Expert Rev Clin Immunol. 2022 Aug 1. doi: 10.1080/1744666X.2022.2108407. Online ahead of print.

ABSTRACT

INTRODUCTION: Inflammatory bowel diseases (IBDs) are known to be caused by a combination of genetic and environmental factors that vary in their influence on the development of the disease. Environmental exposures seem to influence IBD susceptibility, whereas genetic background is thought to modulate the impact of the environment on disease course and phenotype.

AREAS COVERED: A broad review of the involvement of genes and the environment in IBD pathogenesis was performed, and information regarding the main genetic and environmental factors - categorized into lifestyle factors, drugs, diet, and microbes - was updated. Monogenic very early onset IBD (VEO-IBD) was also discussed.

EXPERT OPINION: In the upcoming years, better understanding of gene-environment interactions will contribute to the possibility of a better prediction of disease course, response to therapy, and therapy-related adverse events with the final goal of personalized and more efficient patient management.

PMID:35912838 | DOI:10.1080/1744666X.2022.2108407

Front Cell Dev Biol. 2022 Jul 13;10:899368. doi: 10.3389/fcell.2022.899368. eCollection 2022.

ABSTRACT

Organoids are complex multicellular three-dimensional (3D) in vitro models that are designed to allow accurate studies of the molecular processes and pathologies of human organs. Organoids can be derived from a variety of cell types, such as human primary progenitor cells, pluripotent stem cells, or tumor-derived cells and can be co-cultured with immune or microbial cells to further mimic the tissue niche. Here, we focus on the development of 3D lung organoids and their use as disease models and drug screening tools. We introduce the various experimental approaches used to model complex human diseases and analyze their advantages and disadvantages. We also discuss validation of the organoids and their physiological relevance to the study of lung diseases. Furthermore, we summarize the current use of lung organoids as models of host-pathogen interactions and human lung diseases such as cystic fibrosis, chronic obstructive pulmonary disease, or SARS-CoV-2 infection. Moreover, we discuss the use of lung organoids derived from tumor cells as lung cancer models and their application in personalized cancer medicine research. Finally, we outline the future of research in the field of human induced pluripotent stem cell-derived organoids.

PMID:35912110 | PMC:PMC9326165 | DOI:10.3389/fcell.2022.899368

Front Pediatr. 2022 Jul 14;10:930281. doi: 10.3389/fped.2022.930281. eCollection 2022.

ABSTRACT

Since the beginning of 2020, a remarkably low incidence of respiratory virus hospitalizations has been reported worldwide. We prospectively evaluated 587 children, aged <12 years, admitted for respiratory tract infections from 1 September 2021 to 15 March 2022 in four Italian pediatric hospitals to assess the burden of respiratory viruses during the COVID-19 pandemic in Italy. At admission, a Clinical Respiratory Score was assigned and nasopharyngeal or nasal washing samples were collected and tested for respiratory viruses. Total admissions increased from the second half of October 2021 to the first half of December 2021 with a peak in early November 2021. The respiratory syncytial virus (RSV) incidence curve coincided with the total hospitalizations curve, occurred earlier than in the pre-pandemic years, and showed an opposite trend with respect to the incidence rate of SARS-CoV-2. Our results demonstrated an early peak in pediatric hospitalizations for RSV. SARS-CoV-2 may exhibit a competitive pressure on other respiratory viruses, most notably RSV.

PMID:35911833 | PMC:PMC9329524 | DOI:10.3389/fped.2022.930281

Brain Commun. 2022 Jun 6;4(3):fcac144. doi: 10.1093/braincomms/fcac144. eCollection 2022.

