Comparison of subtyping approaches and the underlying drivers of microbial signatures for chronic rhinosinusitis

Abstract

23Chronic rhinosinusitis (CRS) is a heterogeneous condition characterised by persistent sinus 24 inflammation and microbial dysbiosis. This study aimed to identify clinically relevant sub-25 groups of CRS patients based on distinct microbial signatures, with a comparison to the 26 commonly used phenotypic subgrouping approach. The underlying drivers of these distinct 27 microbial clusters were also investigated, together with associations with epithelial barrier 28 integrity. 29Sinus biopsies were collected from CRS patients (n=23), and disease controls (n=8). 30 Expression of 42 tight junction genes was evaluated using quantitative PCR, together with 31 microbiota analysis and immunohistochemistry for measuring mucosal integrity and 32 inflammation. 33 CRS patients clustered into two distinct microbial sub-groups using probabilistic modelling 34 Dirichlet (DC) multinomial mixtures. DC1 exhibited significantly reduced bacterial diversity, 35 increased dispersion, and was dominated by Pseudomonas, Haemophilus, and 36Achromobacter. DC2 had significantly elevated B-cells, incidence of nasal polyps, and 37 higher numbers of Anaerococcus, Megasphaera, Prevotella, Atopobium, and 38Propionibacterium. In addition, each DC exhibited distinct tight junction gene and protein 39 expression profiles compared with controls. Stratifying CRS patients based on clinical 40 phenotypic subtypes (absence or presence of nasal polyps (CRSsNP or CRSwNP 41 respectively) or with cystic fibrosis (CRSwCF)) did account for a larger proportion of the 42 variation in the microbial dataset compared with DC groupings. However, no significant 43 differences between CRSsNP and CRSwNP cohorts were observed for inflammatory 44 markers, beta-dispersion and alpha diversity measures. 453In conclusion, both approaches used for stratifying CRS patients had benefits and pitfalls, but 46 DC clustering did provide greater resolution when studying tight junction impairment. Future 47 studies in CRS should give careful consideration into the patient subtyping approach used. 48 49 50 Importance 51Chronic rhinosinusitis (CRS) is a major human health problem that significantly reduces 52 quality of life. While various microbes have been implicated, there is no clear understanding 53 of the role they play in CRS pathogenesis. Another equally important observation made for 54 CRS patients is that the epithelial barrier in the sino-nasal cavity is defective. Finding a 55 robust approach to subtype CRS patients would be the first step towards unravelling the 56 pathogenesis of this heterogeneous condition. Previous work has explored stratification based 57 on clinical presentation of the disease (with or without polyps), inflammatory markers, 58 pathology, or microbial composition. Comparing between the different stratification 59 approaches used in these studies has not been possible due to different cohorts, analytical 60 methods, or sample sites used. In this study, two approaches of subtyping CRS patients were 61 compared and the underlying drivers of the hetero...

Multiomic analysis identifies natural intrapatient temporal variability and changes in response to systemic corticosteroid therapy in chronic rhinosinusitis

“…Associations have previously been identified between the microbiota and inflammatory signaling and subtypes in CRS 8,9,59‐61 . In this study, few associations were observed between microbial data and nasal polyp transcription or proteins.…”

International consensus statement on allergy and rhinology: rhinosinusitis 2021

“…To understand if, and how, bacteria influence host immune processes, several groups have associated microbiota surveys with host cytokine profiling or tissue function assays. Biswas and colleagues evaluated 23 CRS subjects (8 CRSwNP, 8 CRSsNP, and 7 cystic fibrosis) and 8 controls, and found 2 subgroups of CRS patients 750 . One group was characterized by low bacterial diversity and dominance of pathogens such as Pseudomonas , Haemophilus , and Achromobacter .…”

Upper‐airway dysbiosis related to frequent sweets consumption increases the risk of asthma in children with chronic rhinosinusitis

“…Specific dysbiosis was described in eosinophilic inflammation and atopic subjects 32 . Therefore, it was suspected that local dysbiosis not only is disease‐specific but also depends on disease endotype 33 . However, we were not able to define distinct dysbiosis profiles in atopic subjects.…”