BACKGROUND:In people with cystic fibrosis (pwCF), identification of exocrine pancreatic insufficiency (EPI) is essential to prevent steatorrhea and, if not managed actively, can lead to catastrophic consequences. Fecal elastase-1 (FE-1) is a widely used test to screen for EPI in cystic fibrosis (CF). Once thought permanent, some patients with EPI on CF transmembrane conductance regulator (CFTR)-directed therapies (modulators) have been noted to show improvement in EPI. Here, we evaluated the utility of FE-1 in pwCF. METHODOLOGY:We performed a scoping review and searched several databases for the terms/concepts of "cystic fibrosis" and "fecal elastase-1" and their synonyms. The search period was from 1-1-2003 to 7-31-2025. We included all age groups and used a web-based platform for compiling and sorting out the articles. RESULTS:We combined the eligible studies to synthesize information on four questions: Utilization of FE-1 in CF (when to screen for EPI, how often to screen); Comparison of diagnostic accuracy of FE-1 versus other tests; Definition of ideal cut-off for FE-1 in evaluating EPI in CF; Utilization of FE-1 in pwCF managed on CFTR-directed therapies. CONCLUSION:All pwCF should have EPI evaluated at diagnosis. Among various tests, FE-1 is the most commonly utilized test for screening EPI. A value of < 200 μg/g of stool is consistent with EPI and is highly sensitive for EPI diagnosis. A value of < 100 μg/g is highly specific for severe EPI. Repeating FE-1 should be considered in the current era of modulators, especially with a change in clinical status.

Although the pancreas is the organ that produces the most critical digestive enzymes, there are other important contributors to the cleavage of food into absorbable units. Pre-pancreatic digestion of carbohydrates occurs through the action of salivary amylase. Pre-pancreatic digestion of fats is mediated by lingual and gastric lipases, and their action may be important as a signal for coordinated digestion. Pepsin, which is present in the stomach, initiates the digestion of dietary proteins into peptides and amplifies distal proteolysis. The major post-pancreatic intestinal carbohydrate-digesting enzymes are sucrase-isomaltase, maltase-glucoamylase and lactase-phlorizin hydrolase. There are no post-pancreatic mucosal enzymes that act on dietary triglycerides; however, the complete digestion of phospholipids depends on several brush border phospholipases. Intestinal processing is an important contributor to digestion of proteins, although mucosal proteases may serve as signaling proteins rather than as primary adjuncts to dietary protein digestion and absorption. This review describes the role of these non-pancreatic digestive enzymes in supporting nutritional health.

Background Pancreatic enzyme replacement therapy (PERT) prevents malnutrition in people with exocrine pancreatic insufficiency, including those with cystic fibrosis (CF). We developed a lipase that is stable against proteolysis and at the pH of the fed stomach, so it can be taken during a meal to promote mixing of enzyme and substrate. We designed a dose-ranging study of ANG003, a microbial PERT combining this lipase with low pH-stable protease and amylase, also of microbial origin. Methods This was a multicenter, randomized evaluation of ANG003 in subjects with CF, studied once without PERT and again after randomization to a single dose level of four possible combinations of lipase, protease, and amylase. We developed blood-based substrate absorption challenge tests employing DHA+EPA, whey and potato starch to determine dose-response to each of these enzymes, respectively. Results ANG003 improved DHA+EPA absorption with a statistically significant increase with 80 mg and 120 mg lipase doses compared to 20 mg (p = 0.03; p = 0.004). The absorption of total fats followed a similar pattern to DHA+EPA. There was a significant increase in absorbed amino acid equivalents, reflecting proteolysis, over no PERT in the highest (75 mg) dose of protease (p = 0.03). In subjects without diabetes, glucose was slightly lower while c-peptide levels remained unchanged with all amylase doses. Adverse events were mild and transient. No serious adverse events occurred. Conclusions ANG003 lipase significantly improves DHA+EPA and total fat absorption in a dose dependent manner. Results for ANG003 protease and amylase activity suggest that doses lower than those in current porcine-derived PERTs may be efficacious.

