{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T11:24:58Z","timestamp":1788175498046,"version":"build-2803163510"},"reference-count":104,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:00:00Z","timestamp":1783382400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    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\n                    <jats:italic>Acinetobacter johnsonii<\/jats:italic>\n                    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-\u03baB)-related pathways. Third,\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    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-4R\u03b1) 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.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1841979","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T05:45:18Z","timestamp":1783403118000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["The microbiota-metabolite-immune axis in the olfactory cleft microenvironment: mechanisms and therapeutic implications for dysbiosis-driven olfactory dysfunction in chronic rhinosinusitis"],"prefix":"10.3389","volume":"17","author":[{"given":"Jin-Xiang","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology Head and Neck Surgery, Zhongshan Hospital of Traditional Chinese Medicine, Affiliated to Guangzhou University of Chinese Medicine","place":["Zhongshan, Guangdong, China"]},{"name":"The Tenth Clinical Medical College of Guangzhou University of Chinese Medicine","place":["Zhongshan, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guan-Jiang","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology Head and Neck Surgery, Zhongshan Hospital of Traditional Chinese Medicine, Affiliated to Guangzhou University of Chinese Medicine","place":["Zhongshan, Guangdong, China"]},{"name":"The Tenth Clinical Medical College of Guangzhou University of Chinese Medicine","place":["Zhongshan, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4193\/Rhin20.600","article-title":"European position paper on rhinosinusitis and nasal polyps 2020","volume":"58","author":"Fokkens","year":"2020","journal-title":"Rhinology"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fncir.2024.1406218","article-title":"Structures and functions of the normal and injured human olfactory epithelium","volume":"18","author":"Kikuta","year":"2024","journal-title":"Front Neural Circuits"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(91)90418-x","article-title":"A novel multigene family may encode odorant receptors: a molecular basis for odor recognition","volume":"65","author":"Buck","year":"1991","journal-title":"Cell"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4193\/Rhin22.483","article-title":"Position paper on olfactory dysfunction: 2023","volume":"61","author":"Whitcroft","year":"2023","journal-title":"Rhinology"},{"key":"B5","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1038\/s41572-020-00218-1","article-title":"Adult chronic rhinosinusitis","volume":"6","author":"Bachert","year":"2020","journal-title":"Nat Rev Dis Primers"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1159112","article-title":"Disturbed microbiota-metabolites-immune interaction network is associated with olfactory dysfunction in patients with chronic rhinosinusitis","volume":"14","author":"Han","year":"2023","journal-title":"Front Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1002\/alr.22770","article-title":"Olfactory cleft mucus inflammatory proteins in CRS: a case-control study","volume":"11","author":"Smith","year":"2021","journal-title":"Int Forum Allergy Rhinol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1111\/all.13559","article-title":"Type 2\/Th2-driven inflammation impairs olfactory sensory neurogenesis in mouse chronic rhinosinusitis model","volume":"74","author":"Rouyar","year":"2019","journal-title":"Allergy"},{"key":"B9","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1111\/coa.13639","article-title":"Olfactory changes after endoscopic sinus surgery for chronic rhinosinusitis: a meta-analysis","volume":"46","author":"Zhao","year":"2021","journal-title":"Clin Otolaryngol Off J Ent-Uk ; Off J Netherlands Soc For Oto-Rhino-Laryngology Cervico-Facial Surg"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1007\/s00405-022-07496-3","article-title":"Presurgical olfactory function as an indicator of the outcome of functional endoscopic sinus surgery in chronic rhinosinusitis with nasal polyps","volume":"279","author":"Hintschich","year":"2022","journal-title":"Eur Arch Oto-Rhino-Laryngology Off J Eur Fed Oto-Rhino-Laryngological Societies (Eufos) Affiliated German Soc For Oto-Rhino-Laryngology - Head Neck Surg"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fsurg.2022.870682","article-title":"Improvement of subjective olfactory dysfunction in chronic rhinosinusitis with nasal polyps after endoscopic sinus surgery","volume":"9","author":"Ye","year":"2022","journal-title":"Front Surg"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1007\/s11882-023-01115-9","article-title":"Effects