Gut–Sinus Axis and the Role of the Microbiome in the Pathogenesis of Chronic Rhinosinusitis: A Literature Review

Abstract

Chronic rhinosinusitis (CRS) is a persistent inflammatory disorder of the nasal and paranasal mucosa, typically attributed to local infection or anatomical obstruction. However, recent evidence suggests that CRS may also reflect systemic inflammatory dysregulation influenced by the gut microbiome, establishing a potential ‘gut–sinus axis’. This systematic review aims to synthesise current evidence linking gut microbiome alterations to the pathogenesis and clinical course of CRS and to explore emerging therapeutic strategies targeting this axis. Five databases were comprehensively searched for studies published between January 2000 and October 2025. Data were extracted and evaluated for quality using the JBI and SYRCLE tools. A total of 441 records were retrieved, of which 20 studies met the inclusion criteria. Human studies consistently showed gut dysbiosis in CRS, characterised by reductions in Roseburia, Bifidobacterium, Faecalibacterium and Akkermansia species. These microbial shifts correlated with increased levels of systemic cytokines, such as interleukin-6, interleukin-17 and tumour necrosis factor-α, and disease severity. Animal and interventional studies confirmed that high-fibre diets and short-chain fatty acid (SCFA) supplementation modified airway inflammation, whereas antibiotic-induced dysbiosis exacerbated it. Current evidence substantiates a gut–sinus axis mediated by immune, metabolic and neuroendocrine pathways. Dysbiosis-driven reductions in SCFA-producing bacteria appear central to systemic pro-inflammatory signalling implicated in CRS.

1. Introduction

Chronic rhinosinusitis (CRS) is a chronic inflammatory disorder of the mucosal lining of the nasal cavity and paranasal sinuses (PNS), persisting for more than 12 weeks despite appropriate medical therapy. CRS affects approximately 5–12% of the global population, with prevalence varying according to geographic region, diagnostic criteria and study methodology [1]. The condition is characterised by mucosal oedema, impaired mucociliary clearance and sustained inflammation, which may occur with or without nasal polyp formation [2]. Although historically regarded as a localised disorder resulting from infection, inflammation or anatomical obstruction of mucous drainage pathways, CRS is increasingly recognised as a manifestation of broader systemic immune dysregulation. Its pathogenesis involves complex interactions among immune regulatory pathways, environmental exposures and microbial factors [3].

The multifactorial nature of CRS contributes to therapeutic challenges, often resulting in recurrent exacerbations and substantial impairment in quality of life. Despite its significant global burden, CRS remains incompletely understood. While the contribution of sinonasal microbial infections has long been established, emerging evidence suggests that the gut microbiome may also influence immune pathways within the sinonasal mucosa [4]. This concept parallels the bidirectional interactions described in the gut–lung and gut–skin axes, whereby intestinal microbial communities modulate distal mucosal immune responses [5]. Dysbiosis, defined as alterations in the composition or function of the resident microbiota, has been associated with systemic immune perturbations, although causality and directionality remain to be fully elucidated. The gut and upper airways share common mucosal immune mechanisms, including IgA production, cytokine signalling and mucosal-associated lymphoid tissue activity [6]. Consequently, gut microbial imbalance may contribute to sinonasal inflammatory disease through systemic immunomodulatory pathways.

The gut microbiota is predominantly composed of anaerobic bacterial genera, including Bacteroides, Clostridium, Bifidobacterium, Faecalibacterium and Roseburia [7]. These organisms ferment dietary fibre to produce short-chain fatty acids (SCFAs), principally acetate, propionate and butyrate. SCFAs enhance mucin production, preserve epithelial tight junction integrity and inhibit nuclear factor-κB (NF-κB)-mediated inflammatory signalling. Through activation of G-protein-coupled receptors (GPCRs), such as GPR41 and GPR43, circulating SCFAs exert immunomodulatory effects at distal mucosal sites, including the respiratory epithelium. A reduction in SCFA-producing taxa may therefore increase susceptibility to sinonasal inflammation [8,9]. Additional proposed mechanisms linking gut microbiota to CRS include modulation of regulatory T-cell (Treg) differentiation, production of anti-inflammatory mediators and neuroendocrine signalling pathways (Figure 1) [10].

