Biology subjects

Price, C. E.

Publications and source records attributed to Price, C. E..

4 recordsLinked to original sources

bioRxiv2023

Persistent delay in maturation of the developing gut microbiota in infants with cystic fibrosis

The healthy human infant gut microbiome undergoes stereotypical changes in taxonomic composition between birth and maturation to an adult-like stable state. During this time, extensive communication between microbiota and the host immune system contributes to health status later in life. Although there are many reported associations between microbiota compositional alterations and disease in adults, less is known about how microbiome development is altered in pediatric diseases. One pediatric disease linked to altered gut microbiota composition is cystic fibrosis (CF), a multi-organ genetic disease involving impaired chloride secretion across epithelia and heightened inflammation both in the gut and at other body sites. Here, we use shotgun metagenomics to profile the strain-level composition and developmental dynamics of the infant fecal microbiota from several CF and non-CF longitudinal cohorts spanning from birth to greater than 36 months of life. We identify a set of keystone species whose prevalence and abundance reproducibly define microbiota development in early life in non-CF infants, but are missing or decreased in relative abundance in infants with CF. The consequences of these CF-specific differences in gut microbiota composition and dynamics are a delayed pattern of microbiota maturation, persistent entrenchment in a transitional developmental phase, and subsequent failure to attain an adult-like stable microbiota. We also detect the increased relative abundance of oral-derived bacteria and higher levels of fungi in CF, features that are associated with decreased gut bacterial density in inflammatory bowel diseases. Our results define key differences in the gut microbiota during ontogeny in CF and suggest the potential for directed therapies to overcome developmental delays in microbiota maturation.

microbiology↗

bioRxiv2022

Predicting Clinical Outcomes in Infants With Cystic Fibrosis From Stool Microbiota using Random Forest Algorithms

The gut-lung axis describes the interaction between microbiota in the gut and health status of the airway, whereby there is a bidirectional relationship facilitated by systemic transport of microbially-derived metabolites and immune factors. Cystic fibrosis (CF) is a genetic disease that is associated with dysbiosis of the gut microbiota. Recent literature has shown that the microbial dysbiosis in the CF gut can alter the hosts inflammatory status and that there are distinct microbial compositions in children with CF who have low versus high intestinal inflammation. These distinct microbial profiles can be used as signatures in children with CF (cwCF) to predict health outcomes. Here, we use supervised machine learning to train a random forest model on the distinct microbial composition of cwCF to predict: age (as a validation of the method), frequency of upper respiratory infection (URIfreq), and neutrophil to lymphocyte ratio (NLR), a clinical marker for systemic inflammation that negatively correlates with lung function. We find that the out of bag error, a measure of model accuracy, is lower when predicting age for cwCF compared to children without CF, consistent with previous data. We are able to predict high URIfreq with only 16% error and high NLR with 27% error. This machine learning pipeline may allow physicians and microbiome researchers to use the stool microbiota of cwCF as a tool for identifying individuals with the more negative airway clinical outcomes from this population, and potentially allow for early intervention. ImportanceChildren with CF (cwCF) often experience chronic respiratory infections, leading to progressive, irreversible lung function decline and significant morbidity and premature mortality. Modulator therapy has revolutionized the treatment of eligible adults with CF. cwCF as young as age 6 are now eligible to receive modulator therapy, although by early childhood many children have already experienced pulmonary exacerbations. Here we show that for cwCF, stool microbiota composition is associated with higher upper respiratory infection frequency and increased systemic inflammation. Our findings may aid in developing diagnostic tools that can allow physicians further understanding of which intestinal microbiota profiles are associated with health outcomes and to identify targets for preventative treatment for cwCF.

