An in vitro medium for modeling gut dysbiosis associated with cystic fibrosis.

The gut physiology of pediatric and adult persons with cystic fibrosis (pwCF) is altered relative to healthy persons. The CF gut is characterized, in part, as having excess mucus, increased fat content, acidic pH, increased inflammation, increased antibiotic perturbation, and the potential for increased oxygen availability. These physiological differences shift nutritional availability and the local environment for intestinal microbes, thus likely driving significant changes in microbial metabolism, colonization, and competition with other microbes. The impact of any specific change in this physiological landscape is difficult to parse using human or animal studies. Thus, we have developed a novel culture medium representative of the CF gut environment, inclusive of all the aforementioned features. This medium, called CF-MiPro, maintains CF gut microbiome communities, while significantly shifting nonCF gut microbiome communities toward a CF-like microbial profile, characterized by low Bacteroidetes and high Proteobacteria abundance. This medium is able to maintain this culture composition for up to 5 days of passage. Additionally, microbial communities passaged in CF-MiPro produce significantly less immunomodulatory short-chain fatty acids (SCFA), including propionate and butyrate, than communities passaged in MiPro, a culture medium representative of healthy gut physiology, confirming not only a shift in microbial composition but also altered community function. Our results support the potential for this in vitro culture medium as a new tool for the study of CF gut dysbiosis. IMPORTANCE Cystic fibrosis is an autosomal recessive disease that disrupts ion transport at mucosal surfaces, leading to mucus accumulation and altered physiology of both the lungs and the intestines, among other organs, with the resulting altered environment contributing to an imbalance of microbial communities. Culture media representative of the CF airway have been developed and validated; however, no such medium exists for modeling the CF intestine. Here, we develop and validate a first-generation culture medium inclusive of features that are altered in the CF colon. Our findings suggest this novel medium, called CF-MiPro, as a maintenance medium for CF gut microbiome samples and a flexible tool for studying key drivers of CF-associated gut dysbiosis.

Premodulator microbiome alterations associated with postmodulator growth outcomes in pediatric cystic fibrosis: Can we predict outcomes?

OBJECTIVES: The gut microbiota plays an important role in childhood growth. Our longitudinal cohort includes children with children with cystic fibrosis (CwCF) treated with highly effective modulator therapy. We aimed to elucidate early premodulator microbial signatures associated with postmodulator weight for CwCF later in childhood. METHODS: Stool samples were collected from CwCF at 13 days to 60 months. Metagenomic sequencing determined differentially abundant taxa. Children with body mass index or weight for length Z-scores within 1 standard deviation of the mean (SD) were considered normal weight, those >1 SD were classified as risk of overweight while children <1 SD were considered undernourished, although no CwCF met this latter criterion here. Multivariate regression models were applied to identify significant associations between metadata and microbial taxonomic relative abundances. RESULTS: One hundred and eighty-nine stool samples were analyzed from 39 CwCF. We identified statistically significant differences in early microbiome patterns among those at risk of being overweight compared to those who were normal weight when adjusted for age, sex, CF mutation, and early feeding method. Early microbiome was a stronger driver of growth status than current modulator use. Among those at risk of overweight, several taxa that were consistently in lower abundance included Eggerthella lentha, Ruminococcus, Bacteroides, with increase in abundance of Bacteroides stercoris. CONCLUSIONS: The early microbiome strongly predicts growth in the setting of modulator use for CwCF and we identify microbiome signatures associated with risk of being overweight. We highlight the possibility for interventions or early alternations to nutritional guidance for prevention of comorbid complications.

An In Vitro Medium for Modeling Gut Dysbiosis Associated with Cystic Fibrosis.

The gut physiology of pediatric and adult persons with cystic fibrosis (pwCF) is altered relative to healthy persons. The CF gut is characterized, in part, as having excess mucus, increased fat content, acidic pH, increased inflammation, increased antibiotic perturbation and the potential for increased oxygen availability. These physiological differences shift nutritional availability and the local environment for intestinal microbes, thus likely driving significant changes in microbial metabolism, colonization and competition with other microbes. The impact of any specific change in this physiological landscape is difficult to parse using human or animal studies. Thus, we have developed a novel culture medium representative of the CF gut environment, inclusive of all the aforementioned features. This medium, called CF-MiPro, maintains CF gut microbiome communities, while significantly shifting non-CF gut microbiome communities toward a CF-like microbial profile, characterized by low Bacteroidetes and high Proteobacteria abundance. This medium is able to maintain this culture composition for up to 5 days of passage. Additionally, microbial communities passaged in CF-MiPro produce significantly less immunomodulatory short chain fatty acids (SCFA), including propionate and butyrate, than communities passaged in MiPro, a culture medium representative of healthy gut physiology, confirming not only a shift in microbial composition but altered community function. Our results support the potential for this in vitro culture medium as a new tool for the study of gut dysbiosis in CF.

Use of proton pump inhibitors is associated with lower hemoglobin levels in people with cystic fibrosis.

BACKGROUND: Proton pump inhibitors (PPIs) and histamine H2-receptor antagonists (H2RAs) are commonly prescribed to people with cystic fibrosis (PwCF) to treat gastroesophageal reflux disease (GERD) and/or protect pancreatic enzymes from degradation in the stomach. Acid suppressive medications (ASMs) could theoretically reduce hemoglobin (Hgb) levels by restricting enteral iron absorption, but evidence of an association between use of ASMs and lower Hgb levels is lacking in PwCF. METHODS: We used unadjusted and covariate-adjusted generalized linear mixed models (GLMMs) to estimate the fixed effects of using versus never using ASMs on annual Hgb levels of PwCF in the U.S. Cystic Fibrosis Foundation Patient Registry (CFFPR) from 2011 to 2017. RESULTS: There were 9850 users and 9007 never-users of ASMs from 2011 to 2017 who met inclusion criteria. Not adjusting for covariates, Hgb estimates were lower for male and female H2RA and/or PPI users versus never-users. Adjusting for covariates, mean Hgb was 0.1 g/dl (95% CI: 0.03, 0.17) lower for males that exclusively used PPIs than it was for male never-users of ASMs (p = .008). Adjusting for covariates, mean Hgb levels were 0.11 g/dl (95% CI: 0.04, 0.18) lower for females that exclusively used PPIs and 0.16 g/dl (95% CI: 0.05, 0.27) lower for females that used PPIs and H2RAs concurrently than it was for female never-users of ASMs (p = .005 and p = .002 for respective comparisons). CONCLUSIONS: Males and females with cystic fibrosis (CF) who used PPIs and females with CF who concurrently used PPIs and H2RAs had lower Hgb levels than never-users of ASMs of the same sex in the CFFPR from 2011 to 2017.

Assessing the Association Between Maternal Education and Access to Pediatric Specialty Care.

Background. Timely access to pediatric specialty care continues to be a pervasive issue. We aimed to identify factors associated with unmet pediatric specialty care needs by assessing the association with maternal level of education. Methods. A sample was extracted from the 2011-2012 National Survey of Children's Health, which identified a subset of patients with unmet specialty care needs. Logistic regression models determined the strength of association between our sample and maternal level of education. Results. An estimated 12.5% of US children had unmet specialty care needs. Independent of confounding variables, children with mothers educated at a level of high school or less were 41% more likely to have unmet specialty care needs compared to those with mothers who were educated at a level greater than high school. Conclusions. Maternal level of education can be used as a risk factor to assess whether a child will have unmet specialty care needs.