Despite these emerging insights, most CRS research has focused primarily on the local sinonasal microbiome, particularly species of Staphylococcus and Corynebacterium [11]. The present review aims to synthesise current evidence regarding the role of the gut microbiota in CRS pathogenesis and to explore the potential clinical implications of microbiome-targeted therapeutic strategies.

2. Materials and Methods

This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was prospectively registered with the International Prospective Register for Systematic Reviews (PROSPERO; ID: 1160893).

The objective of this review was to synthesise translational evidence supporting the proposed gut–sinus axis. A comprehensive literature search was performed to identify relevant studies published between January 2000 and October 2025. Five electronic databases (PubMed, Scopus, Embase, Web of Science and ScienceDirect) were systematically searched for peer-reviewed articles available in English. The search strategy combined controlled vocabulary and free-text terms using Boolean operators (“AND”, “OR”). Key terms included (“gut microbiome” OR “gut microbiota” OR “gut flora” OR “intestinal microbiota”) AND (“chronic rhinosinusitis” OR “sinusitis” OR “sinonasal polyp” OR “paranasal sinus”).

All retrieved records were imported into Microsoft Excel for organisation, duplicate removal and screening. Two reviewers independently screened titles and abstracts, followed by full-text evaluation of potentially eligible studies. Eligible studies included human clinical investigations and experimental animal models designed as randomised controlled trials, cohort studies or case–control studies that examined gut microbiome composition and its mechanistic or clinical relevance to sinonasal inflammation or chronic rhinosinusitis (CRS). Studies focusing exclusively on the sinonasal microbiota or solely on gut microbiota without relevance to CRS, as well as review articles, were excluded. Disagreements between reviewers were resolved through discussion and consensus.

Given the broad translational scope of this review, both human and animal studies were intentionally included to capture clinical, theoretical and interventional evidence. Substantial methodological and clinical heterogeneity was anticipated a priori. Variability across species, study designs, CRS phenotypes, microbiome sampling methods, sequencing platforms, interventions and outcome measures precluded meaningful quantitative pooling of effect sizes. Therefore, a structured narrative synthesis was undertaken, with studies grouped according to design (human observational, interventional, animal experimental and Mendelian randomisation) and organised by key mechanistic themes.

Data extraction was performed independently by the authors using a standardised framework. Extracted variables included author information, geographic location, study period, design, sample size, CRS phenotype definition and classification tools (e.g., Sinonasal Outcome Test [SNOT]), microbiome analysis methodology, intervention details, outcome measures and principal statistical findings. Study quality was assessed using the Joanna Briggs Institute (JBI) critical appraisal tools for human studies and the SYRCLE risk-of-bias tool for animal studies.

Institutional ethical approval was not required, as all data were derived from previously published studies.

3. Results

A total of 424 records were identified across five electronic databases. Following duplicate removal and independent screening, 20 studies met the eligibility criteria and were included in the final analysis (Figure 2). These comprised nine human studies, three Mendelian randomisation or genetic analyses and eight experimental animal studies (

Table 1. Summary of key conclusions from the studies included in the review.

