Lane Elizabeth, Petsakou Afroditi, Liu Ying, Chen Weihang, Qadiri Mujeeb, Hu Yanhui, Perrimon Norbert
Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, 7 02115, USA.
HHMI, Harvard Medical School, Boston, MA, 02115, USA.
bioRxiv. 2025 Jul 5:2025.07.02.662792. doi: 10.1101/2025.07.02.662792.
Cystic Fibrosis (CF) is a monogenic genetic disease caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) chloride/bicarbonate channel, which is expressed in certain epithelia cells. Current therapies focus on restoring CFTR function but many gut-related pathologies persist, highlighting the need for complementary treatments to improve the quality of life of patients living with CF. In this study, we use as a model to investigate the gut-specific effects of loss. We demonstrate that enterocyte-specific knockdown of in flies recapitulates several CF pathologies, including reduced intestinal motility, nutrient malabsorption, and decreased energy stores. Using single-nuclei RNA sequencing (snRNA-seq), we identify significant transcriptional changes in the CF model gut, including the upregulation of which leads to reduced cholinergic signaling. Cholinergic signaling has been shown to affect CFTR function but this is the first time CFTR loss of function has been shown to alter cholinergic signaling. Functional assays confirm that cholinergic sensitivity is diminished in CF guts and restoring cholinergic signaling via knockdown rescues multiple CF-associated phenotypes. Furthermore, we identify the transcription factor Forkhead (Fkh), the homolog of human FOXA1/FOXA2, which is known to be a positive regulator of in the intestine, as a positive regulator of expression in CF guts. This study establishes the gut as a powerful model to investigate CF pathogenesis, genetic modifiers, and identifies Ace and Fkh as genetic modifiers. This work also suggests that enhancing cholinergic signaling may represent a viable therapeutic strategy for gastrointestinal manifestations of CF.
囊性纤维化（CF）是一种单基因遗传病，由囊性纤维化跨膜传导调节因子（CFTR）氯离子/碳酸氢根通道突变引起，该通道在某些上皮细胞中表达。目前的治疗方法侧重于恢复CFTR功能，但许多与肠道相关的病理状况仍然存在，这凸显了需要补充治疗以改善CF患者的生活质量。在本研究中，我们使用[具体内容缺失]作为模型来研究[具体内容缺失]缺失的肠道特异性影响。我们证明，在果蝇中肠上皮细胞特异性敲低[具体内容缺失]可重现几种CF病理状况，包括肠道蠕动减少、营养吸收不良和能量储备减少。使用单核RNA测序（snRNA-seq），我们在CF模型肠道中鉴定出显著的转录变化，包括[具体内容缺失]的上调，这导致胆碱能信号传导减少。胆碱能信号传导已被证明会影响CFTR功能，但这是首次证明CFTR功能丧失会改变胆碱能信号传导。功能测定证实CF肠道中的胆碱能敏感性降低，通过敲低[具体内容缺失]恢复胆碱能信号传导可挽救多种与CF相关的表型。此外，我们鉴定出转录因子叉头（Fkh），它是人类FOXA1/FOXA2的同源物，已知是肠道中[具体内容缺失]的正调节因子，作为CF肠道中[具体内容缺失]表达的正调节因子。本研究建立了[具体内容缺失]肠道作为研究CF发病机制、遗传修饰因子的强大模型，并鉴定出Ace和Fkh作为遗传修饰因子。这项工作还表明，增强胆碱能信号传导可能是CF胃肠道表现的一种可行治疗策略。
