Cystic Fibrosis-Related Gut Dysbiosis: A Systematic Review

Caley, L.R.; White, Helen; Goffau, Marcus C. de; Floto, R. Andres; Parkhill, Julian; Marsland, Benjamin J.; Peckham, Daniel

doi:10.1007/s10620-022-07812-1

Cited by 21 publications

(8 citation statements)

References 155 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This encompasses pulmonary antibiotic usage, which was a key explanator across our multivariate analyses and of high prevalence across pwCF undertaking extended ETI. Though not investigated in the current study, additional research into the ability of specific dietary intake and probiotic usage to shape the microbiota and patient outcomes is desirable [62–64], especially since resilience of the gut microbiota has been recently suggested following diet and exercise intervention in pwCF [65]. It could be that long-term substantial changes to such factors are necessary for subsequent beneficial changes to the intestinal microbiome in an era of modulator therapy.…”

Section: Discussionmentioning

confidence: 99%

Impact of extended Elexacaftor/Tezacaftor/Ivacaftor therapy on the gut microbiome in cystic fibrosis

Marsh,

Dos Santos,

Yule

et al. 2024

Preprint

View full text Add to dashboard Cite

BackgroundThere is a paucity of knowledge on the longer-term effects of CF transmembrane conductance regulator (CFTR) modulator therapies upon the gut microbiome and associated outcomes. In a pilot study, we investigated longitudinal Elexacaftor/Tezacaftor/Ivacaftor (ETI) therapy on the gut microbiota, metabolomic functioning, and clinical outcomes in people with CF (pwCF).Study designFaecal samples from 20 pwCF were acquired before and then following 3, 6, and 17+ months of ETI therapy. Samples were subjected to microbiota sequencing and targeted metabolomics to profile and quantify short-chain fatty acid composition. Ten healthy matched controls were included for comparison. Clinical data, including markers of intestinal function were integrated to investigate relationships.ResultsExtended ETI therapy increased core microbiota diversity and composition, which translated to gradual shifts in whole microbiota composition towards that observed in healthy controls. Despite becoming more similar over time, CF microbiota and functional metabolite compositions remained significantly different to healthy controls. Antibiotic treatment for pulmonary infection significantly explained a relatively large degree of variation within the whole microbiota and rarer satellite taxa. Clinical outcomes were not significantly different following ETI.ConclusionsA positive trajectory towards the microbiota observed in healthy controls was found. However, we posit that progression was predominately impeded by pulmonary antibiotics administration. We recommend future studies use integrated omics approaches within a combination of long-term longitudinal patient studies and model experimental systems. This will deepen our understanding of the impacts of CFTR modulator therapy and respiratory antibiotic interventions upon the gut microbiome and gastrointestinal pathophysiology in CF.

show abstract

Section: Discussionmentioning

confidence: 99%

Impact of extended Elexacaftor/Tezacaftor/Ivacaftor therapy on the gut microbiome in cystic fibrosis

Marsh,

Dos Santos,

Yule

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Cystic fibrosis is a genetic disease affecting the normal functions of multiple organs including the lungs, pancreas and gastrointestinal tract with a pronounced inability of patients to digest and absorb proteins and lipids [ 61 ]. A gut dysbiosis notably characterized by a bloom of Enterobacteriaceae is associated with cystic fibrosis [ 62 ]. Indeed, E. coli that normally represents less than 1% of the gut microbiota can reach more than 90% in the fecal microbiota of young children with cystic fibrosis, compared with age-matched healthy controls [ 63 ].…”

Section: Proteobacteria/ Enterobacteriaceae Expans...mentioning

confidence: 99%

Enterobacteriaceae in the Human Gut: Dynamics and Ecological Roles in Health and Disease