Citation	Study Design/Model	Population/Sample	Intervention/Exposure	Primary Findings
Mukerji SS et al., 2009 [12].	RCT, human	77 adults with CRS	Oral Lactobacillus rhamnosus R0011 vs. placebo, 4 weeks	No significant symptom difference; safe adjunct
Ried K et al., 2022 [13].	RCT, human	173 adults with seasonal allergic rhinitis	Multi-strain probiotic formulation (8 weeks)	Reduced sneezing and nasal congestion
De Boeck I et al., 2025 [14].	Double-blind RCT, human	92 patients	Oral Lactobacillus rhamnosus GG chewable vs. placebo	Reduced nasal inflammation, improved symptom scores
Endam LM et al., 2020 [15].	Observational, human	24 patients with refractory CRS	14-day course of sinus irrigations with Lactobacillus lactis-containing solution	Post-treatment increase in gut concentration of Dolosigranulum, improvement in sinus symptoms, Qol and mucosal scores
Michalik M et al., 2023 [16].	Observational, human	30 CRS patients	Faecal microbiome profiling	Reduced Akkermansia and Roseburia spp.
Liang Y et al., 2024 [17].	Observational, human	39 (eCRSwNP, non-eCRS, controls)	Faecal microbiome profiling (16S rRNA)	Reduced Faecalibacterium and SCFA-producers in eCRS
Bai W et al., 2024 [18].	Case–control, human	101 (68 CRS, 33 controls)	Gut microbiome sequencing	Lower Bifidobacterium, altered F/B ratio
Lambert PA et al., 2021 [19].	Cross-sectional, human	35 (25 CRS, 10 controls)	Xylitol or Lactococcus lactis nasal irrigation	Changes in sinonasal microbial composition and increased commensal taxa
Graspeuntner et al., 2025 [20].	Interventional human (open-label)	34 CRS patients	1,8-cineole administration and stool microbiome profiling	Modest shifts in gut microbiota composition post-treatment
Pu K et al., 2024 [21].	Mendelian randomisation (genetic)	Population-level genetic datasets	Genetic instruments for gut microbiota taxa vs. chronic sinusitis	Suggests causal links between certain gut taxa and sinusitis risk
Lu N et al., 2025 [22].	Mendelian randomisation/observational	Population genomics + clinical datasets	Gut microbiota associations with nasal polyps	Identifies taxa potentially associated with nasal polyp formation
Xun C et al., 2025 [23].	Mendelian randomisation/observational	Population genomics + clinical datasets	Circulating metabolites associated with CRSwNP	Identifies metabolites associated with nasal polyp formation
Russell SL et al., 2012 [24].	Experimental, mouse	Neonatal mice	Early-life antibiotics	Increased allergic airway disease later in life
Trompette A et al., 2014 [25].	Experimental, mouse	BALB/c mice	High-fibre diet/propionate supplement	Increased SCFAs → less airway inflammation (↓Th2)
Smith PM et al., 2013 [26].	Experimental, rat	Rodent model	Butyrate supplementation	Reverses systemic inflammation and endothelial injury
Macia L et al., 2015 [27].	Experimental, mouse	Wild-type and GPR43/GPR109A KO mice	SCFA supplementation	SCFA receptors mediate systemic anti-inflammatory effects
Cait A et al., 2018 [28].	Experimental, mouse	Antibiotic-treated and control mice	Antibiotic-induced dysbiosis ± SCFA	Dysbiosis worsens allergic airway inflammation; SCFA rescues
Sencio V et al., 2020 [29].	Experimental, mouse (influenza)	C57BL/6 mice	Influenza infection → gut dysbiosis	Reduced SCFAs impair lung antibacterial immunity
Lin L et al., 2025 [30].	Experimental, mouse	Antibiotic-treated mice	SCFA supplementation post-antibiotics	Restores Treg function and barrier immunity
Lai Y et al., 2025 [31].	Experimental, mouse	Ovalbumin induced asthmatic mice	Faecal microbiota transplantation (FMT)	Transfers heightened airway inflammation phenotype

CRS: chronic rhinosinusitis, CRSwNP: CRS with nasal polyposis, eCRS: eosinophilic CRS, eCRSwNP: eosinophilic CRS with nasal polyposis, Qol: quality of life, SCFA: short-chain fatty acids.

). Studies were organised hierarchically by design—randomised controlled trials, observational human studies, Mendelian randomisation analyses and experimental animal models—and presented chronologically within each category to facilitate structured interpretation [12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31].