ABSTRACT

We have studied the molecular mechanisms of variants in solute carrier Family 6 Member 1 associated with neurodevelopmental disorders, including various epilepsy syndromes, autism and intellectual disability. Based on functional assays of solute carrier Family 6 Member 1 variants, we conclude that partial or complete loss of γ-amino butyric acid uptake due to reduced membrane γ-amino butyric acid transporter 1 trafficking is the primary aetiology. Importantly, we identified common patterns of the mutant γ-amino butyric acid transporter 1 protein trafficking from biogenesis, oligomerization, glycosylation and translocation to the cell membrane across variants in different cell types such as astrocytes and neurons. We hypothesize that therapeutic approaches to facilitate membrane trafficking would increase γ-amino butyric acid transporter 1 protein membrane expression and function. 4-Phenylbutyrate is a Food and Drug Administration-approved drug for paediatric use and is orally bioavailable. 4-Phenylbutyrate shows promise in the treatment of cystic fibrosis. The common cellular mechanisms shared by the mutant γ-amino butyric acid transporter 1 and cystic fibrosis transmembrane conductance regulator led us to hypothesize that 4-phenylbutyrate could be a potential treatment option for solute carrier Family 6 Member 1 mutations. We examined the impact of 4-phenylbutyrate across a library of variants in cell and knockin mouse models. Because γ-amino butyric acid transporter 1 is expressed in both neurons and astrocytes, and γ-amino butyric acid transporter 1 deficiency in astrocytes has been hypothesized to underlie seizure generation, we tested the effect of 4-phenylbutyrate in both neurons and astrocytes with a focus on astrocytes. We demonstrated existence of the mutant γ-amino butyric acid transporter 1 retaining wildtype γ-amino butyric acid transporter 1, suggesting the mutant protein causes aberrant protein oligomerization and trafficking. 4-Phenylbutyrate increased γ-amino butyric acid uptake in both mouse and human astrocytes and neurons bearing the variants. Importantly, 4-phenylbutyrate alone increased γ-amino butyric acid transporter 1 expression and suppressed spike wave discharges in heterozygous knockin mice. Although the mechanisms of action for 4-phenylbutyrate are still unclear, with multiple possibly being involved, it is likely that 4-phenylbutyrate can facilitate the forward trafficking of the wildtype γ-amino butyric acid transporter 1 regardless of rescuing the mutant γ-amino butyric acid transporter 1, thus increasing γ-amino butyric acid uptake. All patients with solute carrier Family 6 Member 1 variants are heterozygous and carry one wildtype allele, suggesting a great opportunity for treatment development leveraging wildtype protein trafficking. The study opens a novel avenue of treatment development for genetic epilepsy via drug repurposing.

PMID:35911425 | PMC:PMC9336585 | DOI:10.1093/braincomms/fcac144

Front Cell Infect Microbiol. 2022 Jul 13;12:941014. doi: 10.3389/fcimb.2022.941014. eCollection 2022.

ABSTRACT

Women with cystic fibrosis (CF) have a significantly lower life expectancy compared to men, which is indicated by an earlier impairment of lung function due to chronic colonization with biofilm formed by Pseudomonas aeruginosa. There is growing evidence that blood serum concentrations of the steroid sex hormone estradiol (E2) correlate with the occurrence of pulmonary exacerbations in CF but also play a role in the mucoid switch of P. aeruginosa. This study aims to shed light on possible microbiological reasons for sexual dimorphism in CF by investigating the influence of E2 on biofilm formation of P. aeruginosa CF isolates. For this purpose, 10 CF isolates of the respiratory tract derived from different CF patients have been treated with E2 in a microtiter plate biofilm model. Biofilms have been examined by crystal violet assays, field emission scanning electron microscopy (FE-SEM), 3D laser scanning microscopy (LSM), and quorum sensing (QS) reporter assays of the supernatants taken from biofilms. This allowed us to simultaneously investigate the effects of E2 on attached biofilm mass, biofilm ultrastructure, and QS activity. Upon E2 treatment, six out of 10 investigated CF isolates showed an increase of attached biofilm mass, whereas biofilms from two tested non-CF laboratory strains (PAO1 and ATCC19660) did not. Moreover, FE-SEM and 3D LSM analyses of the E2 responsive CF biofilms revealed ultrastructural remodeling of biofilm structure at different scales with increased formation of prominent biofilm spots, enhanced coverage with extracellular polymeric substance (EPS), and extended average surface roughness. QS activity measurements performed in biofilm supernatants via luminescence acyl homoserine lactone (AHL) reporter assays further showed that E2 treatment may also modulate QS signaling, as shown in an E2 sensitive CF isolate. Together, our results suggest the biofilm modulating effects of E2 on various clinical CF isolates that are documented by both biomass and ultrastructural changes of biofilms. The gained new insight into the influence of steroid hormones on P. aeruginosa biofilm phenotypes might pave the way for novel future approaches in personalized medicine based on the patients' sex and hormonal status.

