Gut-lung axis in allergic asthma: microbiota-driven immune dysregulation and therapeutic strategies

Allergic asthma, a prevalent chronic respiratory disorder, imposes a substantial global health burden. Epidemiological data reveal that 60%–80% of asthma cases exhibit allergic phenotypes, constituting the predominant disease subtype (Zhang et al., 2025). Notably, geographic disparities exist in prevalence trends: high-income countries demonstrate plateauing incidence rates of allergic disorders, whereas low- and middle-income nations face escalating trends, potentially reflecting environmental and socioeconomic determinants (Genuneit and Standl, 2022). Clinically, this condition manifests through characteristic airway hyperresponsiveness, episodic dyspnea, nonproductive cough, and chest constriction, with symptom severity correlating with allergen exposure levels (Shah and Newcomb, 2018). Importantly, 40%–60% of patients present with allergic multimorbidity, particularly concurrent allergic rhinitis and atopic dermatitis, which synergistically exacerbate disease progression and substantially impair quality of life metrics (Humbert et al., 2019).

The gut microbiota, comprising a complex ecosystem of commensal microorganisms, exerts systemic immunomodulatory effects through bidirectional gut-lung axis communication. With estimated microbial densities exceeding 10¹⁴ organisms and compositionally diverse taxonomy, this microbial consortium critically regulates host physiological homeostasis, including nutrient assimilation, xenobiotic metabolism, and intestinal epithelial barrier fortification (Yang and Chun, 2021). Mounting evidence from multi-omics studies implicates microbial imbalance in the pathogenesis of diverse disease states, spanning metabolic syndrome, autoimmune disorders, and neuropsychiatric conditions (Ding et al., 2024). Mechanistically, microbial-derived metabolites such as short-chain fatty acids (SCFAs) serve as key immunoregulatory mediators, modulating T-cell differentiation pathways and attenuating systemic inflammation through G protein-coupled receptor interactions (Li et al., 2022a). We hypothesize that gut microbiota modulation can recalibrate Th2/Th17-Treg imbalances in allergic asthma.

Emerging evidence has elucidated critical cross-talk between gut microbial communities and pulmonary pathophysiology through the gut-lung axis—a bidirectional immunoregulatory network involving microbial metabolites and immune cell trafficking. Contemporary research demonstrates that taxonomic alterations and functional perturbations in gut microbiota (microbial imbalance) significantly impact respiratory disease trajectories, particularly in COPD and allergic asthma exacerbations, as evidenced by longitudinal clinical cohort studies (Shi et al., 2021). Mechanistic investigations reveal that depleted microbial diversity compromises pulmonary immune homeostasis, predisposing hosts to enhanced type 2 inflammation and impaired antiviral defense mechanisms, as substantiated by preclinical models of allergic airway disease (Neag et al., 2022). Microbial-derived metabolites, including but not limited to SCFAs, exert distal immunomodulatory effects through systemic circulation and vagus nerve signaling—notably regulating Treg cell differentiation and suppressing neutrophilic infiltration in bronchial tissues via G protein-coupled receptor (GPCR) signaling pathways (Alswat, 2024). These mechanistic insights are revolutionizing our understanding of asthma pathogenesis, positioning microbiota-targeted interventions (e.g., probiotics, postbiotics) as promising disease-modifying approaches in precision allergology.

The gut microbiota in healthy individuals forms a phylogenetically complex ecosystem comprising bacteria, archaea, fungi, and viruses, with bacterial dominance primarily observed in four phyla: Firmicutes, Bacteroidetes (including genera like Prevotella), Actinobacteria (exemplified by Bifidobacterium species), and Clostridia (particularly the butyrate-producing species Faecalibacterium prausnitzii). This microbial consortium demonstrates substantial α-diversity (intra-individual species richness) and functional redundancy, enabling robust ecosystem stability that facilitates immune tolerance, epithelial barrier maintenance, and metabolic homeostasis through mechanisms including short-chain fatty acid (SCFA) biosynthesis (notably butyrate) and essential vitamin production (Liu et al., 2024; Mirmohammadali and Rosenkranz, 2023). Bidirectional communication with the central nervous system further establishes the microbiota’s role in regulating mood and cognitive functions through neuroendocrine, immune, and neural pathways, a relationship termed the gut-brain axis (Alves et al., 2024; Salami, 2021). These multifunctional interactions underscore the necessity of preserving microbial compositional integrity for systemic health maintenance.

