The metabolic footprint of the airway bacterial community in cystic fibrosis

Abstract Background Progressive, chronic bacterial infection of the airways is a leading cause of death in cystic fibrosis (CF). Culture-independent methods based on sequencing of the bacterial 16S rRNA gene describe a distinct microbial community that decreases in richness and diversity with disease progression. Understanding the functional characteristics of the microbial community may aid in identifying potential therapies and may assist in management, but current methods are cumbersome. Here, we demonstrate the use of an oxidative metabolic assay as a complement to sequencing methods to describe the microbiome in the airways of patients with CF. Methods Expectorated sputum was collected from 16 CF subjects and 8 control subjects. The Biolog Gen III Microplate was used in a community-level physiological profiling (CLPP)-based assay to examine oxidative metabolic activity. 16S rRNA V4 amplicon sequencing was used to characterize the taxonomy and diversity of the samples. Correlations were then identified among the oxidative activity and taxonomy data. In an additional paired analysis, sputum from seven CF subjects were collected at two separate clinic visits and compared for oxidative activity, taxonomy, and diversity. Results Significant differences in oxidative metabolic activity, microbial taxonomy, and diversity were found between the CF and control sputum samples. Oxidative activity correlated positively with total genera but not with other measures of diversity or taxonomy, demonstrating that the metabolic assay complements the structural aspects of the microbiome. As expected, Pseudomonas was significantly enriched in CF samples, while Streptococcus and Prevotella were similarly abundant in both CF and control samples. Paired analysis of CF samples at separate clinic visits revealed comparable oxidative activity that correlated with similar stability in taxonomy and diversity. Conclusions The CLPP assay used in this study complements existing sequencing methods to delineate the oxidative metabolic footprint of the CF airway bacterial community. This method may be useful to study the CF microbial community over time and with changes in disease state

Brain network decoupling with increased serum neurofilament and reduced cognitive function in Alzheimer’s disease

Neurofilament light chain, a putative measure of neuronal damage, is measurable in blood and cerebrospinal fluid and is predictive of cognitive function in individuals with Alzheimer Disease. There has been limited prior work linking neurofilament light and functional connectivity and no prior work has investigated neurofilament light associations with functional connectivity in autosomal dominant Alzheimer Disease. Here we assessed relationships between blood neurofilament light, cognition, and functional connectivity in a cross-sectional sample of 106 autosomal dominant Alzheimer Disease mutation carriers and 76 non-carriers. We employed an innovative network-level enrichment analysis approach in order to assess connectome-wide associations with neurofilament light. Neurofilament light was positively correlated with deterioration of functional connectivity within the default mode network and negatively correlated with connectivity between default mode network and executive control networks including the cingulo-opercular, salience, and dorsal attention networks. Further, reduced connectivity within the default mode network and between the default mode network and executive control networks was associated with reduced cognitive function. Hierarchical regression analysis revealed that neurofilament levels and functional connectivity within the default mode network and between the default mode network and the dorsal attention network explained significant variance in cognitive composite scores when controlling for age, sex, and education. A mediation analysis demonstrated that functional connectivity within the default mode network and between the default mode network and dorsal attention network partially mediated the relationship between blood neurofilament light levels and cognitive function. Our novel results indicate that blood estimates of neurofilament levels correspond to direct measurements of brain dysfunction, shedding new light on the underlying biological processes of Alzheimer Disease. Further, we demonstrate how variation within key brain systems can partially mediate the negative effects of heighted total serum neurofilament levels, suggesting potential regions for targeted interventions. Finally, our results lend further evidence that low-cost and minimally invasive blood measurements of neurofilament may be a useful marker of brain functional connectivity and cognitive decline in Alzheimer disease