the gut–lung axis as a potential conduit for eukaryotic signals, representing an emerging frontier for research rather than a confirmed mechanism in human disease.

Bacteria release nanosized extracellular vehicles (EVs) that carry a cargo of microbial components (e.g., DNA, RNA, proteins). These EVs can traverse biological barriers, enter the systemic circulation, and deliver their cargo directly to cells in the lungs. Preliminary evidence suggests that bacterial EVs could serve as vectors for inter-organ signaling, potentially carrying anti-inflammatory cargo to AMs, while those from pathobionts could carry virulence factors that exacerbate inflammation (84). This represents a nascent but intriguing frontier for understanding gut-lung communication and future therapeutic design.

To conclusively establish causality and dissect human-specific mechanisms, advanced model systems like organs-on-chips are invaluable. These microfluidic devices can co-culture human gut and lung organoids or epithelial cells, allowing for the real-time study of immune cell trafficking and metabolite exchange in a controlled, human-relevant system (85). While integrated gut-lung organ-chip models remain under development, they hold considerable promise for delineating human-specific causal mechanisms and serving as platforms for preclinical therapeutic screening.

The mechanistic underpinnings of the gut-lung axis in COPD highlight a complex interplay of soluble metabolites, mobile immune cells, and neural signals. The dysregulation of these pathways—SCFA-receptor signaling, AhR activation, and bile acid metabolism—offers a rich landscape of druggable targets. Future research must leverage human-relevant models, such as organ chips, to validate these mechanisms and accelerate the development of targeted therapies, including engineered probiotic consortia, metabolite-based biologics, and nanocarriers for targeted delivery to the gut or lung. A deep, mechanistic understanding of this axis is paramount for ushering in a new era of microbiome-based pharmacology for COPD.

Probiotic administration, particularly with Lactobacillus and Bifidobacterium strains, demonstrates benefits in improving lung function and reducing systemic pro-inflammatory cytokines (88, 89).

Lactobacillus spp.: Certain strains ameliorate lung inflammation and mitigate gut dysbiosis in murine models (90). Their efficacy is linked to the enhancement of Treg responses and SCFAs production. Notably, some airway-derived Lactobacillus strains are potent producers of indole-3-acetic acid (IAA). Intranasal administration of these specific strains was shown to restore IAA levels, activate the IL-22 signaling pathway, and attenuate neutrophilic inflammation and emphysema in COPD models (90).

Bifidobacterium spp.: These probiotics primarily contribute to fortifying the intestinal barrier, reducing the translocation of pro-inflammatory microbial products like LPS, which is crucial for dampening the systemic inflammation (19). It is important to note that probiotic effects are often strain-specific, and the optimal strains, combinations, and formulations for COPD management remain an active area of investigation.

Prebiotics function as selective substrates to cultivate a beneficial gut environment. Inulin supplementation has been shown to delay symptom progression and reduce exacerbation frequency in COPD patients, primarily by stimulating SCFA-producing bacteria such as Lachnospiraceae (91). Similarly, partially hydrolyzed guar gum (PHGG), under investigation in a phase II clinical trial (NCT05126654), aims to selectively enrich Parabacteroides goldsteinii, a bacterium whose abundance is inversely correlated with COPD severity (92). Table 3 lists select probiotic and prebiotic interventions in COPD.

Nano-carriers like G4 PAMAM dendrimers can be complexed with hydrophobic metabolites such as indole-3-acetic acid (IAA), dramatically improving their aqueous solubility and protecting them from premature degradation (104).

Formulations such as poly (lactic-co-glycolic acid) (PLGA) nanoparticles can be engineered for the sustained release of SCFAs or other agents, achieving targeted delivery to either the gut or the lung (105).

