Contribution of Short Chain Fatty Acids to the Growth of Pseudomonas aeruginosa in Rhinosinusitis

Abstract

Background: Chronic rhinosinusitis (CRS) is characterized by complex bacterial infections with persistent inflammation. Based on our rabbit model of sinusitis, blockage of sinus ostia generated a shift in microbiota to a predominance of mucin degrading microbes (MDM) with acute inflammation at 2 weeks. This was followed by conversion to chronic sinus inflammation at 3 months with a robust increase in pathogenic bacteria (e.g., Pseudomonas). MDMs are known to produce acid metabolites [short chain fatty acids (SCFA)] that have the potential to stimulate pathogen growth by offering a carbon source to non-fermenting sinus pathogens (e.g., Pseudomonas). The objective of this study is to evaluate the concentrations of SCFA within the mucus and its contribution to the growth of P. aeruginosa. Methods: Healthy and sinusitis mucus from the rabbit model were collected and co-cultured with the PAO1 strain of P. aeruginosa for 72 h and colony forming units (CFUs) were determined with the targeted quantification of three SCFAs (acetate, propionate, butyrate). Quantification of SCFAs in healthy and sinusitis mucus from patients with P. aeruginosa was also performed via high performance liquid chromatography. Results: To provide evidence of fermentative activity, SCFAs were quantified within the mucus samples from rabbits with and without sinusitis. Acetate concentrations were significantly greater in sinusitis mucus compared to controls (4.13 ± 0.53 vs. 1.94 ± 0.44 mM, p < 0.01). After 72 h of co-culturing mucus samples with PAO1 in the presence of mucin medium, the blue-green pigment characteristic of Pseudomonas was observed throughout tubes containing sinusitis mucus. CFUs were higher in cultures containing mucus samples from sinusitis (8.4 × 10 9 ± 4.8 × 10 7) compared to control (1.4 × 10 9 ± 2.0 × 10 7) or no mucus (1.5 × 10 9 ± 2.1 × 10 7) (p < 0.0001). To provide evidence of fermentative activity in human CRS with P. aeruginosa, the presence of SCFAs in human Cho et al. Anaerobes in Recalcitrant CRS mucus was analyzed and all SCFAs were significantly higher in CRS with P. aeruginosa compared to controls (p < 0.05). Conclusion: Given that SCFAs are solely derived from bacterial fermentation, our evidence suggests a critical role for mucin-degrading bacteria in generating carbonsource nutrients for pathogens. MDM may contribute to the development of recalcitrant CRS by degrading mucins, thus providing nutrients for potential pathogens like P. aeruginosa.

Association of Increased Circulating Acetic Acid With Poor Survival in Pseudomonas aeruginosa Ventilator-Associated Pneumonia Patients

“…SCFAs could inhibit cytokines and nitric oxide production by monocytes/macrophages and not improve the survival of pulmonary-sepsis ( Ciarlo et al., 2016 ). Furthermore, recent studies found that excessive SCFAs have detrimental effects on the host ( Zumbrun et al., 2013 ; Cho et al., 2020 ). It has been reported that a high-fiber diet (producing more SCFAs) promotes pathogenic Escherichia coli O157:H7 strain colonization and increases mortality ( Zumbrun et al., 2013 ).…”

“…In addition, SCFAs, especially acetic acid, could also promote the proliferation of PA. The high concentration of acetic acid in sinusitis mucus was a risk factor for chronic rhinosinusitis with PA infection ( Cho et al., 2020 ). On the other hand, some clinical studies also found that SCFAs may be detrimental ( Kurilshikov et al., 2019 ; Behary et al., 2021 ).…”

“…Different from the enhancing effect of low dose-SCFAs, high-dose SCFAs can dampen innate and adaptive immune response during infections ( Ciarlo et al., 2016 ; Sanchez et al., 2020 ). Besides, a recent study observed that SCFAs increase in chronic rhinosinusitis patients infected with PA ( Cho et al., 2020 ). It was proved that SCFAs could promote pathogenically (PA and Escherichia coli) growth ( Zumbrun et al., 2013 ; Ciarlo et al., 2016 ; Cho et al., 2020 ).…”

“…Besides, a recent study observed that SCFAs increase in chronic rhinosinusitis patients infected with PA ( Cho et al., 2020 ). It was proved that SCFAs could promote pathogenically (PA and Escherichia coli) growth ( Zumbrun et al., 2013 ; Ciarlo et al., 2016 ; Cho et al., 2020 ). Given the multiple effects of SCFAs, it is difficult to define whether they are beneficial or detrimental during bacterial infection.…”

A preclinical model to tackle chronic rhinosinusitis

“…Placing Merocel packing (Medtronic, Inc, Minneapolis, MN) inside the rabbits' nasal cavity is challenging due to (1) the size of the nasal cavity (especially for nonrhinologists) and (2) handling the rabbits (monitoring vital signs) under sedation, both of which have an associated learning curve. Also, the thick pathologic mucus seems to drive inflammation in the sinus mucosa, 4 and, if all thick pathologic mucus is suctioned out initially when removing the Merocel, then chronic sinusitis may not develop thereafter. We are curious about the reinduction criteria for the 6 rabbits in the subset of this study.…”