PMID:35909974 | PMC:PMC9326073 | DOI:10.3389/fcimb.2022.941014

Int J Popul Data Sci. 2022 Jun 27;7(1):1725. doi: 10.23889/ijpds.v7i1.1725. eCollection 2022.

ABSTRACT

INTRODUCTION: As people with cystic fibrosis (CF) lead longer, healthier lives, educational qualifications and employment prospects are increasingly important. However, little is known about the social consequences of CF, in particular, any impact on educational achievements and the support children with CF receive in schools.

OBJECTIVES: To assess the educational achievements of children with CF in Wales compared to the general Welsh population, and the additional learning support children with CF receive in schools.

METHODS: We conducted a population-scale data linkage study of all children born in Wales using the Secure Anonymised Information Linkage (SAIL) Databank. We used anonymised individual-level population-scale health and administrative data sources to identify children with CF born between 2000 - 2015, linked to educational attainment records. We calculated the percentage of children that reached expected levels in statutory assessment at age 10-11, Key Stage 2 (KS2), and compared this to educational outcomes in the general population. We also assessed the percentage of children with CF that received extra learning support.

RESULTS: Out of 150 eligible children, 119 had KS2 results. 77% (95% CI: 69%-84%) of children achieved expected levels in English, 81% (95% CI: 73% -87%) in Mathematics and 82% (95% CI: 75% - 88%) in Science. In the comparable general Welsh population, 83.4% to 91.1% achieved the expected level in English, 84.9% to 91.6% in Maths, and 87.1% to 92.2% in Science across the years of the study. 70% of children with CF received extra learning support.

CONCLUSIONS: Children with CF in Wales may have worse educational achievements than the general population. More research is needed to inform policies and interventions to better support children with CF to reach their full educational potential and employment opportunities.

PMID:35909577 | PMC:PMC9284509 | DOI:10.23889/ijpds.v7i1.1725

Clin Transl Med. 2022 Aug;12(8):e972. doi: 10.1002/ctm2.972.

NO ABSTRACT

PMID:35908252 | DOI:10.1002/ctm2.972

J Cyst Fibros. 2022 Jul 27:S1569-1993(22)00631-2. doi: 10.1016/j.jcf.2022.07.011. Online ahead of print.

NO ABSTRACT

PMID:35907767 | DOI:10.1016/j.jcf.2022.07.011

J Infect Dis. 2022 Jul 30:jiac328. doi: 10.1093/infdis/jiac328. Online ahead of print.

NO ABSTRACT

PMID:35906931 | DOI:10.1093/infdis/jiac328

Nat Commun. 2022 Jul 29;13(1):4270. doi: 10.1038/s41467-022-31854-8.

ABSTRACT

Cystic fibrosis is a monogenic lung disease caused by dysfunction of the cystic fibrosis transmembrane conductance regulator anion channel, resulting in significant morbidity and mortality. The progress in elucidating the role of CFTR using established animal and cell-based models led to the recent discovery of effective modulators for most individuals with CF. However, a subset of individuals with CF do not respond to these modulators and there is an urgent need to develop novel therapeutic strategies. In this study, we generate a panel of airway epithelial cells using induced pluripotent stem cells from individuals with common or rare CFTR variants representative of three distinct classes of CFTR dysfunction. To measure CFTR function we adapt two established in vitro assays for use in induced pluripotent stem cell-derived airway cells. In both a 3-D spheroid assay using forskolin-induced swelling as well as planar cultures composed of polarized mucociliary airway epithelial cells, we detect genotype-specific differences in CFTR baseline function and response to CFTR modulators. These results demonstrate the potential of the human induced pluripotent stem cell platform as a research tool to study CF and in particular accelerate therapeutic development for CF caused by rare variants.

