Alterations in intestinal bile acid transport provide a therapeutic target in patients with post-bariatric hypoglycaemia

IF 18.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Nature metabolism Pub Date : 2025-04-04 DOI:10.1038/s42255-025-01262-5

Snehal N. Chaudhari, Yingjia Chen, Rafael Ferraz-Bannitz, Cameron Cummings, Amanda Sheehan, Pilar Casanova Querol, Berkcan Ozturk, Hanna Wang, Gabriel D’Agostino, Fei Ye, Eric G. Sheu, A. Sloan Devlin, Mary-Elizabeth Patti

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Abstract

While Roux-en-Y gastric bypass is an effective treatment for obesity and type 2 diabetes, up to one-third of patients develop post-bariatric hypoglycaemia (PBH). Individuals with PBH exhibit increased postprandial secretion of the intestinal hormone fibroblast growth factor 19 (FGF19, Fgf15 in mice). However, the underlying mechanisms contributing to PBH remain uncertain. Here we demonstrate that faecal and plasma bile acid (BA) profiles are significantly altered in postoperative individuals with PBH versus those without hypoglycaemia. Furthermore, altered BAs in PBH induce FGF19 secretion in intestinal cells in a manner dependent on the apical sodium-dependent BA transporter (ASBT). We demonstrate that ASBT inhibition reduces Fgf15 expression and increases postprandial glucose in hypoglycaemic mice. Our data suggest that dysregulation of luminal BA profiles and transport may contribute to PBH and provide proof of concept that ASBT inhibition could be developed as a new therapeutic strategy for PBH.

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肠道胆汁酸转运的改变为减肥后低血糖患者提供了治疗目标

虽然 Roux-en-Y 胃旁路术是治疗肥胖症和 2 型糖尿病的有效方法，但多达三分之一的患者会出现减肥后低血糖症（PBH）。PBH患者餐后肠道激素成纤维细胞生长因子19（FGF19，小鼠为Fgf15）分泌增加。然而，导致 PBH 的潜在机制仍不确定。在这里，我们证明了术后 PBH 患者的粪便和血浆胆汁酸（BA）谱与未发生低血糖的患者相比发生了显著变化。此外，PBH 中改变的胆汁酸会诱导肠细胞分泌 FGF19，其方式依赖于顶端钠依赖性胆汁酸转运体（ASBT）。我们证明，抑制 ASBT 可降低 Fgf15 的表达，并增加低血糖小鼠的餐后血糖。我们的数据表明，管腔BA分布和转运失调可能是导致PBH的原因之一，并证明了抑制ASBT可作为一种新的PBH治疗策略的概念。

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来源期刊

Nature metabolism ENDOCRINOLOGY & METABOLISM-

CiteScore

27.50

自引率

2.40%

发文量

170

期刊介绍： Nature Metabolism is a peer-reviewed scientific journal that covers a broad range of topics in metabolism research. It aims to advance the understanding of metabolic and homeostatic processes at a cellular and physiological level. The journal publishes research from various fields, including fundamental cell biology, basic biomedical and translational research, and integrative physiology. It focuses on how cellular metabolism affects cellular function, the physiology and homeostasis of organs and tissues, and the regulation of organismal energy homeostasis. It also investigates the molecular pathophysiology of metabolic diseases such as diabetes and obesity, as well as their treatment. Nature Metabolism follows the standards of other Nature-branded journals, with a dedicated team of professional editors, rigorous peer-review process, high standards of copy-editing and production, swift publication, and editorial independence. The journal has a high impact factor, has a certain influence in the international area, and is deeply concerned and cited by the majority of scholars.