Introduction Current methods to measure the effectiveness of pancreatic protease activity are inadequate. We explored the measurement of peptide-derived amino acids following ingestion of dietary whey substrate as a sensitive test of exogenous protease activity in exocrine pancreatic insufficient (EPI) pigs. Methods We studied the activity of aspergillus protease given in combination with a novel lipase and fungal amylase, as well as commercially available pancrelipase in EPI pigs. After a high-fat diet plus a standardized dietary whey substrate, blood was withdrawn at intervals and was analyzed for amine groups using a modified ninhydrin reaction. Plasma peptide-derived amino acids were calculated. Results The AUC 6 peptide-derived amino acid concentration was significantly increased in response to aspergillus protease as follows: 50 mg dose (137% increase; p = 0.05), 75 mg dose (154% increase; p = 0.008) compared to no enzyme. The AUC 6 for peptide-derived amino acids after aspergillus protease increased by 133% for the 50 mg dose (p = 0.0044), by 171% for the 75 mg dose (p = 0.0002), and by 113% with 600 mg pancrelipase (p < 0.0001) when compared to no enzyme. Administration of 75 mg of aspergillus protease led to significantly higher peptide-derived amino acid AUC 6 and Cmax when compared to 600 mg pancrelipase (p = 0.0419 and 0.0103, respectively). Conclusion In EPI pigs, measurement of peptide-derived amino acids following a meal with whey substrate differentiates the activity of aspergillus protease compared to no enzyme and the 75 mg dose was superior to pancrelipase. The evidence presented here in EPI pigs demonstrates that the whey substrate absorption challenge test reflects the proteolytic activity of different doses of exogenous pancreatic proteases.

The COVID-19 pandemic necessitated a rapid shift in clinical research to perform virtual visits and remote endpoint assessments, providing a key opportunity to optimize the use of remote endpoints for clinical trials in cystic fibrosis. The use of remote endpoints could allow more diverse participation in clinical trials while minimizing participant burden but must be robustly evaluated to ensure adequate performance and feasibility. In response, the Cystic Fibrosis Foundation convened the Remote Endpoint Task Force (Supplemental Table 1), a multidisciplinary group of CF researchers with remote endpoint expertise and community members tasked to better understand the current and future use of remote endpoints for clinical research. Here, we describe the current use of remote endpoints in CF clinical research, address key unanswered questions regarding their use and feasibility, and discuss the next steps to determine clinical trial readiness.

Background Gastrointestinal symptoms in cystic fibrosis (CF) are common and intrusive to daily life. Relieving gastrointestinal symptoms was identified as an important research priority and previously explored in an international survey in 2018. However, following the widespread introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators in 2019, the landscape of CF treatment has changed. We repeated an online survey to further describe gastrointestinal symptoms and their effect on quality of life (QoL) in the CFTR modulator era. Methods An electronic survey consisting of closed questions and free text responses was distributed via social media and professional networks for a period of one month between March - April 2022. People with CF (pwCF), their family and friends, and healthcare professionals (HCPs) were invited to take part. Results There were 164 respondents: 88 pwCF (54%), 22 (13%) family, and 54 (33%) healthcare professionals (HCPs). A total of 89/110 (81%) pwCF or family members reported CFTR modulator treatment. The most commonly reported symptoms were wind / gas and rumbling stomach noises (borborygmi) in both the modulator and non-modulator groups in addition to loose motions (modulator group) and bloating (no modulator group). Abdominal pain and bloating had the greatest impact on QoL. For those on a CFTR modulator, the proportion of pwCF reporting “no change” or “worse” for all of the symptoms surveyed was greater than the proportion reporting an improvement. For some symptoms such as stomach pains and reduced appetite, improvements were perceived more commonly in HCPs than what was reported by pwCF. Following modulator introduction, dietary changes to manage GI symptoms were recommended by 28/35 (80%) of HCPs and reported by 38/76 (50%) lay respondents. Changes in medication were recommended by 19/35 (54%) HCPs and reported by 44/76 (58%) of patients and family members. Conclusion This survey has shown that gastrointestinal symptoms remain prevalent in pwCF in the CFTR modulator era, though the nature of these symptoms may have changed. A better understanding of the underlying pathophysiology of these symptoms is essential. Future clinical studies should focus on improving symptoms and QoL.