PMID:35906215 | DOI:10.1038/s41467-022-31854-8

J Cyst Fibros. 2022 Jul 26:S1569-1993(22)00633-6. doi: 10.1016/j.jcf.2022.07.013. Online ahead of print.

ABSTRACT

BACKGROUND: Treatment of cystic fibrosis related diabetes (CFRD) can improve outcomes and use of continuous glucose monitoring (CGM) can positively impact glycemic control. We conducted a systematic review to assess current evidence on CGM compared to self-monitoring of blood glucose (SMBG) in the management of CFRD to determine its effect on glycemic, pulmonary, non-pulmonary and quality of life outcomes.

METHODS: Using pre-defined selection criteria, we searched MEDLINE, Embase, CENTRAL, Evidence-Based Medicine Reviews, grey literature and six relevant journals for studies using CGM and/or SMBG in CFRD with greater than 6 weeks of follow-up and reported change in HbA1c. The primary outcome was weighted mean difference (WMD) in plasma HbA1c between CGM and SMBG groups. Secondary outcomes included exploring interrelationships between CGM metrics and effects on disease-specific pulmonary, non-pulmonary and quality of life outcomes.

RESULTS: A total of 1671 references were retrieved, 862 studies screened and 124 full-texts assessed for eligibility. No studies directly compared CGM to SMBG. A meta-analysis of seventeen studies of 416 individuals (CGM = 138, SMBG = 278) found CGM group had 4.1 mmol/mol (95% CI -7.9 to -0.30, p = 0.034) lower HbA1c compared to SMBG group. Most studies demonstrated moderate-to-high risk of bias. Publication bias was also present. Heterogeneity was high and meta-regression identified duration of follow-up in SMBG group as main contributor.

CONCLUSION: Our findings suggest use of CGM may be associated with improved glycemic control compared to SMBG in CFRD, however evidence of benefit on pulmonary, non-pulmonary and psychosocial outcomes are lacking.

PMID:35906171 | DOI:10.1016/j.jcf.2022.07.013

Prog Biomater. 2022 Jul 29. doi: 10.1007/s40204-022-00198-3. Online ahead of print.

ABSTRACT

Medicinal applications of turmeric-derived curcumin have been known to mankind for long ages. Its potential in managing "cystic fibrosis" has also been evaluated. This autosomal recessive genetic disease is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) which involves an impaired secretion of chloride ions and leads to hypersecretion of thick and sticky mucus and serious complications including airway obstruction, chronic lung infection, and inflammatory reactions. This narrative review aims to highlight the available evidence for the efficacy of curcumin nanoformulations in its potential treatment of cystic fibrosis. Recent research has shown that curcumin acts on the localized mutant CFTR ion channel at the plasma membrane. Preclinical studies have also shown that curcumin nanoformulations have promising effects in the treatment of cystic fibrosis. In this context, the purpose of this narrative review is to highlight the general bioactivity of curcumin, the types of formulations and related studies, thus opening new therapeutic perspectives for CF.

PMID:35904711 | DOI:10.1007/s40204-022-00198-3

Pediatr Gastroenterol Hepatol Nutr. 2022 Jul;25(4):283-292. doi: 10.5223/pghn.2022.25.4.283. Epub 2022 Jul 6.

ABSTRACT

PURPOSE: The prevalence of eosinophilic esophagitis (EoE) has been on the rise since it was first described in the 1990s. Several diseases and exogenous factors have been associated with EoE. Our aim was to investigate the epidemiology of EoE in cystic fibrosis (CF) patients.

METHODS: We identified individuals with CF from September 2014 to September 2019 within a database (IBM Explorys Solutions, Inc.). The prevalence of EoE in patients with CF was compared to the general population.

