Nasal short-chain fatty acid alterations are associated with chronic rhinosinusitis progression and CD4+ T cell differentiation

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Background/objectives Chronic rhinosinusitis (CRS) is a heterogeneous inflammatory disease in which distinct T-cell polarization patterns are closely linked to disease phenotype and therapeutic response. Short-chain fatty acids (SCFAs) are important immunomodulatory metabolites, yet their role in CRS remains poorly understood. This study investigated the associations between nasal SCFAs, CD4 + T-cell subsets, and disease severity in CRS, aiming to provide new insights into the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). Methods Sinonasal polyp or mucosal tissues were collected from the ethmoid sinuses of CRS patients, and from the ethmoid sinuses and middle turbinates of non-CRS controls during endoscopic sinus surgery. Nasal swabs were obtained from the middle meatus for SCFAs analysis. Th1 (CD3 + CD4 + CXCR3 + ), Th2 (CD3 + CD4 + CCR4 + ), and Th17 (CD3 + CD4 + CCR6 + ) cells were quantified in tissue sections by manual counting under 400 × magnification following immunohistochemistry. Disease severity was assessed using Lund–Mackay (LM) and Lund–Kennedy (LK) scores. Results Th1 cell numbers were significantly increased in CRS without nasal polyps (CRSsNP), whereas Th2 and Th17 cells were markedly elevated in CRSwNP. Among SCFAs, acetic acid and butyric acid levels were significantly increased, while hexanoic acid levels were reduced in CRS patients. Acetic acid levels positively correlated with Th1 cells in CRSsNP, Th2 cells in CRSwNP, and Th17 cells in both CRS phenotypes. Butyric acid showed a positive correlation with Th2 cells in CRSwNP, whereas hexanoic acid was negatively correlated with Th2 cells. CRS severity correlated positively with Th2 and Th17 cells in CRSwNP, but with Th1 cells in CRSsNP. Conclusion Nasal SCFAs are closely associated with CD4 + T-cell differentiation and may correlate with the establishment of distinct inflammatory endotypes in CRS, suggesting their potential involvement in disease pathogenesis.