WS04.01Faecal microbiota changes in people with cystic fibrosis after 6 months of elexacaftor/tezacaftor/ivacaftor: findings from the PROMISE study

IF 5.4 2区医学 Q1 RESPIRATORY SYSTEM

Journal of Cystic Fibrosis Pub Date : 2025-06-01 DOI:10.1016/j.jcf.2025.03.510

J.T. Duong , H.S. Hayden , A.J. Verster , C.E. Pope , C. Miller , K. Penewit , S.J. Salipante , S.M. Rowe , G.M. Solomon , D. Nichols , A. Kelly , S.J. Schwarzenberg , S.D. Freedman , L.R. Hoffman

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引用次数: 0

Abstract

Objectives

People with cystic fibrosis (PwCF) often have fecal dysbioses relative to those without CF, characterized by increased pro-inflammatory microbiota and gastrointestinal (GI) inflammation as measured by fecal calprotectin, suggesting that inflammation contributes to CF GI disease. Consistent with findings in European cohorts, the multicenter observational PROMISE study (NCT04038047) found that calprotectin decreased in PwCF treated with elexacaftor/tezacaftor/ivacaftor (ETI). To better understand the dynamics between fecal dysbiosis and GI inflammation, we characterized the microbiomes of fecal samples from PROMISE and the relationships with calprotectin before, 1-month post, and 6-months post ETI.

Methods

Fecal microbiota of stool samples from subjects ≥12 y/o were determined by shotgun metagenomic sequencing with random forest modeling and multivariate linear regression analysis to define relationships between relationships between microbiota and calprotectin before and after ETI.

Results

We analyzed 345 samples from 124 subjects. At baseline, we observed community-level differences in the fecal microbiota among subjects with abnormal compared to normal calprotectin. With ETI, the relative abundances of 7 bacterial species–Escherichia coli, Staphylococcus aureus, Clostridium scindens, Enterocloster clostridioformis, Clostridium butyricum, Anaeroglobus geminatus, and Ruminococcus gnavus–decreased significantly, correlating with calprotectin decrease. We found community-level differences in the fecal microbiota based on CFTR genotype and a distinct pattern of microbiota change in F508del homozygous compared to heterozygous subjects after ETI.

Conclusion

We identified 7 species for which fecal abundances decreased with ETI and correlated with calprotectin decrease, supporting a close relationship between fecal microbiota and inflammation in PwCF. Future work will define these relationships with metabolites and GI symptoms during long-term ETI therapy.

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来自PROMISE研究的结果：囊性纤维化患者在使用elexaftor /tezacaftor/ivacaftor 6个月后粪便微生物群的变化

与没有CF的人相比，囊性纤维化（PwCF）患者通常有粪便生态失调，其特征是通过粪便钙保护蛋白测量促炎微生物群和胃肠道（GI）炎症增加，这表明炎症有助于CF胃肠道疾病。与欧洲队列研究结果一致，多中心观察性PROMISE研究（NCT04038047）发现，使用eleexaftor /tezacaftor/ivacaftor （ETI）治疗的PwCF患者钙保护蛋白下降。为了更好地了解粪便生态失调与胃肠道炎症之间的动态关系，我们对PROMISE粪便样本的微生物组进行了表征，并分析了ETI前、ETI后1个月和ETI后6个月的微生物组与钙保护蛋白的关系。方法采用霰弹枪宏基因组测序、随机森林模型和多元线性回归分析，对≥12岁受试者的粪便样本进行微生物群测定，确定ETI前后微生物群与钙保护蛋白之间的关系。结果我们分析了124名受试者的345份样本。基线时，我们观察到钙保护蛋白异常与正常受试者粪便微生物群在社区水平上的差异。大肠杆菌、金黄色葡萄球菌、科学梭状芽孢杆菌、梭状芽孢杆菌、丁酸梭状芽孢杆菌、双厌氧红杆菌和瘤状瘤胃球菌7种细菌的相对丰度显著降低，与钙保护蛋白的降低相关。我们发现基于CFTR基因型的粪便微生物群在社区水平上存在差异，并且与杂合子相比，F508del纯合子在ETI后的微生物群变化模式明显。结论发现7种细菌的粪便丰度随ETI而下降，并与钙保护蛋白的减少相关，支持PwCF中粪便微生物群与炎症的密切关系。未来的工作将确定长期ETI治疗期间代谢物和胃肠道症状之间的关系。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Cystic Fibrosis 医学-呼吸系统

CiteScore

10.10

自引率

13.50%

发文量

1361

审稿时长

50 days

期刊介绍： The Journal of Cystic Fibrosis is the official journal of the European Cystic Fibrosis Society. The journal is devoted to promoting the research and treatment of cystic fibrosis. To this end the journal publishes original scientific articles, editorials, case reports, short communications and other information relevant to cystic fibrosis. The journal also publishes news and articles concerning the activities and policies of the ECFS as well as those of other societies related the ECFS.