Background People with cystic fibrosis (CF) can experience recurrent chest infections, pancreatic exocrine insufficiency and gastrointestinal symptoms. New cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs improve lung function but gastrointestinal effects are unclear. We aimed to see if a CFTR modulator (tezacaftor-ivacaftor,TEZ/IVA) improves gastrointestinal outcomes in CF. Methods We conducted a randomised, double-blind, placebo-controlled, two-period crossover trial (2019-2020) at Nottingham University Hospitals. The effects of TEZ/IVA on gut physiology were measured using MRI. Participants were randomly assigned to treatment sequences AB or BA (A:TEZ/IVA, B:placebo, each 28 days), with a 28-day washout period. Participants had serial MRI scans at baseline and after 19-23 days of each treatment. Due to the COVID-19 pandemic, a protocol amendment allowed for observer-blind comparisons prior to and during TEZ/IVA. In such cases, participants were not blind to the treatment but researchers remained blind. The primary outcome was oro-caecal transit time (OCTT). Secondary outcomes included MRI metrics, symptoms and stool biomarkers. Results We randomised 13 participants. Before the COVID-19 pandemic 8 participants completed the full protocol and 1 dropped out. The remaining 4 participants followed the amended protocol. There were no significant differences between placebo and TEZ/IVA for OCTT (TEZ/IVA >360minutes [225,>360] vs. placebo 330minutes [285,>360], p=0.8) or secondary outcomes. There were no adverse events. Conclusions Our data contribute to a research gap in the extra-pulmonary effects of CFTR modulators. We found no effect after TEZ/IVA on MRI metrics of gut function, GI symptoms or stool calprotectin. Effects might be detectable with larger studies, longer treatment or more effective CFTR modulators. ClinicalTrials.gov registration NCT04006873 (02/07/2019)

Protein maldigestion and malabsorption lead to malnutrition and are a feature of exocrine pancreatic insufficiency (EPI). Although it is the current standard, measurement of nitrogen in stool to assess protease activity is indirect. Up to 80% of hydrolysed proteins ap-pear in blood in the form of peptides, so we developed a method to measure peptide-derived amino acids in plasma as a relevant measure of proteolysis, verified its accuracy, precision, and linearity, and validated it in a porcine model. We modified a ninhydrin method. Large proteins were eliminated from plasma with 10kDa-cut-off centrifugal filters. Free and total amino acids were mea-sured in permeate before and after its hydrolysis. Peptide-derived amino acids were quantified by subtracting free amino acids from total amino acids. We verified the method in vitro and by comparing results in healthy and EPI pigs. The accuracy of the analysis was close to 100%, with excellent precision (mean relative standard deviation for low, medium, and high amino acid levels 1/40.88%) and with stringent linearity (r2 1/40.986, %RE 1/45.23). The high-throughput ninhydrin method detected levels of peptide-derived amino acids in vivo with maximal changes seen approximately 2 hours postprandially in young pigs. The AUC and Cmax were significantly higher in healthy compared to EPI pigs (P 1/4 .0026 and P 1/4 .0037, respectively). The high-throughput ninhydrin method is a sensitive, reliable, and practical method for the estimation of dietary peptide-derived amino acids. This assay endpoint could serve as a direct biomarker of protein digestion and absorption.