microbiology↗

bioRxiv2022

Development of the Intestinal Microbiome in Cystic Fibrosis in Early Life

Cystic Fibrosis is a heritable disease that causes altered physiology at mucosal sites; these changes result in chronic infection in the lung, significant gastrointestinal complications as well as dysbiosis of the gut microbiome, although the latter has been less well explored. Here, we describe the longitudinal development of the gut microbiome in a cohort of children with cystic fibrosis (cwCF) from birth through early childhood (0-4 years of age) using 16S rRNA gene amplicon sequencing of stool samples as a surrogate for the gut microbiota. Similar to healthy populations, alpha diversity of the gut microbiome increases significantly with age, but diversity plateaus [~]2 years of age for this CF cohort. Several taxa that have been associated with dysbiosis in CF change with age towards a more healthy-like composition; notable exceptions include Akkermansia, which decreases with age, and Blautia, which increases with age. We also examined the relative abundance and prevalence of nine taxa associated with CF lung disease, several of which persist across early life, highlighting the possibility of the lung being seeded directly from the gut early in life. Finally, we applied the Crohns dysbiosis index to each sample, and found that high Crohns-associated dysbiosis early in life (<2 years) was associated with significantly lower Bacteroides in samples collected from 2-4 years of age. Together, these data indicate a persisting dysbiosis in the gut microbiota as well as markers associated with inflammatory bowel disease early in life for cwCF. IMPORTANCECystic Fibrosis is a heritable disease that disrupts ion transport at mucosal surfaces, causing a buildup of mucus and dysregulation of microbial communities in both the lungs and the intestines. Persons with CF are known to have dysbiotic gut microbial communities, but the development of these communities over time beginning at birth have not been thoroughly studied. Here, we describe the development of the gut microbiome of cwCF throughout the first four years of life, during the critical window of both gut microbiome and immune development. Our findings indicate a persisting dysbiosis, the possibility of the gut microbiota as a reservoir of airway pathogens and a surprisingly early indication of a microbiota associated with inflammatory bowel disease.

microbiology↗

bioRxiv2019

Exogenous alginate protects Staphylococcus aureus from killing by Pseudomonas aeruginosa

Cystic fibrosis (CF) patients chronically infected with both Pseudomonas aeruginosa and Staphylococcus aureus have worse health outcomes than patients who are mono-infected with either P. aeruginosa or S. aureus. We showed previously that mucoid strains of P. aeruginosa can co-exist with S. aureus in vitro due to transcriptional downregulation of several toxic exoproducts typically produced by P. aeruginosa, including siderophores, rhamnolipids, and HQNO (2-heptyl-4-hydroxyquinoline N-oxide). Here we demonstrate that exogenous alginate protects S. aureus from P. aeruginosa in both planktonic and biofilm co-culture models under a variety of nutritional conditions. S. aureus protection in the presence of exogenous alginate is due to transcriptional downregulation of pvdA, a gene required for the production of the iron scavenging siderophore pyoverdine, as well as down-regulation of the PQS (Pseudomonas quinolone signal; 2-heptyl-3,4-dihydroxyquinoline) quorum sensing system. The impact of exogenous alginate is independent of endogenous alginate production. We further demonstrate that co-culture of mucoid P. aeruginosa with non-mucoid P. aeruginosa can mitigate the killing of S. aureus by the non-mucoid strain of P. aeruginosa, indicating that the mechanism we describe here may function in vivo in the context of mixed infections. Finally, we investigated a panel of mucoid clinical isolates that retain the ability kill S. aureus at late time points, and show that each strain has a unique expression profile, indicating that mucoid isolates can overcome the effects of mucoidy in a strain-specific manner.\n\nIMPORTANCECF patients are chronically infected by polymicrobial communities of microorganisms. The two dominant bacterial pathogens that infect CF patient lungs are P. aeruginosa and S. aureus, with [~]30% of patients co-infected by both species. Patients infected with both P. aeruginosa and S. aureus have worse outcomes than mono-infected patients, and both species persist within the same physical space in the lungs of CF patients. A variety of host and environmental factors have been demonstrated to promote P. aeruginosa-S. aureus co-existence, despite evidence that P. aeruginosa kills S. aureus when these organisms are co-cultured in vitro. Thus, a better understanding of P. aeruginosa-S. aureus interactions, particularly mechanisms by which these microorganisms are able to co-exist in proximal physical space, will lead to better informed treatments for chronic polymicrobial infections.

microbiology↗