Microbial diversity serves as a key biomarker for health status and pathological susceptibility. Epidemiological evidence associates reduced gut microbiota diversity with increased incidence of metabolic disorders (obesity, diabetes), cardiovascular pathologies, and immune-mediated conditions including allergic diseases (Guo et al., 2020; Shi et al., 2024). The diversity-immune function nexus manifests through microbial regulation of immune cell differentiation and inflammatory responses, where high diversity correlates with enhanced immune homeostasis and reduced chronic inflammation risks (Liu et al., 2024; Sottas et al., 2021). This immunological modulation, coupled with direct metabolic contributions, positions microbiota diversity preservation as a critical factor not merely for gastrointestinal health, but for comprehensive disease prevention strategies spanning multiple physiological systems.

Emerging evidence highlights significant compositional disparities between the gut microbiota of allergic asthma patients and healthy populations. Ke et al. demonstrated an inverse correlation between childhood gut microbiota diversity and susceptibility to asthma/allergic conditions, implicating depauperate microbiota as a potential risk amplifier (Ke et al., 2021). Asthma patients characteristically exhibit diminished α-diversity, a feature mechanistically linked to dysregulated immune homeostasis (Heinrich et al., 2023; Hsu et al., 2021). Concurrently, these individuals display depletion of immunomodulatory taxa like Bifidobacterium and Lactobacillus, alongside pathobiont enrichment such as Escherichia coli—a microbial signature that may perpetuate inflammatory cascades (Heinrich et al., 2023; Li et al., 2022b). Mechanistically, early-life microbial colonization patterns exert long-term immunological consequences, exemplified by Clostridium difficile establishment at 1 month predicting asthma development by age 6–7 years (van Nimwegen et al., 2011). Parallel microbial imbalance extends to respiratory ecosystems, where asthma severity correlates positively with reduced bacterial diversity and elevated proteobacterial abundance in the airway microbiome (Carr et al., 2019). Age-stratified analyses further reveal distinct microbiota configurations between asthmatic and non-asthmatic cohorts across developmental stages (Lee et al., 2019). Exogenous modifiers including antibiotic exposure and dietary patterns potentially exacerbate these ecological perturbations, creating feedforward loops that may intensify symptomatology. Therapeutic modulation through targeted probiotics or precision nutrition emerges as a promising strategy to restore microbial equilibrium, with clinical studies suggesting concomitant improvements in both immunological parameters and quality-of-life metrics (Liao et al., 2022; Ozerskaia et al., 2021). This review systematically delineates gut microbiota alterations in allergic asthma (summarized in Table 1), providing a framework to understand their pathogenic contributions and therapeutic potential.

The gut microbiota-derived metabolites exhibit significant biological activities through intricate biosynthetic pathways and host-microbe interactions. Short-chain fatty acids (SCFAs), principal microbial fermentation products of dietary fibers, are synthesized via carbohydrate-active enzymes expressed by commensal bacteria. These ≤6-carbon molecules–predominantly acetate, propionate, and butyrate–exist in strictly regulated colonic ratios (Fernandes et al., 2014). Acetate production predominates through the Wood-Ljungdahl pathway in acetogenic bacteria, demonstrating superior metabolic efficiency compared to other SCFAs (Miller and Wolin, 1996). Propionate biosynthesis occurs via three distinct routes: Bacteroidetes species preferentially employ the succinate pathway (Reichardt et al., 2014), while Firmicutes utilize acrylate and propanediol pathways, particularly when metabolizing pentoses/hexoses (Macfarlane and Macfarlane, 2003). Butyrogenesis is specialized to select Firmicutes taxa expressing butyryl-CoA:acetate CoA-transferase, with Faecalibacterium prausnitzii being a key producer (Louis et al., 2010). SCFAs are key factors linking gut microbial imbalance with allergic airway diseases. Clinically relevant SCFA deficiencies are observed in allergic rhinitis patients and infants predisposed to later asthma/wheezing development (Zhou et al., 2021), establishing these metabolites as critical mediators in allergic airway pathogenesis (Cheng et al., 2022; Roduit et al., 2019). Some scholars speculate that low levels of butyrate may be associated with increased severity in asthma patients.