Collectively, the included studies suggest that alterations in gut microbiome composition are associated with immune dysregulation in the sinonasal tract and may contribute to the pathogenesis of CRS. Human studies were conducted primarily in East Asia, Europe and North America, whereas animal investigations predominantly employed murine models. Considerable methodological heterogeneity was observed, including differences in sequencing approaches (16S rRNA versus shotgun metagenomics) and sampling strategies (stool specimens versus intestinal lavage). Despite these variations, converging evidence across study designs supports the biological possibility of a gut–sinus axis.

Across observational cohorts, patients with CRS consistently demonstrated features of gut dysbiosis compared with healthy controls. Recurrent findings included reduced abundance of short-chain fatty acid (SCFA)-producing genera such as Roseburia, Bifidobacterium and Faecalibacterium, alongside relative enrichment of potentially pro-inflammatory taxa including Clostridium and members of the Enterobacteriaceae family. Figure 3 summarises taxa repeatedly reported across studies and does not represent pooled quantitative estimates.

Reduced Faecalibacterium abundance was associated with eosinophilic CRS (eCRS) and correlated with radiological disease severity on computed tomography. Michalik et al. further reported decreased levels of Akkermansia and Roseburia in patients with CRS [16].

Four interventional studies evaluated microbiome-modulating strategies [12,13,14,15]. Mukerji et al. administered Lactobacillus rhamnosus R0011 for four weeks and observed short-term symptomatic improvement, although sustained benefit was not demonstrated at eight weeks [12]. Endam et al. reported that intranasal irrigation with Lactococcus lactis was associated with increased gut abundance of Dolosigranulum and improvement in sinonasal symptoms [15]. Similarly, Ried et al. and De Boeck et al. demonstrated reductions in inflammatory markers and symptomatic improvement following probiotic supplementation [13,14]. In contrast, Graspeuntner et al. observed only modest alterations in gut microbial composition following administration of 1,8-cineole [20].

Animal models primarily investigated the immunological consequences of dietary and microbiome manipulation on airway inflammation [24,25,26,27,28,29,30,31]. High-fibre diets and SCFA supplementation were consistently associated with attenuation of allergic airway inflammation. Studies demonstrated that SCFAs exert anti-inflammatory effects through G-protein-coupled receptors, particularly GPR43 and GPR109A [27]. Conversely, antibiotic-induced dysbiosis exacerbated inflammatory responses, which were partially reversed by SCFA administration [28].

Three Mendelian randomisation studies provided genetic evidence supporting a potential causal relationship between specific gut microbial taxa and CRS phenotypes [21,22,23]. Variations in taxa belonging to the Ruminococcaceae and Lachnospiraceae families were associated with increased susceptibility to CRSwNP (Figure 4). These findings strengthen the inference that gut microbiome composition may contribute to CRS pathophysiology rather than merely reflecting secondary changes.

4. Discussion

4.1. Overview of Principal Findings

This systematic review synthesising 20 eligible studies provides converging evidence supporting the existence of a gut–sinus axis in CRS. Across nine human studies, a recurrent pattern of gut microbial dysbiosis was observed in patients with CRS compared with healthy controls, characterised predominantly by depletion of short-chain fatty acid (SCFA)-producing genera, including Faecalibacterium, Roseburia, Akkermansia and Bifidobacterium [16,17,18,19]. Several studies further demonstrated associations between these microbial alterations and elevated systemic inflammatory cytokines, particularly interleukin (IL)-6 and IL-17 [16,17,18,19,25].

Experimental murine models consistently demonstrated that dietary fibre supplementation and SCFA administration attenuate allergic airway inflammation, whereas antibiotic-induced dysbiosis exacerbates inflammatory responses [24,25,26,27,28,29,30,31]. In addition, three Mendelian randomisation analyses suggested potential causal relationships between specific gut microbial taxa—particularly members of the Ruminococcaceae and Lachnospiraceae families—and susceptibility to CRSwNP [21,22,23]. Collectively, these findings indicate that systemic immune modulation driven by gut dysbiosis contributes to sinonasal inflammation.