RESULTS: The database included 36,111,860 patients during the 5-year study period: 12,950 with CF (0.036%) and 28,090 with EoE (0.078%). EoE prevalence was higher in CF patients than the general population (46 in 10,000 vs. 7.8 in 10,000, p<0.001). Patients with CF and EoE were more likely to be male (50% vs. 33.5%, p<0.008), children (33.3% vs. 16.5%, p<0.001), and non-Hispanic (100% vs. 88.7%, p<0.001) than CF patients without EoE. CF with EoE patients were more likely to be children than EoE only (33.3% vs. 10.5%, p<0.001). Allergic conditions were generally more prevalent in CF with EoE than CF only (83.3% vs. 68.3%, p=0.01) and EoE only (83.3% vs. 69.3%, p=0.014).

CONCLUSION: EoE is nearly 6-times more prevalent in CF patients. Those patients had higher incidence of other atopic conditions. EoE must be considered in the differential diagnosis of patients with CF presenting with dysphagia, refractory gastroesophageal reflux, vomiting, and other esophagus-related symptoms.

PMID:35903489 | PMC:PMC9284113 | DOI:10.5223/pghn.2022.25.4.283

Front Microbiol. 2022 Jul 12;13:913882. doi: 10.3389/fmicb.2022.913882. eCollection 2022.

ABSTRACT

Quorum sensing (QS) is an attractive target for the treatment of multidrug-resistant Pseudomonas aeruginosa, against which new antibiotics are urgently needed. Because LasR is at the top of the QS hierarchy controlling Rhl and PQS systems, most QS inhibitors have been targeted to LasR. However, it has recently been reported that in clinical isolates of P. aeruginosa, LasR is frequently mutated and nonfunctional, and RhlR independently acts to produce virulent factors that maintain toxicity. Thus, for effective treatment of chronic cystic fibrosis infections, RhlR antagonists is needed to prevent the LasR-independent Rhl system, but RhlR antagonists have rarely been reported. In this study, we found that curvularin, an aromatic compound with a cyclized alkyl side chain isolated from Phoma macrostoma, at a low micromolar concentration of 1-30 μM potently and selectively inhibited pyocyanin and rhamnolipid production without affecting the cell viability of P. aeruginosa. Only high concentration (more over 100 μM) curvularin negligibly inhibited biofilm formation and elastase production, suggesting that curvularin at low concentrations selectively inhibits RhlR. The QS antagonism by curvularin was investigated in experiments using QS competition and signaling molecules assays with QS gene expression analysis, and the results showed that, indeed, at low concentrations, curvularin selectively antagonized RhlR; in contrast, it negligibly antagonized LasR only when applied at a high concentration. The exclusive RhlR antagonizing activity of curvularin at low concentrations was confirmed using QS mutants; specifically, curvularin at low concentrations inhibited pyocyanin and rhamnolipid production by selectively antagonizing N-butanoyl homoserine lactone (BHL)-activated RhlR. Moreover, by targeting RhlR, curvularin reduced the in vivo virulence of wild-type P. aeruginosa as well as lasR mutants in Caenorhabditis elegans. Overall, low-concentration curvularin is a pure RhlR antagonist in P. aeruginosa, and to the best of our knowledge, this is the first report describing an RhlR antagonist from natural resources. Hence, curvularin has great potential for the development of chronic P. aeruginosa infection therapeutics and for the study of RhlR function in the complex QS system.

PMID:35903467 | PMC:PMC9315252 | DOI:10.3389/fmicb.2022.913882

Front Endocrinol (Lausanne). 2022 Jul 12;13:935354. doi: 10.3389/fendo.2022.935354. eCollection 2022.

