Fungal sinusitis is a typical unilateral lesion in the clinic. It has been reported that the levels of IgA, plasma cells, and lymphocytes in the secretion of fungal sinusitis are elevated. In contrast, other inflammatory cells are not infiltrated, suggesting that mucosal immunity induced by fungal sinus balls plays a vital role in the progression of the disease[15]. In addition to the unilateral soft tissue density, shadow in the imaging examination can also be expressed as sinus wall bone changes. It is undeniable that the content of the sinus in fungal sinusitis (fungal mass, sinus secretion) is related to clinical manifestations. Still, due to technical limitations, few pieces of literature describe the composition of sinus contents and their clinical relationship. In the past few decades, with the development of science and technology and the concept of "omics", metabolomics-related techniques have made possible component analysis for complex samples. In this study, we first explored the metabolic differences of fungal sinusitis using metabolomics and initially linked them with clinical manifestations.
Twenty-six metabolites were found related to the disease. In this study, the vast majority of the molecules with putative identification were lipids. Glycerophospholipids were the most detected metabolites associated with the fungal ball. The cell membrane of fungi is enriched with diverse lipids belonging to the class glycerophospholipids, sphingolipids, and sterols. Glycerophospholipids serve as a stable structural component of biological membranes with sn-3 configuration of the glycerol backbone, playing a pivotal role in regulating transport, signal transduction, and protein function regulation[16]. PC and PE are essential and represent the major components of both cellular and subcellular membranes. The decrease of PC is related to the degradation of microbial cells in a fungal ball. PE can also be formed via calcium-dependent head group exchange with pre-existing phospholipids[17]. This study showed that PE level was positively correlated with osteogenesis but negatively correlated with serum calcium ion level. It is speculated that PE participates in key metabolites of sinus wall bone changes. PE is required for energy-dependent severe substrate accumulation. Sinus wall bone hyperplasia in sinus CT is one of the typical features of fungal rhinosinusitis, and we speculate that it may be related to PE metabolism. However, there is still a lack of in-depth research on its mechanism.
Both phosphatidylserine (PS) and phosphatidylethanolamine (PE) were connected to the diglycerides of the sphingolipid metabolic pathway through metabolic conversion. The conversion between the three regulates cell differentiation, proliferation, and apoptosis in other diseases, including Alzheimer's disease, atherosclerosis, chronic inflammation, etc[11, 18, 19]. The role of the bass bridge is to connect the protein on the plasma membrane through sugar. Enrichment of lipids in different cell corners could be attributed to acyl chain remodeling, presented in the pathways in this study[20]. Ceramide, sphingosine, and sphingosine 1-phosphate (S1P) are the primary bioactive mediators of sphingolipid metabolism. S1P might be involved in the immune and inflammatory responses of potent cytokines. These ceramide-rich platforms involve various signaling cascades in immune cells, including B cell activation, bacterial pathogen infection, and release of cytokines during infection; they are also essential in inducing apoptosis[21]. Studies have shown that S1P influences bone remodeling[22]. In this study, the content of S1P increased, suggesting that the expression of S1P is related to the bone changes characteristic of fungal sinusitis. In addition, AhR (aryl hydrocarbon receptor) and IDO1(2,3-dioxygenase 1) have been reported to play a vital role in linking the catabolism of microbial tryptophan and host endogenous tryptophan metabolites to regulatory T cell function in the mucosal region[23]. A positive feedback loop between IDO1 and AhR is necessary to drive the co-evolution of symbiotic fungi with the mammalian immune system and microbiota, host survival under stable inflammatory conditions, and fungal symbiosis to prevent immune dysregulation[24], which is consistent with the non-invasive characteristics of the fungal ball. In this study, tryptophan metabolism can elicit both hyper- and anti-inflammatory effects, regulated by Tenuazonic acid (fungal toxins), but the mechanism requires further research.
We tried to correlate metabolites and imaging. As a principal constituent of the lipid fraction present in the calcification front during normal bone formation, the thickness of the posterior lateral wall of the maxillary sinus was positively correlated with the PC (O-16:0/0:0) level, indicating PC had a boosting effect on osteogenesis. Li et al. found that PC metabolism in human osteoblasts and its metabolites contribute to the growth and mineralization of human osteosarcoma cells through metabolomic studies[25]. PC also could affect the osteogenic transdifferentiation of vascular smooth muscle cells into calcified vascular cells[26]. On the other hand, the highest CT value of the high-density area in the maxillary sinus was positively correlated with phosphatidylethanolamine, a key metabolite in the interconversion of glycerophospholipid metabolism and sphingolipid metabolism to augment inflammatory signaling.
The following limitations exist in this study. Firstly, the metabolomic differences between different groups of fungi were not obtained by diversity analysis of fungi; secondly, the relatively small sample size may have biased the selection. Further studies should include an analysis of microbial community composition and distribution of large samples.