of endoscopic sinus surgery on olfactory function","volume":"23","author":"Ramirez-Gil","year":"2023","journal-title":"Curr Allergy Asthma Rep"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1296","DOI":"10.1038\/s41598-018-19438-3","article-title":"The nasal microbiome mirrors and potentially shapes olfactory function","volume":"8","author":"Koskinen","year":"2018","journal-title":"Sci Rep"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.01549-23","article-title":"Reduced olfactory performance is associated with changed microbial diversity, oralization, and accumulation of dead biomaterial in the nasal olfactory area","volume":"12","author":"Kumpitsch","year":"2024","journal-title":"Microbiol Spectr"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1267194","article-title":"Recent advances in mass spectrometry-based proteomics and metabolomics in chronic rhinosinusitis with nasal polyps","volume":"14","author":"Guo","year":"2023","journal-title":"Front Immunol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1111\/cea.12666","article-title":"A comprehensive review of the nasal microbiome in chronic rhinosinusitis (CRS)","volume":"46","author":"Mahdavinia","year":"2016","journal-title":"Clin Exp Allergy J Br Soc For Allergy Clin Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2015.02.008","article-title":"Sinus microbiota varies among chronic rhinosinusitis phenotypes and predicts surgical outcome","volume":"136","author":"Ramakrishnan","year":"2015","journal-title":"J Allergy Clin Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1007\/s12016-023-08976-y","article-title":"Diverse endotypes of chronic rhinosinusitis and clinical implications","volume":"65","author":"Xie","year":"2023","journal-title":"Clin Rev Allergy Immunol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.mib.2017.10.023","article-title":"Bacterial microbiota of the nasal passages across the span of human life","volume":"41","author":"Bomar","year":"2018","journal-title":"Curr Opin Microbiol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-020-0587-9","article-title":"Single-cell analysis of olfactory neurogenesis and differentiation in adult humans","volume":"23","author":"Durante","year":"2020","journal-title":"Nat Neurosci"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2014.00182","article-title":"A lifetime of neurogenesis in the olfactory system","volume":"8","author":"Brann","year":"2014","journal-title":"Front Neurosci"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1242\/dev.201552","article-title":"Horizontal basal cells self-govern their neurogenic potential during injury-induced regeneration of the olfactory epithelium","volume":"150","author":"Louie","year":"2023","journal-title":"Dev (Cambridge England)"},{"key":"B23","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1002\/ar.10047","article-title":"Neural regeneration and the peripheral olfactory system","volume":"269","author":"Schwob","year":"2002","journal-title":"Anat Rec"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2023.06.029","article-title":"Middle meatus microbiome in patients with eosinophilic chronic rhinosinusitis in a Japanese population","volume":"152","author":"Kidoguchi","year":"2023","journal-title":"J Allergy Clin Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.2147\/JIR.S443420","article-title":"Remodeling of paranasal sinuses mucosa functions in response to biofilm-induced inflammation","volume":"17","author":"Kaliniak","year":"2024","journal-title":"J Inflammation Res"},{"key":"B26","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1007\/s11882-017-0726-x","article-title":"Therapy of sinonasal microbiome in CRS: a critical approach","volume":"17","author":"Psaltis","year":"2017","journal-title":"Curr Allergy Asthma Rep"},{"key":"B27","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1038\/s41398-025-03346-y","article-title":"Nasal microbiome in relation to olfactory dysfunction and cognitive decline in older adults","volume":"15","author":"Song","year":"2025","journal-title":"Transl Psychiatry"},{"key":"B28","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1038\/s41531-021-00254-y","article-title":"Deep nasal sinus cavity microbiota dysbiosis in Parkinson's disease","volume":"7","author":"Pal","year":"2021","journal-title":"NPJ Parkinson's Dis"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.11.018","article-title":"Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease","volume":"167","author":"Sampson","year":"2016","journal-title":"Cell"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.0c00172","article-title":"SARS-CoV-2: olfaction, brain infection, and the urgent need for clinical samples allowing earlier virus detection","volume":"11","author":"Butowt","year":"2020","journal-title":"ACS Chem Neurosci"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3390\/ijms222011207","article-title":"Chronic rhinosinusitis and Alzheimer's disease-a possible role for the