ABSTRACT

Since cystic fibrosis (CF) was first described in 1938, there have been many discoveries and innovations in the field, each having a profound impact on survival, growth and quality of life. For example, the introduction of enteric-coated pancreatic enzyme microspheres increased fat absorption and improved nutritional status. Early detection of CF through newborn screening facilitated prompt nutritional intervention for infants at high risk of malnutrition. Use of anti-pseudomonal therapy, such as inhaled tobramycin, increased weight gain and pulmonary function in addition to reducing pulmonary exacerbations. Similarly, DNAse and hypertonic saline improved pulmonary function and reduced exacerbations. The identification of the CFTR gene and its protein product were fundamental in understanding the pathophysiology of CF and paved the way for advances in both diagnosis and management. In fact, CFTR modulator therapies have revolutionized the care for individuals with CF. Here, we examine the impact of these interventions on the nutritional status, growth and pubertal maturation of children and adolescents with CF.

PMID:35903281 | PMC:PMC9317724 | DOI:10.3389/fendo.2022.935354

Adv Redox Res. 2022 Jul;5:100040. doi: 10.1016/j.arres.2022.100040. Epub 2022 Jun 9.

ABSTRACT

Cystic fibrosis-related diabetes (CFRD) is one the most common comorbidities in cystic fibrosis (CF). Pancreatic oxidative stress has been postulated in the pathogenesis of CFRD, but no studies have been done to show an association. The main obstacle is the lack of suitable animal models and no immediate availability of pancreas tissue in humans. In the CF porcine model, we found increased pancreatic total glutathione (GSH), glutathione disulfide (GSSG), 3-nitrotyrosine- and 4-hydroxynonenal-modified proteins, and decreased copper zinc superoxide dismutase (CuZnSOD) activity, all indicative of oxidative stress. CF pig pancreas demonstrated increased DHE oxidation (as a surrogate marker of superoxide) in situ compared to non-CF and this was inhibited by a SOD-mimetic (GC4401). Catalase and glutathione peroxidase activities were not different between CF and non-CF pancreas. Isolated CF pig islets had significantly increased DHE oxidation, peroxide production, reduced insulin secretion in response to high glucose and diminished secretory index compared to non-CF islets. Acute treatment with apocynin or an SOD mimetic failed to restore insulin secretion. These results are consistent with the hypothesis that CF pig pancreas is under significant oxidative stress as a result of increased O2 ●- and peroxides combined with reduced antioxidant defenses against reactive oxygen species (ROS). We speculate that insulin secretory defects in CF may be due to oxidative stress.

PMID:35903252 | PMC:PMC9328447 | DOI:10.1016/j.arres.2022.100040

Front Mol Biosci. 2022 Jul 12;9:905468. doi: 10.3389/fmolb.2022.905468. eCollection 2022.

ABSTRACT

Cystic Fibrosis (CF) patients are prone to contracting bacterial lung infections with opportunistic pathogens, especially Pseudomonas aeruginosa. Prolonged P. aeruginosa infections have been linked to chronic inflammation in the CF lung, whose hallmarks are increased levels of cytokines (i.e., TNF-α, IL-1β, IL-6) and neutrophil attraction by chemokines, like IL-8. Recently, insulin-like growth factor binding protein 6 (IGFBP-6) has been shown to play a putative role in the immune system and was found at higher levels in the sera and synovial tissue of rheumatoid arthritis patients. Moreover, it has been demonstrated that IGFBP-6 has chemoattractant properties towards cells of the innate (neutrophils, monocytes) and adaptive (T cells) immunity. However, it is not known whether IGFBP-6 expression is dysregulated in airway epithelial cells under infection/inflammatory conditions. Therefore, we first measured the basal IGFBP-6 mRNA and protein levels in bronchial epithelial cells lines (Wt and F508del-CFTR CFBE), finding they both are upregulated in F508del-CFTR CFBE cells. Interestingly, LPS and IL-1β+TNFα treatments increased the IGFBP-6 mRNA level, that was reduced after treatment with an anti-inflammatory (Dimethyl Fumarate) in CFBE cell line and in patient-derived nasal epithelial cultures. Lastly, we demonstrated that IGFBP-6 reduced the level of pro-inflammatory cytokines in both CFBE and primary nasal epithelial cells, without affecting rescued CFTR expression and function. The addition of a neutralizing antibody to IGFBP-6 increased pro-inflammatory cytokines expression under challenge with LPS. Together, these data suggest that IGFBP-6 may play a direct role in the CF-associated inflammation.