4.2. Pathophysiological Mechanisms Supporting the Gut–Sinus Axis

The proposed gut–sinus axis appears to involve interconnected immune, metabolic and neuroimmune pathways.

4.2.1. Immune Crosstalk

Multiple human studies reported elevated circulating inflammatory mediators in patients with CRS exhibiting gut dysbiosis. Zhao et al. [32] identified positive correlations between altered gut microbial composition and increased serum IL-6 and IL-17 levels. These cytokines are central drivers of chronic mucosal inflammation and Th17-mediated immune responses [33].

The depletion of SCFA-producing bacteria across several cohorts is particularly relevant, as SCFAs promote regulatory T-cell (Treg) differentiation, maintain epithelial barrier integrity, and suppress pro-inflammatory signalling [9,10]. Reduced SCFA availability may therefore impair systemic immune tolerance and promote a pro-inflammatory Th1/Th17 milieu. This interpretation is supported by experimental study demonstrating that SCFA supplementation modulates immune responses through G-protein-coupled receptors (GPR43 and GPR109A), resulting in attenuation of airway inflammation [27]. These findings align with the taxonomic alterations observed in human CRS populations.

4.2.2. Metabolic and Barrier Effects

Gut dysbiosis may also enhance translocation of microbial-derived products, including lipopolysaccharide, into systemic circulation, thereby activating Toll-like receptor-mediated inflammatory pathways. Experimental models show that antibiotic-induced dysbiosis increases susceptibility to allergic airway inflammation, an effect partially reversed by SCFA supplementation [28,30]. These findings suggest that metabolic disruption secondary to microbiome imbalance contributes to systemic immune activation and mucosal inflammatory priming.

4.2.3. Neuroimmune Interactions

Emerging evidence implicates the microbiota–gut–brain axis in regulating systemic inflammatory tone. Microbial metabolites can influence vagal signalling and hypothalamic–pituitary–adrenal axis activity, thereby modulating cytokine production [34,35,36,37]. Although CRS-specific neuroimmune investigations remain limited, these pathways provide additional evidence for gut-mediated modulation of sinonasal inflammation.

4.3. Evidence Linking Gut Microbiome Alterations to CRS

While dysbiosis appears consistently associated with CRS, variability in the specific taxa involved is notable. Differences in dietary habits, geographic microbiome profiles, sequencing depth and CRS endotypes (e.g., CRSwNP versus CRSsNP) likely contribute to these discrepancies [38,39,40]. Long-term antimicrobial exposure, frequently encountered in CRS management, may further compound gut microbial imbalance and warrants systematic investigation.

Although direct CRS models incorporating targeted gut microbiome manipulation remain limited, studies in allergic rhinitis and asthma demonstrate that probiotic supplementation can downregulate Th2 cytokines and enhance epithelial barrier function in the upper airway [41,42]. These mechanisms are plausibly relevant to CRS.

Parallel investigations of the sinonasal microbiota consistently report reduced bacterial diversity and relative expansion of pathogenic species, particularly Staphylococcus aureus and Corynebacterium spp. [43,44]. The interaction between gut and sinonasal microbiota may therefore be bidirectional: gut dysbiosis may influence systemic immune responses that facilitate pathogenic sinonasal colonisation, while chronic sinonasal inflammation may alter systemic immune and hormonal environments that secondarily affect gut microbial composition.

4.4. Translational Limitations of Animal Models

Animal studies provide important insights but must be interpreted cautiously. Most experimental models assess allergic airway inflammation rather than established CRS phenotypes. Furthermore, murine microbiome composition, immune maturation, environmental exposures and dietary patterns differ substantially from those of humans.

Although high-fibre diets and SCFA supplementation consistently attenuate airway inflammation in animal models, their efficacy in chronic sinonasal inflammation requires validation in well-designed human clinical trials. Accordingly, animal findings should be considered hypothesis-generating rather than definitive evidence.

4.5. Clinical and Translational Implications

Current CRS management primarily targets local inflammation and mechanical obstruction through topical corticosteroids, saline irrigation and functional endoscopic sinus surgery [45]. These approaches may not address systemic immunological drivers.