Background Changes in upper airway microbiota may impact early disease manifestations in infants with cystic fibrosis (CF). To investigate early airway microbiota, the microbiota present in the oropharynx of CF infants over the first year of life was assessed along with the relationships between microbiota and growth, antibiotic use and other clinical variables. Methods Oropharyngeal (OP) swabs were collected longitudinally between 1 and 12 months of age from infants diagnosed with CF by newborn screen and enrolled in the Baby Observational and Nutrition Study (BONUS). DNA extraction was performed after enzymatic digestion of OP swabs. Total bacterial load was determined by qPCR and community composition assessed using 16S rRNA gene analysis (V1/V2 region). Changes in diversity with age were evaluated using mixed models with cubic B-splines. Associations between clinical variables and bacterial taxa were determined using a canonical correlation analysis. Results 1,052 OP swabs collected from 205 infants with CF were analyzed. Most infants (77%) received at least one course of antibiotics during the study and 131 OP swabs were collected while the infant was prescribed an antibiotic. Alpha diversity increased with age and was only marginally impacted by antibiotic use. Community composition was most highly correlated with age and was only moderately correlated with antibiotic exposure, feeding method and weight z-scores. Relative abundance of Streptococcus decreased while Neisseria and other taxa increased over the first year. Conclusions Age was more influential on the oropharyngeal microbiota of infants with CF than clinical variables including antibiotics in the first year of life.

BACKGROUND:High daily doses of pancreatic enzyme replacement therapy (PERT) were historically associated with risk of fibrosing colonopathy (FC) in people with cystic fibrosis (pwCF), leading to development of PERT dosing guidelines and reformulated products. This study quantified incidence of FC in pwCF treated with PERT following those measures. METHODS:This large prospective cohort study included eligible pwCF enrolled in the Cystic Fibrosis Foundation Patient Registry with ≥1 clinic visit in 2012-2014 and follow-up through 2020. Data on PERT exposure, demographics, and medical history were collected. Clinical data, imaging, and histopathology of suspected cases were examined by an independent adjudication panel of physicians familiar with this complication. RESULTS:Base Study Population included 26,025 pwCF who contributed 155,814 person-years [mean (SD) 6.0 (2.0) years] of follow-up. Over 7.8 years, 29 pwCF had suspected FC; three cases were confirmed by adjudication, 22 cases were confirmed as not FC, and four cases were indeterminate. There were 22,161 pwCF exposed to any PERT, with mean PERT use time of 5.583 person-years and mean daily dose of 8328 U lipase per kg per day. All three confirmed cases and four indeterminate cases of FC occurred during current use of PERT. Incidence rates per 1000 person-years exposed were 0.0242 (95 % CI [0.0050, 0.0709]) for confirmed FC and 0.0566 (95 % CI [0.0227, 0.1166]) for indeterminate or confirmed FC. CONCLUSIONS:The incidence of FC in pwCF is very low in the era of current treatment guidelines and more stringent quality standards for PERT products.

Objectives: Airway clearance therapy (ACT) is an important component of therapy for cystic fibrosis (CF) but is associated with significant treatment burden. Highly effective CFTR modulator therapy (HEMT) has improved pulmonary function for many people with CF(pwCF). We sought to understand changes in attitudes and practices about ACT in the post-HEMT era. Study design: Surveys of CF community members and CF care team members Methodology: Separate surveys were created for the CF community and CF care providers to evaluate attitudes towards ACT and exercise in the post-HEMT era. We solicited answers from pwCF via the CF Foundation’s Community Voice and from CF care providers via CF Foundation listservs. Surveys were available between July 20 and August 3, 2021. Results: Surveys were completed by 153 community members (parents of children and pwCF) and 192 CF care providers. Belief that exercise can substitute partially for ACT was endorsed similarly by community members (59%) and providers (68%) . After starting HEMT, 36% of parents of children and 51% of adults did fewer ACT treatments including 13% who stopped ACT. Adults reported altering their ACT regimen more than parents of children. Half of providers had changed their ACT recommendations for those on HEMT. Fifty-three percent of respondents had discussed changing ACT with their care team (36% of parents, 58% of pwCF). Conclusions: Providers should be aware that ACT management changes may have been undertaken by pwCF who have pulmonary benefits of HEMT. Treatment burden should be considered in co-management decisions regarding ACT and exercise.