While nanotechnology offers promising solutions for bioavailability, its clinical translation necessitates a thorough evaluation of safety. Key concerns include the potential cytotoxicity of certain materials, long-term accumulation in tissues, and inadequate biodegradation. The inflammatory response to nanoparticles, especially in the already compromised COPD lung, must be carefully assessed. Future work must therefore focus on designing biocompatible, biodegradable carriers with well-understood clearance pathways, a critical prerequisite for their successful clinical translation to ensure therapeutic benefits outweigh potential risks.

Taxonomic shifts provide the first layer of biomarker discovery. Ratios such as the Bacteroidales/Lactobacillus index have been correlated with COPD severity and exacerbation risk (22).

Functional metabolites provide a more dynamic readout. Levels of fecal SCFAs are consistently reduced in COPD patients and inversely correlate with systemic inflammation (84).

Personalized medicine: The inherent heterogeneity of COPD demands tailored strategies. The DI-GM enables the design of individualized dietary plans (107). Probiotic and prebiotic interventions are advancing toward greater specificity, guided by baseline microbiome profiling (108). This integrated approach, combining biomarker profiling with targeted interventions, represents the future of microbiome-based personalized medicine for COPD (19). The integration of such biomarkers into clinical practice could enable a more precise stratification of COPD patients, moving beyond the current GOLD classification towards a ‘treatable traits’ approach that includes microbiota and metabolic status. Table 4 lists promising microbiota-based biomarkers in COPD.

The majority of human studies are observational. While animal models recapitulate disease phenotypes and suggest causality, species-specific differences limit direct extrapolation (113). While randomized controlled trials (RCTs) can establish a causal link between an intervention and a clinical outcome, definitive molecular causality in human studies remains challenging. Advanced epidemiological methods like Mendelian randomization can provide stronger evidence for causal inference by leveraging genetic variants (111). However, the gold standard for establishing mechanistic causality often relies on a combination of human association studies and supportive data from interventional animal models, particularly gnotobiotic mice colonized with human microbiota.

A critical lack of standardization in sample collection (feces vs. mucosal biopsies), DNA extraction, sequencing, and bioinformatic pipelines hinders reproducibility and comparability of results (114).

The frequent use of antibiotics for managing exacerbations profoundly disrupts gut microbial diversity (115). Furthermore, a critical and often overlooked confounder is the widespread use of inhaled and systemic corticosteroids. Corticosteroids are potent immunomodulators that can directly alter the composition and function of the gut and lung microbiota (22, 116, 117). Therefore, the microbiota profile of a COPD patient is a composite of the disease itself and its treatment. Future studies must rigorously account for corticosteroid use (118). Furthermore, the pervasive use of inhaled and systemic corticosteroids in COPD management presents a major confounder, as these agents can directly modulate both gut and lung microbiota composition and host immune responses, independent of the disease process itself.

The gut microbiome is shaped by a multitude of factors including diet, geography, age, genetics, and concomitant medications. This vast heterogeneity challenges the development of universal interventions (119).

Future mechanistic studies should employ advanced gnotobiotic models, such as humanized microbiota mice, where germ-free animals are colonized with a defined human microbial community. Combined with antibiotic perturbation-recolonization experiments, these models can definitively validate the causal role of specific bacterial taxa or consortia in COPD pathogenesis and treatment response (120).

The integration of metagenomics, metabolomics, and proteomics is essential to unravel the complex “microbiome-metabolite-host” interactions. This multi-omics approach should be applied in longitudinal cohorts to capture dynamic changes during disease exacerbation and stability. The goal is to transition towards precision microbiome medicine, where a patient’s microbial profile guides the selection of bespoke interventions (121).

Microbiota-based therapies present unique regulatory pathways. Live Biotherapeutic Products (LBPs), FMT, and nano-formulated metabolites fall into novel regulatory categories. Key concerns include the risk of pathogen transmission, the long-term ecological stability of transplanted or supplemented microbes, and the unknown long-term safety profile of engineered nanomaterials. Developing clear regulatory frameworks and conducting rigorous, long-term safety studies are imperative for clinical adoption (122).