nasal microbiome in causing neurodegeneration in the elderly","volume":"22","author":"Harrass","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens14010014","article-title":"Changes in the microbiome during chronic rhinosinusitis","volume":"14","author":"de Mezer","year":"2024","journal-title":"Pathog (Basel Switzerland)"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/alr.22391","article-title":"Olfactory cleft mucus proteins associated with olfactory dysfunction in a cohort without chronic rhinosinusitis","volume":"9","author":"Yoo","year":"2019","journal-title":"Int Forum Allergy Rhinol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2019.00112","article-title":"Purinergic signaling in the vertebrate olfactory system","volume":"13","author":"Rotermund","year":"2019","journal-title":"Front Cell Neurosci"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1512093","article-title":"Hyperuricemia-induced complications: dysfunctional macrophages serve as a potential bridge","volume":"16","author":"Gu","year":"2025","journal-title":"Front Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1172\/JCI28075","article-title":"MyD88-dependent IL-1 receptor signaling is essential for gouty inflammation stimulated by monosodium urate crystals","volume":"116","author":"Chen","year":"2006","journal-title":"J Clin Invest"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1171138","article-title":"Editorial: NLRP3 activation and regulation in innate immune responses","volume":"14","author":"Mortellaro","year":"2023","journal-title":"Front Immunol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-022516-034339","article-title":"Macrophage polarization","volume":"79","author":"Murray","year":"2017","journal-title":"Annu Rev Physiol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/nature04516","article-title":"Gout-associated uric acid crystals activate the NALP3 inflammasome","volume":"440","author":"Martinon","year":"2006","journal-title":"Nature"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1002\/alr.21226","article-title":"Interferon gamma causes olfactory dysfunction without concomitant neuroepithelial damage","volume":"3","author":"Pozharskaya","year":"2013","journal-title":"Int Forum Allergy Rhinol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1002\/alr.21855","article-title":"Role of the type I tumor necrosis factor receptor in inflammation-associated olfactory dysfunction","volume":"7","author":"Sousa Garcia","year":"2017","journal-title":"Int Forum Allergy Rhinol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1002\/alr.23202","article-title":"Olfactory cleft mucus eosinophil-derived neurotoxin better reflects olfactory loss than blood eosinophil counts in patients with chronic rhinosinusitis","volume":"13","author":"Wu","year":"2023","journal-title":"Int Forum Allergy Rhinol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00873.2024","article-title":"Abnormal purine metabolism in nasal epithelial cells affects allergic rhinitis by regulating Th17\/Treg cells","volume":"328","author":"Xu","year":"2025","journal-title":"Am J Physiol Cell Physiol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22062973","article-title":"Tryptophan metabolism and gut-brain homeostasis","volume":"22","author":"Roth","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B45","doi-asserted-by":"publisher","first-page":"3294","DOI":"10.1038\/s41467-018-05470-4","article-title":"Microbial tryptophan catabolites in health and disease","volume":"9","author":"Roager","year":"2018","journal-title":"Nat Commun"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21051579","article-title":"Anti-inflammatory and anti-oxidative activity of indole-3-acetic acid involves induction of HO-1 and neutralization of free radicals in RAW264.7 cells","volume":"21","author":"Ji","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202500295R","article-title":"Multifaceted role of microbiota-derived indole-3-acetic acid in human diseases and its potential clinical application","volume":"39","author":"Shaheen","year":"2025","journal-title":"FASEB J Off Publ Fed Am Societies For Exp Biol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.08.003","article-title":"Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22","volume":"39","author":"Zelante","year":"2013","journal-title":"Immunity"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2018.05.003","article-title":"Gut microbiota regulation of tryptophan metabolism in health and disease","volume":"23","author":"Agus","year":"2018","journal-title":"Cell Host Microbe"},{"key":"B50","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1007\/s11882-025-01231-8","article-title":"Microbial metabolites in allergic diseases: beyond short-chain fatty acids","volume":"25","author":"Morillas-Armenta","year":"2025","journal-title":"Curr Allergy Asthma Rep"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.3390\/biology10030205","article-title":"Butyrate alleviates cytokine-induced barrier