Introduction The coefficient of fat absorption (CFA) quantifies fat that remains in stool after digestion and is not a direct measure of lipolysis. CFA has been used to assess treatment of pancreatic insufficiency but does not correlate with pancreatic enzyme replacement therapy dose. We explored use of an omega-3 substrate absorption challenge test as a sensitive test of lipolysis and absorption. Methods We studied a novel microbially-derived lipase (SNSP003) employing an established surgical model commonly used to study the uptake of macronutrients, the exocrine pancreatic insufficient pig. Pigs were fed a high-fat diet and given a standardized omega-3 substrate challenge to test the effect of lipolysis on its absorption. Blood was drawn at 0, 1, 2, 4, 6, 8, 12, and 24 hours following the substrate challenge and was analyzed for omega-3 and total fat levels (c14:c24). SNSP003 was also compard to porcine pancrelipase. Results The absorption of omega-3 fats was significantly increased following administration of 40, 80 and 120 mg SNSP003 lipase by 51% (p = 0.02), 89%, (p = 0.001) and 64% (p = 0.01), respectively, compared to that observed when no lipase was administered to the pigs, with Tmax at 4 hours. The two highest SNSP003 doses were compared to porcine pancrelipase and no significant differences were observed. Both doses increased plasma total fatty acids (141% for the 80 mg dose (p = 0.001) and 133% for the 120 mg dose (p = 0.006), compared to no lipase) and no significant differences were observed between the SNSP003 lipase doses and porcine pancrelipase. Conclusion The omega-3 substrate absorption challenge test differentiates among different doses of a novel microbially-derived lipase and correlates with global fat lipolysis and absorption in exocrine pancreatic insufficient pigs. No significant differences were observed between the two highest novel lipase doses and porcine pancrelipase. Studies in humans should be designed to support the evidence presented here that suggests the omega-3 substrate absorption challenge test has advantages over the coefficient of fat absorption test to study lipase activity.

Background and aims: People with cystic fibrosis (PwCF) suffer from gastrointestinal (GI) symptoms af-fecting their quality of life (QOL). Despite the relevance of GI symptoms to the overall health of PwCF, a paucity of studies only have comprehensively assessed the prevalence, severity and QOL of GI symptoms in both children and adults with Cystic Fibrosis (CF). Methods: Eligible participants >= 2 years of age across 26 US CF centers were followed for 4 weeks. Three validated GI electronic patient-reported outcome measures (ePROMs) with a recall period of 2 weeks and a stool-specific questionnaire were administered weekly over four weeks. Total and domain scores of ePROMs were evaluated overall and in subgroups using linear mixed-effect models. Results: Of 402 enrolled, 58% were >= 18 years of age (52% male). The mean (SD) of the total score for PAC-SYM was 0.52 (0.55), for PAGI-SYM was 0.63 (0.67), and for PAC-QOL was 0.67 (0.55). For specific ePROM questions, prevalence of moderate to very severe symptoms were as follows: straining (20.3%), fullness (18.3%), incomplete bowel movements (17.1%), bloating (16.4%), distension (16.4%), abdominal pain (upper-5.1%, lower-7.5%). Comparing participants >= 18 versus < 18, a higher prevalence of bloating (63.7% versus 27.3%), lower abdominal pain (39.8% vs 26.2%), stomach fullness (75.6% versus 56.2%), and abdominal distension (60.2% versus 34.9%) was found. Both age groups reported high treatment dissatis-faction as measured with PAC-QOL, mean 1.39 (95% CI: 1.30, 1.47). Conclusion: GI symptoms were reported in all age ranges irrespective of gender, with higher prevalence observed amongst older and female subgroups. Dissatisfaction with GI targeted treatments were reported in a large proportion of participants despite therapy, highlighting an unmet need for clinical interven-tions. ClinicalTrials.gov: NCT03801993 (c) 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Cystic fibrosis (CF) clinicians may see patients who have difficult-to-manage symptoms that do not have a clear CF-related etiology, such as unusual gastrointestinal (GI) complaints, vasculitis, or arthritis. Alterations in immunity, inflammation and intraluminal dysbiosis create a milieu that may lead to autoimmunity, and the CF transmembrane regulator protein may have a direct role as well. While autoantibodies and other autoimmune markers may develop, these may or may not lead to organ involvement, therefore they are helpful but not sufficient to establish an autoimmune diagnosis. Autoimmune involvement of the GI tract is the best-established association. Next steps to understand autoimmunity in CF should include a more in-depth assessment of the community perspective on its impact. In addition, bringing together specialists in various fields including, but not limited to, pulmonology, gastroenterology, immunology, and rheumatology, would lead to cross-dissemination and help define the path forward in basic science and clinical practice.

