Immunometabolic markers and the sputum microbiome in bronchiectasis

<b>Introduction:</b> Pseudomonas infection, in bronchiectasis (BE) is associated with severe disease, mortality and poorer quality of life. Understanding the mechanisms behind these associations might reveal new targets of treatment for this subset of BE patients. <b>Methods:</b> Sputum was collected from patients participating in the multicentre BRIDGE study (NCT03791086) and analysed for airway metabolites (L-lactate, glucose) using enzymatic assays. Inflammatory cytokines were measured using ELISA. L-lactate is measured as lactate source from host. Metabolites in sputum supernatants were compared to resistin levels, inflammatory cytokines, and microbiome by 16S sequencing. <b>Results:</b> N=296 patients were analysed. L-lactate (p&lt;0.002), glucose (p&lt;0.026), and resistin (p&lt;0.001) showed significant differences in beta-diversity by PERMANOVA. LEfSe analysis shows Pseudomonas is driving the differences in lactate (p&lt;0.0001), glucose (p=0.004), and samples with high resistin (p&lt;0.0001). Low resistin samples are associated with Streptococcus (p&lt;0.0001). Glucose ranged 0-21.22mM (mean 1.49mM, SD 3.29), and L-lactate ranged 0-16.37mM (mean 3.35mM, SD 3.76). L-lactate associated with increased neutrophil elastase (r=0.18,p=0.015), resistin (r=0.44,p&lt;0.0001), MMP9 (r=0.53,p&lt;0.0001) and CXCL8 (r=0.37,p&lt;0.0001). There was no relationship between glucose and these markers. <b>Conclusion:</b> Metabolites in bronchiectasis sputum correlate with markers of neutrophilic inflammation and relate to microbial diversity. Pseudomonas infection drives differences in lactate and glucose and could be related to metabolic reprogramming in neutrophils.