dysfunction by modifying claudin-2 levels","volume":"10","author":"Huang","year":"2021","journal-title":"Biology"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1098\/rsob.230014","article-title":"Short chain fatty acids: key regulators of the local and systemic immune response in inflammatory diseases and infections","volume":"13","author":"Ney","year":"2023","journal-title":"Open Biol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacig.2023.100163","article-title":"Short-chain fatty acids ameliorate allergic airway inflammation via sequential induction of PMN-MDSCs and Treg cells","volume":"2","author":"Huang","year":"2023","journal-title":"J Allergy Clin Immunol Global"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01853","article-title":"Bile acids activated receptors regulate innate immunity","volume":"9","author":"Fiorucci","year":"2018","journal-title":"Front Immunol"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-022-00839-x","article-title":"The role of Staphylococcus aureus enterotoxin B in chronic rhinosinusitis with nasal polyposis","volume":"20","author":"Chegini","year":"2022","journal-title":"Cell Communication Signaling Ccs"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1111\/all.13875","article-title":"EUFOREA consensus on biologics for CRSwNP with or without asthma","volume":"74","author":"Fokkens","year":"2019","journal-title":"Allergy"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2019.12.915","article-title":"Superantigen-related T(H)2 CD4(+) T cells in nonasthmatic chronic rhinosinusitis with nasal polyps","volume":"145","author":"Rha","year":"2020","journal-title":"J Allergy Clin Immunol"},{"key":"B58","doi-asserted-by":"publisher","first-page":"26138","DOI":"10.1038\/s41598-024-77459-7","article-title":"Analysis of olfactory function in patients with chronic rhinosinusitis and Staphylococcus aureus enterotoxin positivity","volume":"14","author":"Kim","year":"2024","journal-title":"Sci Rep"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1097\/ACI.0b013e3282f4178f","article-title":"Role of staphylococcal superantigens in upper airway disease","volume":"8","author":"Bachert","year":"2008","journal-title":"Curr Opin Allergy Clin Immunol"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/1144563","article-title":"Role and function of regulatory T cell in chronic rhinosinusitis with nasal polyposis","volume":"2022","author":"Lei","year":"2022","journal-title":"J Immunol Res"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1111\/all.16338","article-title":"The IL-4-IL-4R\u03b1 axis modulates olfactory neuroimmune signaling to induce loss of smell","volume":"80","author":"Hara","year":"2025","journal-title":"Allergy"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1002\/alr.23073","article-title":"Chronic interleukin-13 expression in mouse olfactory mucosa results in regional aneuronal epithelium","volume":"13","author":"Saraswathula","year":"2023","journal-title":"Int Forum Allergy Rhinol"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2468-19.2020","article-title":"Increased retinoic acid catabolism in olfactory sensory neurons activates dormant tissue-specific stem cells and accelerates age-related metaplasia","volume":"40","author":"H Glin","year":"2020","journal-title":"J Neurosci Off J Soc For Neurosci"},{"key":"B64","doi-asserted-by":"publisher","first-page":"1036","DOI":"10.1038\/s41467-025-67786-2","article-title":"IL-17a induces age-related olfactory dysfunction by impairing regeneration and promoting respiratory metaplasia in mice","volume":"17","author":"Wang","year":"2025","journal-title":"Nat Commun"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1016\/j.anai.2020.08.001","article-title":"Group 2 innate lymphoid cells in nasal polyposis","volume":"126","author":"Stevens","year":"2021","journal-title":"Ann Allergy Asthma Immunol Off Publ Am Coll Allergy Asthma Immunol"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1111\/all.12440","article-title":"Association between group 2 innate lymphoid cells enrichment, nasal polyps and allergy in chronic rhinosinusitis","volume":"69","author":"Miljkovic","year":"2014","journal-title":"Allergy"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23148032","article-title":"Different roles of dendritic cells for chronic rhinosinusitis treatment according to phenotype","volume":"23","author":"Tai","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2021.03.024","article-title":"Rethinking neutrophils and eosinophils in chronic rhinosinusitis","volume":"148","author":"Delemarre","year":"2021","journal-title":"J Allergy Clin Immunol"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.2500\/ajra.2009.23.3413","article-title":"Characterization of bacterial and fungal biofilms in chronic rhinosinusitis","volume":"23","author":"Foreman","year":"2009","journal-title":"Am J Rhinol Allergy"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1111\/j.1398-9995.2011.02678.x","article-title":"Adaptive immune responses