Background Cystic fibrosis (CF) is a multi-organ disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). Individuals with CF often have gastrointestinal (GI) dysbiosis due to chronic inflammation and antibiotic use. Previous studies suggested a role for vitamin D in reversing the GI dysbiosis found in CF. Objective To explore the potential role of a combination of high-dose oral cholecalciferol (vitamin D3) and fermentable dietary fiber, inulin, to impact bacterial composition, richness, and diversity of intestinal and airway microbiota in adults with CF. Methods This was a 2 × 2 factorial, double-blinded, placebo-controlled, randomized, pilot clinical trial in which adults with CF received oral cholecalciferol (vitamin D3) (50,000 IU/week) and/or inulin (12 g/day) for 12 weeks. Thus, there were 4 study groups (n = 10 subjects per group); 1) placebo 2) vitamin D3 3) inulin 4) vitamin D3 plus inulin. Stool and sputum samples were collected at baseline (just before) and after the intervention and were analysed using 16S ribosomal RNA gene sequencing for gut and airway microbiota composition. Statistical analyses assessed alpha and beta diversity to evaluate microbial community changes. Results Of a total of 254 screened participants, 40 eligible participants were randomized to one of the 4 treatment arms. Participants receiving vitamin D3 plus inulin exhibited greater changes in microbiome indexes in both intestinal and airway relative to those in the other study groups. Specific taxonomic changes supported the potential beneficial influence of this combination to mitigate both intestinal and airway dysbiosis in adults with CF. Conclusion This pilot study established that the combination of oral vitamin D3 and the prebiotic inulin was well tolerated over 12 weeks in adults with CF and altered gut and airway bacterial communities. Future research appear warranted to define clinical outcomes and the role of microbiota changes therein with this approach.

Cystic fibrosis (CF) is a recessive disorder arising from mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CFTR is expressed in numerous tissues, with high expression in the airways, small and large intestine, pancreatic and hepatobiliary ducts, and male reproductive tract. CFTR loss in these tissues disrupts regulation of salt, bicarbonate, and water balance across their epithelia, resulting in a systemic disorder with progressive organ dysfunction and damage. Pancreatic exocrine damage ultimately manifests as pancreatic exocrine insufficiency that begins as early as infancy. Pancreatic remodeling accompanies this early damage, during which abnormal glucose tolerance can be observed in toddlers. With increasing age, however, insulin secretion defects progress such that CF-related diabetes (CFRD) occurs in 20% of teens and up to half of adults with CF. The relevance of CFRD is highlighted by its association with increased morbidity, mortality, and patient burden. While clinical research on CFRD has greatly assisted in the care of individuals with CFRD, key knowledge gaps on CFRD pathogenesis remain. Furthermore, the wide use of CFTR modulators to restore CFTR activity is changing the CFRD clinical landscape and the field’s understanding of CFRD pathogenesis. For these reasons, the National Institute of Diabetes and Digestive and Kidney Diseases and the Cystic Fibrosis Foundation sponsored a CFRD Scientific Workshop, 23–25 June 2021, to define knowledge gaps and needed research areas. This article describes the findings from this workshop and plots a path for CFRD research that is needed over the next decade.

Background: Patients with cystic fibrosis (CF) may be at risk for micronutrient depletion, particularly during periods of illness and infection. The purpose of this study was to investigate serum micronutrient status over time in adults with CF initially hospitalized with a pulmonary exacerbation. Materials and Methods: This was an ancillary study of a multicenter trial investigating the role of high-dose vitamin D supplementation in 24 adults with CF (mean age, 29.6 ± 7.3 years). We measured serum concentrations of copper (Cu), iron (Fe), calcium (Ca), magnesium (Mg), potassium (K), and sulfur (S) in subjects at the beginning of a pulmonary exacerbation and again at 3 months. Results: Serum concentrations of Cu, Fe, and Ca were significantly lower at baseline compared with 3 months following the pulmonary exacerbation (Cu: baseline, 1.5 ± 0.6 vs 3 months, 1.6 ± 0.6 μg/mL, P = .027; Fe: 0.8 ± 0.3 vs 1.3 ± 1.1 μg/mL, P = .026; Ca: 9.7 ± 0.8 vs 10.8 ± 2.0 mg/dL, P = .024). Serum concentrations of K, Mg, and S did not change over time (K: baseline, 4.9 ± 0.3 vs 3 months, 5.1 ± 0.5 mEq/L; Mg: 1.8 ± 0.2 vs 2.0 ± 0.3 mg/dL; S: 1288.6 ± 343 vs 1309.9 ± 290 μg/mL; P > .05 for all). Conclusion: Serum concentrations of Cu, Fe, and Ca increased significantly several months following recovery from acute pulmonary exacerbation in adults with CF. This may reflect decreased inflammation, improved food intake, and/or increased absorption following recovery.