PMID:35903151 | PMC:PMC9322660 | DOI:10.3389/fmolb.2022.905468

Front Mol Biosci. 2022 Jul 12;9:975946. doi: 10.3389/fmolb.2022.975946. eCollection 2022.

NO ABSTRACT

PMID:35903150 | PMC:PMC9315944 | DOI:10.3389/fmolb.2022.975946

BMC Pulm Med. 2022 Jul 28;22(1):287. doi: 10.1186/s12890-022-02078-9.

ABSTRACT

BACKGROUND: Relationships between gut microbiomes and airway immunity have been established in murine and human studies of allergy and asthma. Early life Lactobacillus supplementation alters the composition and metabolic productivity of the gut microbiome. However, little is known of how Lactobacillus supplementation impacts the gut microbiota in children with cystic fibrosis (CF) and whether specific microbiota states that arise following gut microbiome manipulation relate to pulmonary outcomes.

METHODS: Stool samples were collected from CF patients enrolled in a multi-center, double-blind, randomized placebo-controlled trial of daily Lactobacillus rhamnosus strain GG (LGG) probiotic supplementation over a 12-month period. Fecal 16S rRNA biomarker sequencing was used to profile fecal bacterial microbiota and analyses were performed in QiiME.

RESULTS: Bifidobacteria-dominated fecal microbiota were more likely to arise in LGG-treated children with CF (P = 0.04). Children with Bifidobacteria-dominated gut microbiota had a reduced rate of pulmonary exacerbations (IRR = 0.55; 95% CI 0.25 to 0.82; P = 0.01), improved pulmonary function (+ 20.00% of predicted value FEV1; 95% CI 8.05 to 31.92; P = 0.001), lower intestinal inflammation (Calprotectin; Coef = - 16.53 μg g-1 feces; 95% CI - 26.80 to - 6.26; P = 0.002) and required fewer antibiotics (IRR = 0.43; 95% CI 0.22 to 0.69; P = 0.04) compared to children with Bacteroides-dominated microbiota who were less likely to have received LGG.

CONCLUSIONS: The majority of pediatric CF patients in this study possessed a Bacteroides- or Bifidobacteria-dominated gut microbiota. Bifidobacteria-dominated gut microbiota were more likely to be associated with LGG-supplementation and with better clinical outcomes.

PMID:35902830 | DOI:10.1186/s12890-022-02078-9

J Clin Invest. 2022 Jul 28:e154571. doi: 10.1172/JCI154571. Online ahead of print.

ABSTRACT

The vast majority of people with cystic fibrosis (CF) are now eligible for CF transmembrane regulator (CFTR) modulator therapy. Remaining individuals harbor premature termination codons (PTCs) or rare CFTR variants with limited treatment options. Although clinical modulator response can be reliably predicted using primary airway epithelial cells, primary cells carrying rare CFTR variants are scarce. To overcome this obstacle, cell lines can be created by overexpression of mouse Bmi-1 and human TERT (hTERT). Using this approach, we developed two non-CF and six CF airway epithelial cell lines, three of which are homozygous for the W1282X PTC variant. Bmi-1/hTERT cell lines recapitulated primary cell morphology and ion transport function. The two F508del-CFTR cell lines responded robustly to CFTR modulators, which was mirrored in the parent primary cells and in the cell donors' clinical response. Cereblon E3 ligase modulators targeting eRF3a rescued W1282X-CFTR function to ~20% of wildtype levels and, when paired with G418, rescued G542X-CFTR function to ~50% of wildtype levels. Intriguingly, eRF3a degraders also diminished epithelial sodium channel (ENaC) function. These studies demonstrate that Bmi-1/hTERT cell lines faithfully mirror primary cell responses to CFTR modulators and illustrate a therapeutic approach to rescue CFTR nonsense mutations.

PMID:35900863 | DOI:10.1172/JCI154571