Oral versus intranasal probiotics for nasal microbiome modulation: a comparative review of route-dependent mechanisms and clinical implications.

Probiotic modulation of the nasal microbiome can be achieved through oral administration, which relies on the gut-nose axis and systemic immunomodulation, or direct intranasal instillation, which provides immediate local action. Despite growing evidence, no systematic comparison of these routes has been published. This narrative review synthesizes clinical and mechanistic evidence comparing oral versus intranasal probiotic strategies to inform route selection based on disease pathophysiology and strain-specific efficacy. We evaluated randomized controlled trials, systematic reviews, meta-analyses, and mechanistic studies investigating probiotic interventions delivered via either route for upper respiratory conditions including allergic rhinitis, chronic rhinosinusitis, and pediatric respiratory infections. Orally administered probiotics may exert nasal effects through two mechanisms: (i) systemic immunomodulation via gut-derived short-chain fatty acids and tryptophan metabolites, supported by clinical data for Weizmannia coagulans BC99 and by a randomized controlled trial in children with perennial allergic rhinitis for Bifidobacterium longum subsp. infantis CCFM111; and (ii) direct oropharyngeal-to-nasopharyngeal trafficking, exemplified by a slow-release chewable Lacticaseibacillus rhamnosus GG formulation that trafficked to the nasopharynx in 41% of users after 8 weeks, with a decrease in nasal IL-13 observed in both probiotic and placebo groups, and improved symptom control in the probiotic group. The B. longum and Lactobacillus plantarum combination NVP-1703 reduced type-2 cytokine ratios in children. Intranasal probiotics, including Bacillus spore sprays and Streptococcus salivarius 24SMB/S. oralis 89a, have shown pathogen displacement and clinical benefit in individual trials involving pediatric acute rhinosinusitis and otitis media, adenoid hypertrophy, and granulomatosis with polyangiitis-associated chronic rhinosinusitis, although within-group improvements in the latter were not consistently confirmed in between-group comparisons. However, a multi-strain Lactobacillus nasal spray failed in a crossover trial in seasonal allergic rhinitis, and a lactic acid bacterial spray of honeybee origin showed no benefit in chronic rhinosinusitis without nasal polyps, underscoring the importance of strain-disease matching. Route selection may tentatively be guided by disease pathophysiology: systemic type-2-driven conditions may favor oral immunomodulation, while acute localized dysbiosis may favor intranasal delivery. Priority research includes direct comparative trials, microbiome-based stratification, and sustained-release formulations. Until then, clinical decision-making must rely on mechanistic plausibility and strain-specific data.