Objective

The mechanisms behind the efficacy of bariatric surgery (BS) for treating obesity and type 2 diabetes, particularly with respect to the influence of the small bowel, remain poorly understood. In vitro and animal models are suboptimal with respect to their ability to replicate the human intestinal epithelium under conditions induced by obesity. Human enteroids have the potential to accelerate the development of less invasive anti-obesity therapeutics if they can recapitulate the pathophysiology of obesity. Our aim was to determine whether adult stem cell-derived enteroids preserve obesity-characteristic patient-specific abnormalities in carbohydrate absorption and metabolism.

Methods

We established 24 enteroid lines representing 19 lean, overweight, or morbidly obese patients, including post-BS cases. Dietary glucose absorption and gluconeogenesis in enteroids were measured. The expression of carbohydrate transporters and gluconeogenic enzymes was assessed and a pharmacological approach was used to dissect the specific contribution of each transporter or enzyme to carbohydrate absorption and metabolism, respectively.

Results

Four phenotypes representing the relationship between patients’ BMI and intestinal dietary sugar absorption were found, suggesting that human enteroids retain obese patient phenotype heterogeneity. Intestinal glucose absorption and gluconeogenesis were significantly elevated in enteroids from a cohort of obese patients. Elevated glucose absorption was associated with increased expression of SGLT1 and GLUT2, whereas elevated gluconeogenesis was related to increased expression of GLUT5, PEPCK1, and G6Pase.

Conclusions

Obesity phenotypes preserved in human enteroids provide a mechanistic link to aberrant dietary carbohydrate absorption and metabolism. Enteroids can be used as a preclinical platform to understand the pathophysiology of obesity, study the heterogeneity of obesity mechanisms, and identify novel therapeutics.

中文翻译：

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来自病态肥胖患者的肠道干细胞衍生的肠类物质保留了肥胖相关的表型：葡萄糖吸收和糖异生增加

客观的

减肥手术 (BS) 治疗肥胖症和 2 型糖尿病的功效背后的机制，尤其是小肠的影响，仍然知之甚少。体外和动物模型在肥胖诱导的条件下复制人类肠道上皮的能力是次优的。如果人类肠类物质能够概括肥胖的病理生理学，那么它们就有可能加速侵入性较小的抗肥胖疗法的开发。我们的目的是确定成人干细胞衍生的肠类物质是否保留了肥胖特征的患者特异性碳水化合物吸收和代谢异常。

方法

我们建立了 24 条肠样线，代表 19 名瘦弱、超重或病态肥胖的患者，包括 BS 后病例。测量了肠内的膳食葡萄糖吸收和糖异生。评估碳水化合物转运蛋白和糖异生酶的表达，并使用药理学方法分别剖析每种转运蛋白或酶对碳水化合物吸收和代谢的具体贡献。

结果

发现了代表患者 BMI 与肠道膳食糖吸收之间关系的四种表型，表明人类肠类物质保留了肥胖患者的表型异质性。来自一组肥胖患者的肠类物质的肠道葡萄糖吸收和糖异生显着升高。葡萄糖吸收升高与 SGLT1 和 GLUT2 表达增加有关，而糖异生升高与 GLUT5、PEPCK1 和 G6Pase 表达增加有关。

结论

保存在人类肠内的肥胖表型提供了与异常膳食碳水化合物吸收和代谢的机制联系。Enteroids 可用作了解肥胖病理生理学、研究肥胖机制的异质性和确定新疗法的临床前平台。