Hvistendahl Mark Krogh, Naimi Rahim Mohammad, Hansen Svend Høime, Rehfeld Jens Frederik, Kissow Hannelouise, Pedersen Jens, Dragsted Lars Ove, Sonne David Peick, Knop Filip Krag, Jeppesen Palle Bekker
Department of Intestinal Failure and Liver Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
JPEN J Parenter Enteral Nutr. 2022 May;46(4):923-935. doi: 10.1002/jpen.2224. Epub 2021 Sep 1.
The gut-liver axis and enterohepatic circulation have gained increasing attention lately. Patients with short bowel syndrome (SBS) are, in fact, human knock-out models that may assist in the understanding of bile acid synthesis and regulation. We evaluated effect of glepaglutide (a long-acting glucagon-like peptide-2 analog) on bile acid synthesis (the enterohepatic circulation of bile acids and liver biochemistry in patients with SBS).
In a single-center, double-blinded, dose-finding, crossover phase 2 trial, 18 patients with SBS were randomly assigned to 2 of 3 treatment arms (0.1, 1, and 10 mg) with daily subcutaneous injections of glepaglutide for 3 weeks. The washout period between the 2 treatment periods was 4-8 weeks. Measurements were performed at baseline and at the end of each treatment period and included postprandial plasma samples for fibroblast growth factor 19 (FGF19), 7α-hydroxy-4-cholesten-3-one (C4), total excretion of fecal bile acids, gene expression of farnesoid X receptor (FXR) in intestinal mucosal biopsies, total plasma bile acids, and liver biochemistry.
Compared with baseline, the median (interquartile range) postprandial response (area under the curve 0-2h) of FGF19 increased by 150 h × ng/L (41, 195; P = 0.001) and C4 decreased by 82 h × µg/L (-169, -28; p = 0.010) in the 10-mg dose. FXR gene expression did not change in any of the groups. Alkaline phosphatase significantly decreased.
Glepaglutide may stimulate the bile acid/FXR/FGF19 axis, leading to increased plasma concentrations of FGF19. Thereby, glepaglutide may ameliorate the accelerated de novo bile acid synthesis and play a role in the prevention and/or treatment of intestinal failure-associated liver disease.
肠-肝轴和肠肝循环近来日益受到关注。事实上，短肠综合征（SBS）患者是有助于理解胆汁酸合成及调节的人体基因敲除模型。我们评估了格列帕鲁肽（一种长效胰高血糖素样肽-2类似物）对胆汁酸合成（胆汁酸的肠肝循环及SBS患者的肝脏生化指标）的影响。
在一项单中心、双盲、剂量探索性、交叉2期试验中，18例SBS患者被随机分配至3个治疗组中的2组（0.1、1和10毫克），每天皮下注射格列帕鲁肽，共3周。两个治疗期之间的洗脱期为4至8周。在基线期和每个治疗期结束时进行测量，包括餐后血浆样本以检测成纤维细胞生长因子19（FGF19）、7α-羟基-4-胆甾烯-3-酮（C4）、粪便胆汁酸总排泄量、肠黏膜活检中法尼醇X受体（FXR）的基因表达、血浆总胆汁酸以及肝脏生化指标。
与基线相比，10毫克剂量组中，FGF19的餐后反应中位数（四分位间距）（曲线下面积0 - 2小时）增加了150小时×纳克/升（41，195；P = 0.001），C4减少了82小时×微克/升（-169，-28；P = 0.010）。FXR基因表达在任何组中均未改变。碱性磷酸酶显著降低。
格列帕鲁肽可能刺激胆汁酸/FXR/FGF19轴，导致FGF19血浆浓度升高。因此，格列帕鲁肽可能改善胆汁酸的加速从头合成，并在预防和/或治疗肠衰竭相关肝病中发挥作用
