The bitter taste receptor T2R38 is an independent risk factor for chronic rhinosinusitis requiring sinus surgery

Abstract

Background The bitter taste receptor T2R38 was recently described to play a role in upper airway innate mucosal defense. When activated by bacterial quorum-sensing molecules, T2R38 stimulates the ciliated epithelial cells to produce nitric oxide (NO), resulting in bactericidal activity and an increase in mucociliary clearance (MCC). Polymorphisms within the T2R38 gene (TAS2R38) confer variability in activation of the receptor yielding dramatic differences in upper airway defensive responses (NO production and accelerated MCC) to microbial stimulation based on genotype. Our objective was to determine whether the non protective TAS2R38 polymorphisms, which render the receptor inactive, correlate with medically recalcitrant chronic rhinosinusitis (CRS) necessitating surgical intervention in the context of known risk factors, and thus identify whether the TAS2R38 genotype is an independent risk factor for patients undergoing functional endoscopic sinus surgery (FESS). Methods CRS patients undergoing primary FESS were prospectively genotyped for TAS2R38. Chi-square analysis was performed on the genotype distribution with respect to other risk factors, including allergies, asthma, nasal polyposis, aspirin sensitivity, diabetes, and smoking exposure. Results Seventy primary FESS patients were genotyped demonstrating a statistically significant skewing from the expected distribution of the general population (p < 0.0383). CRS patients with a particular polymorphism seemed less likely to have allergies, asthma, nasal polyposis, aspirin sensitivity, and diabetes, but this did not demonstrate statistical significance. Conclusion Our investigation suggests that TAS2R38 genotype is an independent risk factor for patients failing medical therapy, necessitating surgical intervention.

International Consensus Statement on Allergy and Rhinology: Rhinosinusitis

“…613,618 TNF and IL1A are important proinflammatory cytokines, and AAOH inactivates lipopolysaccharides. 625 This suggests that dysregulated inflammatory responses may play 626 Gene variations in the TAS2R38 taste receptor 353,354 are associated with gram-negative bacterial carriage and poor response to surgery.…”

“…CRS patients with a nonfunctional mutation in the T2R38 gene are at a higher risk for needing surgical intervention for their disease. 353 Bitter-taste testing for the presence of T2R38 could potentially predict CRS severity or necessary treatment, 354 and bitter compounds themselves could serve as therapeutic agents that activate the host immune response against biofilm formation in CRS. The potential pathogenic role for fungus as a trigger of CRS first emerged in 1983 following a report by Katzenstein et al 356 A key observation of this study was the presence of noninvasive Aspergillus species within eosinophilic mucin recovered from patients with CRS.…”

Nitric Oxide Production is Stimulated by Bitter Taste Receptors Ubiquitously Expressed in the Sinonasal Cavity

“…T2R38 has recently been indicated as a genetic marker for CRS with loss of function polymorphisms of T2R38, which results in decreased defensive response to bitter compounds and serve as a predictor of increased susceptibility to gram-negative infections. 5 The same loss of function polymorphism (AVI) of T2R38 has been linked to increased nicotine and alcohol dependence in African Americans. 26 There have also been polymorphisms found in T2R4 and T2R16 that alter receptor sensitivity to bitter compounds.…”

“…2,3 The clinical importance of T2R38 as a biomarker for CRS has been further elucidated by studying polymorphisms in T2R38 that produce decreased receptor functionality and lead to an increased susceptibility to gram-negative infection and recalcitrant CRS. 4,5 Furthermore, the genotype of T2R38 can predict surgical outcomes of patients with nonpolyposis CRS and even biofilm formation. 6,7 T2R38 is known to be expressed in the ciliated epithelial cells of the upper airway.…”

Sinonasal T2R-Mediated Nitric Oxide Production in Response to Bacillus Cereus

“…1,5,6 Binding of these ligands to sinonasal T2R38 results in production of nitric oxide (NO), which diffuses into the airway to kill bacteria and increase ciliary beat frequency (CBF). 1,7 Genetic variation in T2R38 has been shown to contribute to individual differences in these defensive mechanisms 1 and correlates with chronic rhinosinusitis (CRS) that necessitates surgical intervention, 8,9 poor surgical outcomes, 10 and rhinologic symptoms in patients with cystic fibrosis. 11 Gram-positive bacteria secrete quorum-sensing molecules throughout their life cycles; but, unlike gram-negative bacteria, they do not use AHLs.…”