Background/Objectives:Although single, high doses of vitamin D effectively maintain vitamin D sufficiency in several populations, no studies have evaluated healthy adults over winter, during which vitamin D status declines. This study investigated whether high-dose vitamin D 3 given once to healthy adults before winter will (1) prevent the wintertime decline in vitamin D status, (2) promote vitamin D sufficiency 1 year following the dose and (3) prevent the rise of parathyroid hormone (PTH) concentrations. Subjects/Methods:In this double-blind, placebo-controlled trial, we assessed plasma 25(OH)D and PTH concentrations at baseline, 5, 90 and 365 days after drug administration in 28 healthy adults. In all, >80% of subjects returned at each time point. Results:At baseline, the young, healthy participants had a mean plasma 25(OH)D concentration of 17.5±6.1 ng/ml. Only two subjects exhibited plasma 25(OH)D concentrations >30 ng/ml. At 5 days, subjects randomized to vitamin D 3 had a higher mean plasma 25(OH)D concentration compared with the placebo group (39.1 vs 19.1 ng/ml, P<0.001). Plasma 25(OH)D concentrations returned to baseline at 90 and 365 days in the vitamin D 3 group and remained unchanged in the placebo group. PTH and calcium concentrations were unrelated to changes in 25(OH)D levels and similar between groups over time. Conclusions:A dose of 250 000 IU of vitamin D 3 given once in November resulted in a robust increase in plasma 25(OH)D after 5 days, but it was unable to sustain this increase after 90 days. A larger or more frequent dosing regimen may be needed for long-term vitamin D sufficiency.

Background & aims In vitro studies suggest that vitamin D may reduce hepcidin expression and pro-inflammatory cytokine release from monocytes. However, data assessing the vitamin D-mediated effects on iron recycling in healthy individuals are lacking. We aimed to examine the effect of high-dose vitamin D3on plasma hepcidin, inflammatory cytokine, and ferritin concentrations in healthy adults. Methods This was a pilot, double-blind, placebo-controlled trial in healthy adults (N = 28) randomized to receive a one-time oral dose of 250,000 IU of vitamin D3or placebo. Between- and within-group differences in plasma hepcidin, pro-inflammatory cytokine [interleukin (IL)-1β, IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1)], and ferritin concentrations at baseline and 1 week were determined using two-sample and paired t-tests, respectively. Results At baseline, plasma 25-hydroxyvitamin D [25(OH)D], hepcidin, pro-inflammatory cytokine, and ferritin concentrations did not differ between the two groups, and greater than 70% of subjects in both groups were vitamin D deficient (25(OH)D < 20 ng/mL). After 1 week, plasma hepcidin concentrations decreased by 73% from baseline in those who received vitamin D3(geometric mean ratio [GMR] = 0.27 (95% CI: 0.11–0.62); P = 0.005); there was no significant change in the placebo group (GMR = 0.73 (95% CI: 0.49–1.09); P = 0.11). Plasma cytokine and ferritin concentrations did not change significantly in either group. Conclusions High-dose vitamin D3significantly reduced plasma hepcidin concentrations in healthy adults 1 week post-dosing, without a change in plasma pro-inflammatory cytokine or ferritin concentrations. These data suggest that vitamin D may have a role in regulating iron recycling by acting independently of changes in pro-inflammatory markers.

Introduction: The Certificate Program in Translational Research (CPTR) at the Georgia Clinical and Translational Science Alliance provides PhD students, post-doctoral fellows and faculty with didactic, mentored, and experiential training in clinical and translational research. Methods: Quantitative evaluation includes tracking trainee competency, publications, grants and careers in clinical and translational research. Qualitative evaluation includes interviews with trainees about program experiences. Results: The CPTR provided knowledge and skills in clinical and translational research through coursework, clinical rotation, and collaboration with interdisciplinary scientists. Trainees reported increased confidence in 22 program competencies. Trainees have published more than 290 peer-reviewed articles and received over four million dollars in grants from the NIH, over $15 from the U.S. Department of Defense, and more than $300,000 from foundations. Trainees who completed the program remained in clinical and translational research. Conclusions: Programs like the CPTR are needed to train investigators to advance biomedical discoveries into population health.

Background: This study aims to describe patterns of truncal versus peripheral fat deposition measured by truncal-to-leg fat ratio (TLR) in adolescents and examine associations of TLR with cardiometabolic (CMD) risk factors. Methods: Data were from 3810 adolescents (12-19 years old) in the National Health and Examination Survey (NHANES) 2003-2006. Body fat was assessed by dual-energy X-ray absorptiometry, and CMD risk factors were determined by blood samples and physical examination. Linear and logistic regressions adjusted for BMI z-score and other covariates were used to examine associations of TLR with CMD risk factors as continuous and dichotomized outcomes, respectively. Results: Adolescents who were Mexican American, who have lower income, and with obesity had the highest mean TLR (all p < 0.05). In linear regression, increasing TLR was associated positively with homeostasis model assessment of insulin resistance (HOMA-IR), triglycerides, total cholesterol, systolic blood pressure (BP), c-reactive protein, and alanine aminotransferase (ALT), and negatively with high-density lipoprotein (HDL) cholesterol in both sexes (p < 0.05). TLR was also associated with diastolic BP in boys and low-density lipoprotein cholesterol in girls (p < 0.05). A similar pattern of findings resulted from logistic regression. When further stratified by race/ethnicity, TLR was positively associated with high triglycerides, total cholesterol, and ALT for White and/or Mexican American (p < 0.05), but not Black adolescents, while associations with HOMA-IR and HDL were significant for all race/ethnicities. Conclusions: In this cohort of adolescents, TLR was associated with several risk factors independent of BMI z-score, although some findings were sex or race/ethnicity specific. Body fat distribution may be an important determinant of future CMD.