Microbiome-directed therapies represent a potential paradigm shift toward restoration of immune homeostasis. Probiotic supplementation is a promising yet underexplored strategy. Preliminary studies report symptomatic improvement and reductions in inflammatory biomarkers following administration of Lactobacillus and Bifidobacterium species, although optimal strain selection, dosage and treatment duration remain undefined.

Synbiotics and postbiotics (microbial-derived metabolites) represent additional therapeutic avenues. Dietary interventions emphasising fibre-rich, plant-based nutrition may enhance SCFA production and microbial diversity, thereby indirectly supporting mucosal immune regulation.

Conversely, repeated or prolonged antibiotic exposure may exacerbate dysbiosis, impair immune tolerance and contribute to antimicrobial resistance. These considerations highlight the importance of microbiome preservation as an emerging principle in CRS management. Integration of nutritional and gastroenterological perspectives may provide synergistic benefits in long-term disease control.

4.6. Why Has the Gut Microbiome Been Underexplored in CRS?

CRS has traditionally been conceptualised as a localised sinonasal disorder driven by infection, biofilm formation or anatomical obstruction. This framework has prioritised investigation of the sinonasal microbiota over systemic microbial influences.

Comprehensive dual-site microbiome analysis requires advanced sequencing technologies, bioinformatics expertise and standardised sampling protocols, which may not be routinely available in otolaryngology-focused research environments. Additionally, dietary variation, antibiotic exposure and comorbidities introduce substantial confounding. The absence of standardised CRS phenotyping further complicates interpretation.

These methodological and conceptual barriers likely delayed integration of systemic microbiome perspectives into CRS research.

4.7. Limitations of Current Evidence and Future Directions

Most available studies are cross-sectional, limiting causal inference. Whether gut dysbiosis precedes CRS onset or arises secondary to chronic inflammation remains unclear. Longitudinal cohort studies are needed to clarify temporal relationships.

Heterogeneity in sampling methods, sequencing platforms and analytical pipelines further complicates interpretation. While 16S rRNA sequencing provides broad taxonomic profiling, metagenomic approaches offer greater resolution but vary in depth and reproducibility. Standardisation of sampling, DNA extraction, sequencing and bioinformatic processing is essential to enhance comparability.

Functional interpretation remains another major limitation. Taxonomic shifts alone do not fully capture microbial metabolic activity or host–microbe interactions. Integration of multi-omics approaches—including metagenomics, metabolomics and immunophenotyping—will be critical to identify key metabolites and immune pathways mediating gut–sinus communication.

Future investigations should incorporate parallel gut and sinonasal microbiome sampling before and after therapeutic interventions to establish mechanistic and temporal relationships. Randomised controlled trials evaluating microbiome-targeted strategies—including probiotics, synbiotics, dietary modification and faecal microbiota transplantation—are warranted.

A multidisciplinary framework integrating otolaryngology, gastroenterology, immunology and systems biology will be essential to advance understanding of the gut–sinus axis and identify predictive biomarkers of CRS severity, endotype and treatment response.

5. Conclusions

The current literature indicates that CRS is influenced not only by local chronic inflammation but also by dysbiosis of the gut microbiome. This bidirectional interaction, known as the gut–sinus axis, provides a compelling pathogenetic framework for understanding CRS. Our review summarises the key mechanisms via which this axis may operate, particularly immune crosstalk and microbial metabolite signalling. A reduction in SCFAs appears central, contributing to elevated systemic inflammatory mediators.

Therapeutic approaches aimed at restoring a healthy gut microbiome have shown encouraging results in CRS management. Nonetheless, the existing evidence leaves several important questions unanswered, including the specificity of microbiome alterations, the precise pathways of immune communication between the gut and the sinonasal mucosa and the true clinical value of microbiome-targeted treatments for CRS. Properly designed prospective cohort studies and controlled clinical trials are needed to advance our understanding of these intersecting pathophysiological pathways.