Feed

Chronic rhinosinusitis is the leading cause of olfactory dysfunction in adults. Although mechanical obstruction and type 2 inflammation remain important explanations for smell loss in chronic rhinosinusitis, emerging multi-omics studies suggest that disruption of the olfactory cleft microenvironment may also contribute to olfactory dysfunction. In this review, we propose the microbiota-metabolite-immune (MMI) axis as an integrative framework linking microbial dysbiosis, metabolite perturbation, and local immune remodeling in CRS-associated olfactory dysfunction. We systematically examine four interconnected domains. First, several studies have reported dysbiosis within the olfactory niche, including enrichment of Acinetobacter johnsonii in one CRS-OD cohort together with depletion of putative commensals. Second, altered metabolite profiles in CRS-OD have been associated with disturbed purine metabolism, uric acid accumulation, and reduced levels of the potentially protective metabolite indole-3-acetic acid. These changes may contribute to innate inflammatory signaling, including Toll-like receptor 4/nuclear factor kappa-light-chain-enhancer of activated B cells (TLR4/NF-κB)-related pathways. Third, Staphylococcus aureus superantigens may promote T helper 2 (Th2) polarization, alter regulatory T-cell function, disrupt tight junction integrity, and impair olfactory neurogenesis, thereby sustaining bidirectional immune-microbial crosstalk. Fourth, emerging microbiota-targeted therapeutics, including xylitol irrigation, probiotics, and Interleukin-4 receptor alpha (IL-4Rα) blockade, offer novel intervention strategies. Throughout this review, we distinguish olfactory cleft-specific evidence from broader sinonasal data and acknowledge the current predominance of association studies over causal validation. Taken together, the MMI axis provides a useful framework for understanding CRS-associated OD and for identifying testable therapeutic hypotheses.