Tryptophan metabolism represents another pivotal microbial-host interaction axis. While dietary tryptophan is primarily absorbed intestinally for protein synthesis, colonic microbiota extensively catabolize residual tryptophan through multiple pathways. Direct bacterial conversion yields immunomodulatory indole derivatives (indole, IE, IPA, ILA) via tryptophanase-expressing species like Escherichia coli and Proteus vulgaris (Lee and Lee, 2010; Palusiak, 2013; Smith, 1897). Concurrently, microbial regulation of host tryptophan metabolism occurs through serotonin synthesis and kynurenine pathway modulation(Roager and Licht, 2018). These metabolites demonstrate dual neuroimmune regulatory capacity: indole derivatives activate aryl hydrocarbon receptor (AhR) signaling to promote anti-inflammatory cytokine production (Brown et al., 2022; Zhao et al., 2024), while kynurenine accumulation correlates with chronic inflammatory and neuropsychiatric disorders (Basnet et al., 2023; Diether et al., 2023).

The gut-lung axis operationalizes these metabolites through systemic immunomodulation. SCFAs mitigate allergic airway inflammation via GPR41/43-mediated suppression of Th2 responses and HDAC inhibition-induced Treg cell expansion, as evidenced by their therapeutic efficacy in murine asthma models (Bloor and Mitchell, 2021; Zhang et al., 2025). Clinical translation potential is suggested by probiotic interventions restoring SCFA levels and improving respiratory outcomes (Hu et al., 2021b; Thorburn et al., 2015). Similarly, tryptophan metabolites regulate pulmonary immunity through AhR-dependent IL-22 production and Th17/ILC3 modulation, with microbial imbalance-induced kynurenine/SCFA imbalances exacerbating airway hyperreactivity (Basnet et al., 2023; Padhi et al., 2024). These mechanistic insights position microbial metabolite modulation as a promising therapeutic strategy for allergic asthma and related airway pathologies, bridging microbial ecology with clinical immunology through targeted microbiome engineering approaches.

The dynamic interplay between gut microbiota and the host immune system represents a fundamental axis in maintaining physiological homeostasis (Chen et al., 2022). Through multifaceted mechanisms—including immune cell modulation, metabolite production, and intestinal barrier maintenance—the microbiota directly shapes systemic immune competence. Microbial imbalance is increasingly implicated in immune-mediated pathologies such as autoimmune disorders, allergies, and inflammatory bowel diseases (Al-Rashidi, 2022; Yoo et al., 2020). Key findings from investigations into these interactions are systematically summarized in Table 2 and Figure 1.

We delineate the multifaceted role of gut microbiota in allergic asthma pathophysiology, highlighting microbial-immune interactions as a therapeutic frontier for airway hyperreactivity, remodeling, and allergenic sensitization as shown in Figure 2.

Probiotics, defined as live microorganisms conferring host health benefits, modulate gut microbial equilibrium by enhancing colonization resistance, immunomodulation, and epithelial barrier reinforcement. Clinical applications span gastrointestinal disorders (diarrhea, constipation, inflammatory bowel disease) through mechanisms involving pathogen exclusion, bacteriocin production, and immune cell priming (Li et al., 2024). Prebiotics—non-digestible substrates selectively fermented by commensals—stimulate beneficial taxa proliferation (e.g., Bifidobacterium, Lactobacillus) while increasing short-chain fatty acid (SCFA) production, thereby improving intestinal homeostasis (You et al., 2022). Synbiotic formulations combining probiotics with prebiotics demonstrate synergistic effects, enhancing microbial diversity and metabolic functions more effectively than individual components (Du et al., 2024). Despite therapeutic promise, clinical translation requires rigorous validation through randomized controlled trials to establish strain-specific mechanisms, dosing protocols, and long-term safety profiles (Raghani et al., 2024). Special attention should be paid to leveraging strain specific effects, such as lactobacilli competing with pathogenic bacteria for nutrients and adhesion sites by occupying space on the surface of the intestinal mucosa, thereby inhibiting the overgrowth of harmful bacteria.

