{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:55:39Z","timestamp":1790618139252,"version":"4.1.0"},"reference-count":122,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:00:00Z","timestamp":1781568000000},"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>Chronic rhinosinusitis (CRS) is a heterogeneous inflammatory disorder of the nasal and paranasal sinus mucosa affecting approximately 11% of adults worldwide. Although compositional dysbiosis of the sinonasal microbiome has historically dominated etiological discourse, this framework inadequately accounts for the mechanistic complexity of mucosal immune dysregulation in CRS. Emerging evidence positions microbial metabolites, rather than microbial identity per se, as the proximate immunological mediators of commensal microbiota\u2013host crosstalk. This review presents a comprehensive analysis of the \u201cmicrobial metabolite-immune receptor axis\u201d in CRS, encompassing three classes of protective commensal metabolites and their mechanisms of action. Short-chain fatty acids (SCFAs) activate GPR43 and inhibit histone deacetylases (HDACs) to induce FoxP3+ regulatory T cells (Tregs) and promote ILC3-derived IL-22 production. Tryptophan-derived indole metabolites engage the aryl hydrocarbon receptor (AhR) to sustain ILC3 barrier-protective function and suppress Th2\/Th17 polarization. Secondary bile acids signal through FXR and TGR5 to modulate the Treg\/Th17 balance. In contrast, virulence factors produced by Staphylococcus aureus (the dominant pathobiont in CRSwNP) drive NLRP3 inflammasome activation, macrophage pyroptosis, and epithelial tight junction disruption. The gut\u2013nose metabolite axis further establishes that systemic depletion of gut-derived protective metabolites amplifies nasal mucosal immune dysfunction. Building upon this mechanistic framework, we propose postbiotic supplementation, defined as the direct administration of purified bioactive metabolites, as a precision therapeutic strategy to restore nasal mucosal immune homeostasis. Endotype-specific metabolite candidate selection, guided by individual patient metabolomics profiling, is central to this therapeutic approach.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1831258","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T04:26:55Z","timestamp":1781584015000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Beyond dysbiosis: microbial metabolites as key remodelers of nasal mucosal immune tolerance in chronic rhinosinusitis"],"prefix":"10.3389","volume":"17","author":[{"given":"Guan-Jiang","family":"Huang","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":"Zi-Qing","family":"Chen","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"}]},{"given":"Chao-Qing","family":"Long","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"}]},{"given":"Qi-Ping","family":"Luo","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"}]},{"given":"Zhi-Jun","family":"Fan","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"}]},{"given":"Biao-Qing","family":"Lu","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":[[2026,6,16]]},"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\/fimmu.2026.1776180","article-title":"Real-world sinonasal outcomes in patients with primary diffuse chronic rhinosinusitis treated with mepolizumab across polyp phenotypes","volume":"17","author":"Kumar","year":"2026","journal-title":"Front Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2025.09.023","article-title":"Effects of type 3 and neutrophilic inflammation on type 2 chronic rhinosinusitis with nasal polyps","volume":"157","author":"Oka","year":"2026","journal-title":"J Allergy Clin Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/falgy.2025.1680703","article-title":"Real-life evaluation of the effectiveness of biologics for chronic rhinosinusitis with nasal polyps in Europe: a Delphi study to define key variables for the INVENT registry","volume":"6","author":"Backer","year":"2025","journal-title":"Front Allergy"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/j.1398-9995.2011.02646.x","article-title":"Chronic rhinosinusitis in Europe--an underestimated disease. 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