FXR Stimulation by Obeticholic Acid Treatment Restores Gut Mucosa Functional and Structural Integrity in Individuals With Altered Glucose Tolerance

IF 7.5 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetes Pub Date : 2025-06-17 DOI:10.2337/db25-0035

Francesca De Vito, Raffaella Marasco, Evelina Suraci, Antonio Facciolo, Marta Letizia Hribal, Giorgio Sesti, Francesco Andreozzi, Francesco Luzza, Teresa Vanessa Fiorentino

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引用次数: 0

Abstract

The farnesoid X receptor (FXR)–fibroblast growth factor 19 (FGF19) axis is involved in maintaining glucose homeostasis and gut tight-junction (TJ) integrity. We evaluated whether individuals with prediabetes or type 2 diabetes (T2D) have altered intestinal FXR-FGF19 signaling and barrier function and whether high-glucose (HG) exposure may cause these aberrations. Moreover, we tested beneficial effects of the FXR agonist obeticholic acid (OCA) on intestinal FXR signaling in individuals with prediabetes or T2D. Included were 60 individuals with different glucose tolerance (normal glucose tolerance [NGT; n = 25], prediabetes [n = 19], or T2D [n = 16]) who underwent ileocolonoscopy with collection of ileal mucosa biopsy specimens, which were used for expression profiling analysis of the FXR/FGF19/TJ axis and tissue culture experiments. Individuals with prediabetes or T2D displayed lower ileal levels of FXR and its target genes FGF19 and TJ proteins zonula, occludens-1, occludin, and claudin-1, along with increased proinflammatory nuclear factor-κB (NF-κB) activity and cytokines expression compared with those with NGT. HG exposure on ileal explants collected from NGT individuals hampered the FXR/FGF19/TJ axis. OCA treatment on ileal fragments of individuals with prediabetes/T2D was able to restore FGF19 synthesis and secretion, TJ expression, and counteract NF-κB activity and cytokines expression. In conclusion, OCA treatment counteracts T2D-related intestinal abnormalities in the FXR/FGF19/TJ axis. Article Highlights The intestinal farnesoid X receptor (FXR)/fibroblast growth factor 19 (FGF19) axis is involved in maintaining glucose homeostasis and gut barrier function in animals. Do individuals with prediabetes and type 2 diabetes exhibit a compromised intestinal FXR/FGF19/barrier integrity axis? Can obeticholic acid (OCA) treatment counteract diabetes-related gut mucosa dysfunction? A downregulation of ileal FXR/FGF19/tight-junctions signaling occurs in individuals with hyperglycemia. OCA-mediated FXR activation reverts diabetes-related alterations. OCA-mediated intestinal FXR activation in individuals with hyperglycemia may represent a strategy for restoring FGF19 synthesis with positive effects on gut barrier.

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奥贝胆酸治疗FXR刺激可恢复糖耐量改变个体的肠黏膜功能和结构完整性

farnesoid X受体(FXR) -成纤维细胞生长因子19 （FGF19）轴参与维持葡萄糖稳态和肠道紧密连接（TJ）的完整性。我们评估了糖尿病前期或2型糖尿病（T2D）患者是否改变了肠道FXR-FGF19信号和屏障功能，以及高糖（HG）暴露是否会导致这些异常。此外，我们测试了FXR激动剂奥比胆酸（OCA）对糖尿病前期或t2dm患者肠道FXR信号传导的有益作用。纳入60例不同糖耐量的个体(正常糖耐量[NGT；n = 25]，前驱糖尿病[n = 19]，或T2D [n = 16])接受回肠结肠镜检查，收集回肠粘膜活检标本，用于FXR/FGF19/TJ轴的表达谱分析和组织培养实验。糖尿病前期或T2D患者的回肠FXR及其靶基因FGF19和TJ蛋白zonula、occludens-1、occludin和claudin-1水平较低，促炎核因子-κB （NF-κB）活性和细胞因子表达均高于NGT患者。从NGT个体收集的回肠外植体上暴露HG会阻碍FXR/FGF19/TJ轴。OCA治疗前驱糖尿病/T2D患者回肠片段能够恢复FGF19的合成和分泌、TJ的表达，并抑制NF-κB活性和细胞因子的表达。综上所述，OCA治疗可抵消t2d相关的FXR/FGF19/TJ轴肠道异常。肠法尼类X受体(FXR)/成纤维细胞生长因子19 （FGF19）轴参与维持动物体内葡萄糖稳态和肠道屏障功能。糖尿病前期和2型糖尿病患者是否表现出肠道FXR/FGF19/屏障完整性轴受损？奥贝胆酸（OCA）治疗能对抗糖尿病相关的肠黏膜功能障碍吗？回肠FXR/FGF19/紧密连接信号的下调发生在高血糖个体中。oca介导的FXR激活可逆转糖尿病相关的改变。oca介导的高血糖个体肠道FXR激活可能是恢复FGF19合成的一种策略，对肠道屏障有积极作用。

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来源期刊

Diabetes 医学-内分泌学与代谢

CiteScore

12.50

自引率

2.60%

发文量

1968

审稿时长

1 months

期刊介绍： Diabetes is a scientific journal that publishes original research exploring the physiological and pathophysiological aspects of diabetes mellitus. We encourage submissions of manuscripts pertaining to laboratory, animal, or human research, covering a wide range of topics. Our primary focus is on investigative reports investigating various aspects such as the development and progression of diabetes, along with its associated complications. We also welcome studies delving into normal and pathological pancreatic islet function and intermediary metabolism, as well as exploring the mechanisms of drug and hormone action from a pharmacological perspective. Additionally, we encourage submissions that delve into the biochemical and molecular aspects of both normal and abnormal biological processes. However, it is important to note that we do not publish studies relating to diabetes education or the application of accepted therapeutic and diagnostic approaches to patients with diabetes mellitus. Our aim is to provide a platform for research that contributes to advancing our understanding of the underlying mechanisms and processes of diabetes.