Institute of Clinical Sciences, Department of Surgery, Sahlgrenska Academy, University of Gothenburg, SE41345 Gothenburg, Sweden.
Department of Surgery, Sahlgrenska University Hospital, SE41345 Gothenburg, Sweden.
Nutrients. 2022 May 7;14(9):1961. doi: 10.3390/nu14091961.
Insights into the nature of gut adaptation after different diets enhance the understanding of how food modifications can be used to treat type 2 diabetes and obesity. The aim was to understand how diets, enriched in fat or carbohydrates, affect glucose absorption in the human healthy jejunum, and what mechanisms are involved.
Fifteen healthy subjects received, in randomised order and a crossover study design, two weeks of iso-caloric high-fat diet (HFD) and high-carbohydrate diet (HCD). Following each dietary period, jejunal mucosa samples were retrieved and assessed for protein expression using immunofluorescence and western blotting. Functional characterisation of epithelial glucose transport was assessed ex vivo using Ussing chambers. Regulation of SGLT1 through histone acetylation was studied in vitro in Caco-2 and human jejunal enteroid monolayer cultures.
HFD, compared to HCD, decreased jejunal Ussing chamber epithelial glucose transport and the expression of apical transporters for glucose (SGLT1) and fructose (GLUT5), while expression of the basolateral glucose transporter GLUT2 was increased. HFD also increased protein expression of the ketogenesis rate-limiting enzyme mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2) and decreased the acetylation of histone 3 at lysine 9 (H3K9ac). Studies in Caco-2 and human jejunal enteroid monolayer cultures indicated a ketogenesis-induced activation of sirtuins, in turn decreasing SGLT1 expression.
Jejunal glucose absorption is decreased by a fat-enriched diet, via a ketogenesis-induced alteration of histone acetylation responsible for the silencing of SGLT1 transcription. The work relates to a secondary outcome in ClinicalTrials.gov (NCT02088853).
深入了解不同饮食后肠道适应的本质，可以增强对如何通过饮食改变来治疗 2 型糖尿病和肥胖的理解。本研究旨在了解富含脂肪或碳水化合物的饮食如何影响健康人空肠的葡萄糖吸收，以及涉及哪些机制。
15 名健康受试者随机交叉接受两周的高卡路里高脂肪饮食（HFD）和高碳水化合物饮食（HCD）。在每个饮食周期后，从空肠黏膜中提取样本，并用免疫荧光和 Western blot 检测蛋白表达。使用 Ussing 室在离体条件下评估上皮细胞葡萄糖转运的功能特征。在 Caco-2 和人空肠类器官单层培养物中，研究组蛋白乙酰化对 SGLT1 的调控作用。
与 HCD 相比，HFD 降低了空肠 Ussing 室上皮细胞的葡萄糖转运以及葡萄糖（SGLT1）和果糖（GLUT5）的顶端转运体的表达，而基底外侧葡萄糖转运体 GLUT2 的表达增加。HFD 还增加了酮体生成限速酶线粒体 3-羟-3-甲基戊二酰辅酶 A 合酶（HMGCS2）的蛋白表达，并降低了组蛋白 3 赖氨酸 9（H3K9ac）的乙酰化。Caco-2 和人空肠类器官单层培养物的研究表明，酮体生成诱导了沉默子的激活，进而降低了 SGLT1 的表达。
富含脂肪的饮食通过酮体生成诱导的组蛋白乙酰化改变降低了空肠的葡萄糖吸收，从而导致 SGLT1 转录沉默。本工作涉及 ClinicalTrials.gov（NCT02088853）的次要结果。