Previous wireless motility capsule (WMC) studies demonstrated decreased small intestinal pH in people with CF (PwCF) however the data is lacking on the colonic pH profile. We re-analyzed previously published WMC data to determine colonic pH/bicarbonate concentration and single cell RNA sequencing (sc-RNAseq) to examine the normal expression of acid-base transporters in the colon/rectum.CF patients showed significantly lower pH and bicarbonate concentration values, particularly in the distal rectosigmoid region. There was no difference in colonic motility parameters between CF and non-CF subjects. SLC26A3 is highly expressed bicarbonate transporter in the colon and rectum, more so than CFTR. While dysmotility can alter intraluminal pH, observed changes likely originate from alterations in intestinal ion transport rather than colonic dysmotility. SLC26A3 is abundantly expressed in the human colon and rectum and may be a therapeutic target for restoration of bicarbonate transport. These findings may help better understand the gastrointestinal symptoms in PwCF.

Background: We conducted a survey in an online forum without prior IRB approval which yielded information we wanted to share with the medical community. We sought approaches to ethically publish the survey's results. Objective: Address the ethical issues raised by considering publication of community forum perspectives without prior regulatory oversight or written informed consent. Methods: A research ethics consultation identified two approaches: 1) assessing community perspectives in general on academic publication and 2) obtaining a collaborative ethics consultation to promote diversity in identifying ethical considerations. Results: Most community respondents were in favor of the concept of publication, noting the value of patient perspectives to improve communication, clinical relationships, and care. Considerations identified by the Collaborative included whether publication is likely to have value, would cause harm to participants, and whether publication would threaten trust. The role of formal oversight was reviewed. Conclusions: There is a reasonable ethical justification for publishing insights gained from a community forum based on evidence of community support for, and value to the community of, the publication, even when prior regulatory oversight was not obtained. Proactive strategies can be applied to obviate this issue.

Background: Concerns related to stool consistency are common in the first year of life among children with cystic fibrosis (CF). However, normal stool patterns for infants with CF have not been described. Methods: Secondary analysis was completed from the previously described BONUS cohort which fol-lowed 231 infants with CF through the first 12 months of life. Pain, stool category, stool frequency, feeding type, PERT dose, acid suppression medication, antibiotics usage, stool softener usage and fecal calprotectin were described at 3, 6, and 12 months. Repeated measure ANOVA was used to test the difference in mean stool number. Generalized linear mixed models were used to investigate the relationship between stool characteristics and various factors. Results: The frequency of constipation was stable throughout the first year of life (10-13%) while watery stool significantly decreased from 21.3% at 3 months to 5.8% at 12 months ( p = < 0.001). The num-ber of stools at months 6 (mean = 2.40) and 12 (mean = 2.50) are significantly lower than in month 3 (mean = 2.83), p < 0.025. Exclusive breast feeding was associated with an increased risk for constipation (OR = 2.64 [1.60-4.37], p = 0.002) while exclusive formula feeding and acid suppression was associ-ated with decreased risk for constipation (OR = 0.40 [0.26-0.61], p = < 0.0 0 01 and OR = 0.59 [0.39-0.89], p = 0.01 respectively). Pain was not significantly associated with stool consistency. Conclusion: Stool frequency and consistency evolves in infant with CF in a fashion similar to that reported in non-CF infants over the first year. Constipation was not associated with pain and was less common among infants receiving acid suppression or exclusively formula feeding. (c) 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.