Dietary patterns exert profound effects on gut microbiota composition and functionality (Leeming et al., 2019). High-fiber diets increase SCFA producers by ∼40% (Faecalibacterium, Roseburia) and improving metabolic parameters through GLP-1 secretion and hepatic gluconeogenesis suppression (Fu et al., 2022). Conversely, Western-style diets high in saturated fats and refined sugars drive microbial imbalance, characterized by Bacteroides enrichment and reduced microbial diversity, correlating with chronic inflammation and metabolic syndrome (Mehmood et al., 2021). Temporal dynamics further influence intervention efficacy: transient dietary changes induce reversible microbial shifts, whereas sustained dietary habits remodel enterotypes, suggesting long-term adherence is critical for durable ecological benefits (Li et al., 2024). Precision nutrition strategies, integrating host genetics, microbiota profiling, and lifestyle factors, represent emerging paradigms for personalized microbiota engineering.

Advancements in microbiota research are driving the development of multidimensional intervention frameworks. Combinatorial approaches—integrating probiotics, prebiotics, dietary modifications, and phage therapy—show enhanced efficacy in restoring microbial networks disrupted in conditions like obesity and diabetes (Sumida et al., 2023). Elucidating cross-system interactions (e.g., microbiota-immune-nervous axis crosstalk) will uncover novel therapeutic targets, as evidenced by SCFA-mediated neuroimmune regulation in allergic airway diseases [54]. Clinically, microbiota-targeted therapies are being incorporated into disease-specific protocols, including fecal microbiota transplantation for C. difficile infection and engineered probiotics for inflammatory bowel disease (Xu et al., 2024). However, challenges persist in standardizing microbial products, optimizing personalized dosing, and establishing long-term safety monitoring systems. Moreover, the optimal dosage and long-term safety of probiotics have not yet been determined. Addressing these barriers will be pivotal for translating microbiota science into mainstream clinical practice, ultimately enabling precision medicine approaches for complex chronic diseases.

New evidence highlights the key role of gut microbiota and their metabolites in allergic asthma development. Microbial imbalance—altered diversity, changes in key taxa (e.g., bifidobacteria) and metabolites (e.g., SCFAs, tryptophan derivatives)—may link to immune dysfunction. These microbe-immune interactions improve our understanding of asthma and reveal new microbial-targeted therapies. Probiotics, prebiotics, and dietary changes show potential to reset immune responses and reduce asthma severity. Yet, while microbial shifts correlate with disease, causal links are poorly defined, requiring more mechanistic research using gnotobiotic models and long-term human studies.

Future research should focus on clarifying strain-specific microbial functions, host-microbe interaction pathways (e.g., gut-lung axis signaling), and individual responses influenced by genetics, environment, and diet. Validating strain-specific probiotics through human trials is crucial. Large-scale multi-omics cohorts combined with randomized controlled trials of targeted microbiota interventions are needed to confirm therapeutic effects and improve precision medicine approaches. In short, the gut microbiota is both a biomarker and a modifiable driver of allergic asthma. Unraveling its complex interactions with host immunity and physiology will advance microbiome-based strategies for asthma prevention, personalized treatment, and long-term control.

The author(s) declare that no financial support was received for the research and/or publication of this article.

JL: Data curation, Writing – review and editing, Writing – original draft. YZ: Writing – review and editing, Investigation. SL: Conceptualization, Writing – review and editing, Methodology. RW: Supervision, Writing – original draft, Project administration, Methodology, Validation. JZ: Investigation, Project administration, Formal Analysis, Data curation, Writing – original draft.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The author(s) declare that no Generative AI was used in the creation of this manuscript.

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