利拉鲁肽,胰高血糖素样肽1类似物,用于治疗2型糖尿病和肥胖症,是胆汁酸(BA)腹泻的潜在新治疗方式。这里,我们显示利拉鲁肽的给药显著降低了总BA,尤其是主要的BA,包括胆酸,鹅去氧胆酸,牛磺胆酸,牛磺鹅去氧胆酸,甘胆酸,和β-嗜酸,肝脏和粪便.此外,利拉鲁肽显著降低色氨酸代谢产物,包括L-色氨酸,血清素,5-羟基吲哚-3-乙酸,L-犬尿氨酸,和xanthurenic酸,在结肠中,而显着增加吲哚-3-丙酸。此外,利拉鲁肽显著降低了根尖钠依赖性胆汁酸转运体的表达,介导BA在回肠顶端刷状边缘成员的摄取,回肠BA结合蛋白,和成纤维细胞生长因子15与BA激活的核受体法尼醇X受体和异聚有机溶质转运体Ostα/β的表达降低有关,诱导BA排泄,在回肠.利拉鲁肽急剧降低了食物剥夺小鼠的体重和血糖水平,与血浆胰岛素和5-羟色胺水平降低有关。这些发现表明利拉鲁肽作为结肠原发性BA和5-羟色胺的新型抑制剂的潜力。
Liraglutide, a glucagon-like peptide 1 analog used to treat type 2 diabetes and obesity, is a potential new treatment modality for bile acid (BA) diarrhea. Here, we show that administration of liraglutide significantly decreased total BAs, especially the primary BAs, including cholic acid, chenodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid, glycocholic acid, and β-muricholic acid, in the liver and feces. In addition, liraglutide significantly decreased tryptophan metabolites, including L-tryptophan, serotonin, 5-hydroxy indole-3-acetic acid, L-kynurenine, and xanthurenic acid, in the colon, whereas it significantly increased indole-3-propionic acid. Moreover, the administration of liraglutide remarkably decreased the expression of apical sodium-dependent bile acid transporter, which mediates BA uptake across the apical brush border member in the ileum, ileal BA binding protein, and fibroblast growth factor 15 in association with decreased expression of the BA-activated nuclear receptor farnesoid X receptor and the heteromeric organic solute transporter Ostα/β, which induces BA excretion, in the ileum. Liraglutide acutely decreased body weight and blood glucose levels in association with decreases in plasma insulin and serotonin levels in food-deprived mice. These findings suggest the potential of liraglutide as a novel inhibitor of primary BAs and serotonin in the colon.