Section of Molecular Metabolism and Nutrition, Laboratory of Pediatrics, University of Groningen, University Medical Center Groningen , Groningen , The Netherlands.
Pediatric Gastroenterology and Hepatology, University of Groningen, University Medical Center , Groningen , The Netherlands.
Am J Physiol Gastrointest Liver Physiol. 2019 Mar 1;316(3):G404-G411. doi: 10.1152/ajpgi.00188.2018. Epub 2019 Jan 17.
The gastrointestinal phenotype of cystic fibrosis (CF) features intestinal bile acid (BA) malabsorption, impaired intestinal farnesoid X receptor (FXR) activation, and consequently reduced fibroblast growth factor 19 (FGF19, FGF15 in mice) production. The osmotic laxative polyethylene glycol (PEG) has been shown to decrease intestinal mucus accumulation in CF mice and could, by doing so, improve BA reabsorption. Here we determined the effect of PEG on BA excretion and FXR-FGF15 signaling in CF mice. Male Cftr (CF) and wild-type (WT) littermates were administered PEG 4000 in drinking water and fed either chow or a semisynthetic diet. PEG was withdrawn for 3 days before termination. Fecal BA excretion was measured at PEG dosages of 37 g/l (100%) and 0 g/l (0%). Ileal FXR activation was assessed by gene expression of its downstream targets Fgf15 and small heterodimer partner ( Shp). In CF mice, PEG withdrawal increased fecal BA excretion on either diet compared with full PEG dosage (chow, 2-fold, P = 0.06; semisynthetic, 4.4-fold, P = 0.007). PEG withdrawal did not affect fecal BA excretion in WT mice on either diet. After PEG withdrawal, gene expression levels of intestinal FXR target genes Fgf15 and Shp were decreased in CF mice but unaffected in WT littermates. PEG did not affect the gene expression of the main intestinal BA transporter apical sodium-dependent bile acid transporter (ASBT). PEG treatment ameliorates intestinal BA malabsorption in CF mice and restores intestinal FXR-FGF15 signaling, independent from Asbt gene expression. These findings highlight the potential of PEG in the prevention and treatment of the gastrointestinal phenotype of CF. NEW & NOTEWORTHY A gastrointestinal feature of cystic fibrosis is bile acid malabsorption and consequent impairment of farnesoid X receptor (FXR)-fibroblast growth factor 15 (FGF15) signaling. FXR-FGF15 signaling regulates various metabolic processes and could be implicated in metabolic and gastrointestinal complications of cystic fibrosis, such as diabetes and liver disease. In cystic fibrosis mice, treatment with the osmotic laxative polyethylene glycol is associated with decreased fecal bile acid loss and restoration of FXR-FGF15 signaling.
囊性纤维化（CF）的胃肠道表型特征为肠道胆汁酸（BA）吸收不良、肠法尼醇 X 受体（FXR）激活受损，进而导致成纤维细胞生长因子 19（FGF19，在小鼠中为 FGF15）产生减少。渗透型轻泻剂聚乙二醇（PEG）已被证明可减少 CF 小鼠的肠道粘液积聚，并可由此改善 BA 重吸收。本研究旨在确定 PEG 对 CF 小鼠 BA 排泄和 FXR-FGF15 信号传导的影响。雄性 Cftr（CF）和野生型（WT）同窝仔鼠给予 PEG 4000 饮用水，并分别给予标准饲料或半合成饮食。在处死前，PEG 停用 3 天。PEG 剂量为 37 g/L（100%）和 0 g/L（0%）时，测定粪便 BA 排泄量。通过其下游靶基因 Fgf15 和小异二聚体伴侣（Shp）的基因表达来评估回肠 FXR 激活情况。在 CF 小鼠中，与 PEG 全剂量时相比，PEG 停用后两种饮食的粪便 BA 排泄均增加（标准饲料，2 倍，P=0.06；半合成饮食，4.4 倍，P=0.007）。PEG 停用对 WT 同窝仔鼠两种饮食的粪便 BA 排泄均无影响。PEG 停用后，CF 小鼠的肠道 FXR 靶基因 Fgf15 和 Shp 的基因表达水平降低，但 WT 同窝仔鼠不受影响。PEG 不影响主要肠道 BA 转运体顶端钠依赖性胆汁酸转运体（ASBT）的基因表达。PEG 治疗可改善 CF 小鼠的肠道 BA 吸收不良，并恢复肠道 FXR-FGF15 信号，与 Asbt 基因表达无关。这些发现强调了 PEG 在预防和治疗 CF 胃肠道表型中的潜力。