in Staphylococcus aureus biofilm-associated chronic rhinosinusitis","volume":"66","author":"Foreman","year":"2011","journal-title":"Allergy"},{"key":"B71","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1186\/s12964-023-01347-2","article-title":"The destruction of mucosal barriers, epithelial remodeling, and impaired mucociliary clearance: possible pathogenic mechanisms of Pseudomonas aeruginosa and Staphylococcus aureus in chronic rhinosinusitis","volume":"21","author":"Chegini","year":"2023","journal-title":"Cell Communication Signaling Ccs"},{"key":"B72","doi-asserted-by":"publisher","first-page":"E8","DOI":"10.1002\/lary.26949","article-title":"Staphylococcus aureus V8 protease disrupts the integrity of the airway epithelial barrier and impairs IL-6 production in vitro","volume":"128","author":"Murphy","year":"2018","journal-title":"Laryngoscope"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1002\/alr.22566","article-title":"Staphylococcus aureus biofilm exoproteins are cytotoxic to human nasal epithelial barrier in chronic rhinosinusitis","volume":"10","author":"Panchatcharam","year":"2020","journal-title":"Int Forum Allergy Rhinol"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2012.05.052","article-title":"Defective epithelial barrier in chronic rhinosinusitis: the regulation of tight junctions by IFN-\u03b3 and IL-4","volume":"130","author":"Soyka","year":"2012","journal-title":"J Allergy Clin Immunol"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1356298","article-title":"The interleukin-4\/interleukin-13 pathway in type 2 inflammation in chronic rhinosinusitis with nasal polyps","volume":"15","author":"Bachert","year":"2024","journal-title":"Front Immunol"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1002\/lary.27112","article-title":"Olfactory and middle meatal cytokine levels correlate with olfactory function in chronic rhinosinusitis","volume":"128","author":"Wu","year":"2018","journal-title":"Laryngoscope"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2021.01.021","article-title":"Endotyping chronic rhinosinusitis based on olfactory cleft mucus biomarkers","volume":"147","author":"Soler","year":"2021","journal-title":"J Allergy Clin Immunol"},{"key":"B78","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1002\/lio2.524","article-title":"Microbiomics of irrigation with xylitol or Lactococcus lactis in chronic rhinosinusitis","volume":"6","author":"Lambert","year":"2021","journal-title":"Laryngoscope Investig Otolaryngol"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjoto.2017.03.006","article-title":"Xylitol nasal irrigation in the treatment of chronic rhinosinusitis","volume":"38","author":"Lin","year":"2017","journal-title":"Am J Otolaryngol"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1002\/lary.22176","article-title":"Xylitol nasal irrigation in the management of chronic rhinosinusitis: a pilot study","volume":"121","author":"Weissman","year":"2011","journal-title":"Laryngoscope"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.840323","article-title":"Topical antibiofilm agents with potential utility in the treatment of chronic rhinosinusitis: a narrative review","volume":"13","author":"Hale","year":"2022","journal-title":"Front Pharmacol"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1111\/all.13685","article-title":"Dupilumab reduces local type 2 pro-inflammatory biomarkers in chronic rhinosinusitis with nasal polyposis","volume":"74","author":"Jonstam","year":"2019","journal-title":"Allergy"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines12061377","article-title":"Efficacy and safety of xylitol nasal irrigation after functional endoscopic sinus surgery: a randomized controlled study","volume":"12","author":"Jiang","year":"2024","journal-title":"Biomedicines"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1111\/coa.70057","article-title":"Role of xylitol nasal irrigation in the management of chronic sinusitis: a systematic review and meta-analysis","volume":"51","author":"Kang","year":"2026","journal-title":"Clin Otolaryngol Off J Ent-Uk ; Off J Netherlands Soc For Oto-Rhino-Laryngology Cervico-Facial Surg"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2023.05.011","article-title":"Gut bacterial metabolism contributes to host global purine homeostasis","volume":"31","author":"Kasahara","year":"2023","journal-title":"Cell Host Microbe"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1517\/14740338.2014.872627","article-title":"A systematic review of the safety of probiotics","volume":"13","author":"Didari","year":"2014","journal-title":"Expert Opin Drug Saf"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2021.09.037","article-title":"Olfactory outcomes with dupilumab in chronic rhinosinusitis with nasal polyps","volume":"10","author":"Mullol","year":"2022","journal-title":"J Allergy Clin Immunol In Pract"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)31881-1","article-title":"Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials","volume":"394","author":"Bachert","year":"2019","journal-title":"Lancet (London England)"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1080\/03007995.2024.2434083","article-title":"Dupilumab improves sense of smell and clinical outcomes in patients with severe chronic rhinosinusitis with nasal polyps with anosmia","volume":"41","author":"Lane","year":"2025","journal-title":"Curr Med Res Opin"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.3389\/falgy.2024.1519069","article-title":"Olfactory impairment in Italian patients with chronic rhinosinusitis with nasal polyps: a patient-centered survey","volume":"5","author":"Anastasi","year":"2025","journal-title":"Front Allergy"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(21)00097-7","article-title":"Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): a randomised, double-blind, placebo-controlled, phase 3 trial","volume":"9","author":"Han","year":"2021","journal-title":"Lancet Respir Med"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2021.08.030","article-title":"Efficacy and safety of benralizumab in chronic rhinosinusitis with nasal polyps: a randomized, placebo-controlled trial","volume":"149","author":"Bachert","year":"2022","journal-title":"J Allergy Clin Immunol"},{"key":"B93","doi-asserted-by":"publisher","first-page":"36","DOI":"10.5604\/01.3001.0053.8709","article-title":"Microbiota and antibiotic therapy in rhinosinusitis","volume":"77","author":"Zawadzka-G","year":"2023","journal-title":"Otolaryngologia Polska = Polish Otolaryngol"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1177\/19458924231183848","article-title":"The effect of corticosteroids on sinus microbiota in chronic rhinosinusitis patients with nasal polyposis","volume":"37","author":"Alammar","year":"2023","journal-title":"Am J Rhinol Allergy"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1002\/alr.22743","article-title":"Olfactory cleft mucus proteome in chronic rhinosinusitis: a case-control pilot study","volume":"11","author":"Soler","year":"2021","journal-title":"Int Forum Allergy Rhinol"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1002\/alr.23503","article-title":"Type 2 biomarkers in olfactory cleft mucus correlate with SNOT-22 in chronic rhinosinusitis independent of nasal polyp status","volume":"15","author":"Chapurin","year":"2025","journal-title":"Int Forum Allergy Rhinol"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1002\/lary.20101","article-title":"Effects of olfactory training in patients with olfactory loss","volume":"119","author":"Hummel","year":"2009","journal-title":"Laryngoscope"},{"key":"B98","doi-asserted-by":"publisher","first-page":"bjaf23","DOI":"10.1093\/chemse\/bjaf023","article-title":"The impact of olfactory loss on quality of life: a 2025 review","volume":"50","author":"Oleszkiewicz","year":"2025","journal-title":"Chem Senses"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.2500\/ajra.2016.30.4290","article-title":"Depression in chronic rhinosinusitis: a controlled cohort study","volume":"30","author":"Schlosser","year":"2016","journal-title":"Am J Rhinol Allergy"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2021.799897","article-title":"Associations between cognitive function, depression, and olfactory function in elderly people with dementia in Korea","volume":"13","author":"Cha","year":"2022","journal-title":"Front Aging Neurosci"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12717","article-title":"Rapid olfactory decline during aging predicts dementia and GMV loss in AD brain regions","volume":"19","author":"Pacyna","year":"2023","journal-title":"Alzheimer's Dementia J Alzheimer's Assoc"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2015.12.1324","article-title":"Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers","volume":"137","author":"Tomassen","year":"2016","journal-title":"J Allergy Clin Immunol"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1111\/all.15074","article-title":"Endotypes of chronic rhinosinusitis: Relationships to disease phenotypes, pathogenesis, clinical findings, and treatment approaches","volume":"77","author":"Kato","year":"2022","journal-title":"Allergy"},{"key":"B104","doi-asserted-by":"publisher","first-page":"422","DOI":"10.3390\/microorganisms11020422","article-title":"Associations of microbial diversity with age and other clinical variables among pediatric chronic rhinosinusitis (CRS) patients","volume":"11","author":"Lim","year":"2023","journal-title":"Microorganisms"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1841979\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T05:45:20Z","timestamp":1783403120000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1841979\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,7]]},"references-count":104,"alternative-id":["10.3389\/fimmu.2026.1841979"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1841979","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,7]]},"article-number":"1841979"}}