Moreira de Gouveia,

Bernalier-Donadille,

Jubelin

2024

Biology

View full text Add to dashboard Cite

The human gut microbiota plays a crucial role in maintaining host health. Our review explores the prevalence and dynamics of Enterobacteriaceae, a bacterial family within the Proteobacteria phylum, in the human gut which represents a small fraction of the gut microbiota in healthy conditions. Even though their roles are not yet fully understood, Enterobacteriaceae and especially Escherichia coli (E. coli) play a part in creating an anaerobic environment, producing vitamins and protecting against pathogenic infections. The composition and residency of E. coli strains in the gut fluctuate among individuals and is influenced by many factors such as geography, diet and health. Dysbiosis, characterized by alterations in the microbial composition of the gut microbiota, is associated with various diseases, including obesity, inflammatory bowel diseases and metabolic disorders. A consistent pattern in dysbiosis is the expansion of Proteobacteria, particularly Enterobacteriaceae, which has been proposed as a potential marker for intestinal and extra-intestinal inflammatory diseases. Here we develop the potential mechanisms contributing to Enterobacteriaceae proliferation during dysbiosis, including changes in oxygen levels, alterations in mucosal substrates and dietary factors. Better knowledge of these mechanisms is important for developing strategies to restore a balanced gut microbiota and reduce the negative consequences of the Enterobacteriaceae bloom.

show abstract

“…Gastrointestinal dysbiosis, as seen in celiac disease [ 50 ], inflammatory bowel disease [ 52 ], acute COVID-19 [ 53 ], and post-COVID complications [ 54 ], have all been associated with increased zonulin release. While zonulin levels have not been reported in CF, dysbiosis in CF is well established [ 55 ▪▪ ]. CFTR-/- murine models display increased evidence of zonulin-mediated intestinal permeability [ 56 ].…”

Section: Mechanistic Hypothesismentioning

confidence: 99%

Neuropsychiatric adverse effects from CFTR modulators deserve a serious research effort

VanElzakker,

Tillman,

Yonker

et al. 2023

Current Opinion in Pulmonary Medicine

View full text Add to dashboard Cite

Purpose of review This review highlights the problem of neuropsychiatric adverse effects (AEs) associated with elexacaftor/tezacaftor/ivacaftor (ETI), current suboptimal mitigation approaches, a novel testable mechanistic hypothesis, and potential solutions requiring further research. Recent findings Studies show that a minority of persons with cystic fibrosis (PwCF) initiating cystic fibrosis transmembrane conductance regulator (CFTR) modulators experience neuropsychiatric AEs including worsening mood, cognition, anxiety, sleep, and suicidality. The GABA-A receptor is a ligand-gated chloride channel, and magnetic resonance spectroscopy neuroimaging studies have shown that reduced GABA expression in rostral anterior cingulate cortex is associated with anxiety and depression. Recent research details the impact of peripheral inflammation and the gut-brain axis on central neuroinflammation. Plasma ETI concentrations and sweat chloride have been evaluated in small studies of neuropsychiatric AEs but not validated to guide dose titration or correlated with pharmacogenomic variants or safety/efficacy. Summary Although ETI is well tolerated by most PwCF, some experience debilitating neuropsychiatric AEs. In some cases, these AEs may be driven by modulation of CFTR and chloride transport within the brain. Understanding biological mechanisms is a critical next step in identifying which PwCF are likely to experience AEs, and in developing evidence-based strategies to mitigate them, while retaining modulator efficacy.

show abstract

Cystic Fibrosis-Related Gut Dysbiosis: A Systematic Review

Cited by 21 publications

References 155 publications

Impact of extended Elexacaftor/Tezacaftor/Ivacaftor therapy on the gut microbiome in cystic fibrosis

Impact of extended Elexacaftor/Tezacaftor/Ivacaftor therapy on the gut microbiome in cystic fibrosis

Enterobacteriaceae in the Human Gut: Dynamics and Ecological Roles in Health and Disease

Neuropsychiatric adverse effects from CFTR modulators deserve a serious research effort

Contact Info

Product

Resources

About