Background/Objective Vitamin D has anti-inflammatory and immune-regulating properties. We aimed to determine if high-dose cholecalciferol supplementation for 1 yr in subjects with early CKD improved circulating markers of inflammation and immunity. Subjects/Methods In this double-blind, randomized, placebo-controlled trial, 46 subjects with early CKD (Stage 2–3) were supplemented with oral cholecalciferol (50 000 IU weekly for 12 weeks followed by 50 000 IU every other wk for 40 wks) or a matching placebo for 1 yr. Serum tumor necrosis factor-α, interleukin-6, monocyte chemoattractant protein-1 (MCP-1), interferon gamma-induced protein-10, and neutrophil gelatinase-associated lipocalin were measured at baseline, 12 wks, and 1 yr. Serum cathelicidin (LL-37) was measured at baseline and 12 wks. An in vitro experiment was performed to investigate the effect of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) treatment on MCP-1 secretion in THP-1 monocytes activated with lipopolysaccharide (LPS) and Pseudomonas aeruginosa. Results By 12 wks, serum MCP-1 decreased in the cholecalciferol group (66.2 ± 2.5 to 60.8 ± 2.6 pg/mL, group-by-time interaction P = 0.02) but was not different from baseline at 1 yr. Other markers of inflammation and immunity did not change. In vitro, LPS- and Pseudomonas-activated monocytes treated with1,25(OH)2D3 had significantly less MCP-1 secretion compared to untreated cells. Conclusions High-dose cholecalciferol decreased serum MCP-1 concentrations by 12 wks in patients with early CKD, although the decrease was not maintained for the remainder of the year. In vitro results confirm an MCP-1-lowering effect of vitamin D. Future studies should determine if vitamin D-mediated reductions in MCP-1 concentrations reflect improved clinical outcomes.

Background: Vitamin D deficiency is common in cystic fibrosis (CF), but there is no previous data on free 25-hydroxyvitamin D (25[OH]D) in CF or in relation to healthy individuals. Methods: We assessed total serum 25(OH)D concentration by chemiluminescence and serum free 25(OH)D concentration by both direct measurement (ELISA) and calculation, using serum albumin and vitamin D binding protein (VDBP) levels in 80 subjects (28 healthy adults, 25 clinically stable adults and children with CF and 27 adults experiencing a CF exacerbation). Results: Serum albumin and VDBP concentrations were lower in CF compared with healthy controls. Total serum 25(OH)D concentrations were positively correlated with both calculated and measured free 25(OH)D (P ≥ 0.001 for both). Calculated and directly measured serum free 25(OH)D levels were positively correlated (P ≥ 0.001). Conclusions: Serum levels of directly measured free 25(OH)D positively correlated with total 25(OH)D, suggesting that achieving sufficient total serum 25(OH)D may result in adequate free 25(OH)D levels in CF.

Objectives: This study aimed to evaluate the relationship between lung function and body composition in cystic fibrosis (CF) and examine the presence of normal-weight obesity (NWO), a high body fat percentage with a normal body mass index (BMI), in this population. Methods: In a pilot, cross-sectional study, 32 subjects with CF and a reference group of 20 adults without CF underwent body composition analysis with air displacement plethysmography. NWO was defined as a BMI <25 kg/m2 and body fat >30% (for women) or >23% (for men). Lung function in subjects with CF was determined by the percentage of predicted forced expiratory volume in 1 s (FEV1% predicted). Results: Despite lower BMI and fat-free mass index (P < 0.01), fat mass index and percent body fat did not differ between subjects with CF and the reference group. Among subjects with CF, FEV1% predicted was positively associated with fat-free mass index (β = 6.31 ± 2.93, P = 0.04) and inversely associated with fat mass index (β = -6.44 ± 2.93, P = 0.04), after adjusting for age, sex, and BMI. Ten subjects with CF (31%) had NWO, which corresponded with lower fat-free mass index and FEV1% predicted compared with overweight subjects (P = 0.006 and 0.004, respectively). Conclusions: Excess adiposity, particularly in the form of NWO, was inversely associated with lung function in CF. Larger prospective studies should be undertaken to confirm these findings and determine the long-term metabolic and clinical consequences of excess adiposity in CF. As the lifespan of individuals with CF increases, nutrition screening protocols, which primarily rely on BMI, may require reassessment.