Objective

The mechanism of nutrient sensing in the upper small intestine (USI) and ileum that regulates glucose homeostasis remains elusive. Short-term high-fat (HF) feeding increases taurochenodeoxycholic acid (TCDCA; an agonist of farnesoid X receptor (FXR)) in the USI and ileum of rats, and the increase of TCDCA is prevented by transplantation of microbiota obtained from the USI of healthy donors into the USI of HF rats. However, whether changes of TCDCA-FXR axis in the USI and ileum alter nutrient sensing remains unknown.

Methods

Intravenous glucose tolerance test was performed in rats that received USI or ileal infusion of nutrients (i.e., oleic acids or glucose) via catheters placed toward the lumen of USI and/or ileum, while mechanistic gain- and loss-of-function studies targeting the TCDCA-FXR axis or bile salt hydrolase activity in USI and ileum were performed.

Results

USI or ileum infusion of nutrients increased glucose tolerance in healthy but not HF rats. Transplantation of healthy microbiome obtained from USI into the USI of HF rats restored nutrient sensing and inhibited FXR via a reduction of TCDCA in the USI and ileum. Further, inhibition of USI and ileal FXR enhanced nutrient sensing in HF rats, while inhibiting USI (but not ileal) bile salt hydrolase of HF rats transplanted with healthy microbiome activated FXR and disrupted nutrient sensing in the USI and ileum.

Conclusions

We reveal a TCDCA-FXR axis in both the USI and ileum that is necessary for the upper small intestinal microbiome to govern local nutrient-sensing glucoregulatory pathways in rats.

中文翻译：

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小肠牛磺鹅去氧胆酸-FXR 轴改变大鼠局部营养感知葡萄糖调节途径

客观的

上小肠 (USI) 和回肠中调节葡萄糖稳态的营养感应机制仍然难以捉摸。短期高脂 (HF) 喂养会增加大鼠 USI 和回肠中的牛磺鹅去氧胆酸 (TCDCA；法尼醇 X 受体 (FXR) 的激动剂)，并且通过移植从 USI 获得的微生物群来防止 TCDCA 的增加健康供体进入 HF 大鼠的 USI。然而，USI 和回肠中 TCDCA-FXR 轴的变化是否会改变营养感知仍然未知。

方法

在通过朝向 USI 和/或回肠腔放置的导管接受 USI 或回肠输注营养物质（即油酸或葡萄糖）的大鼠中进行静脉葡萄糖耐量试验，同时针对进行了 USI 和回肠中的 TCDCA-FXR 轴或胆汁盐水解酶活性。

结果

USI 或回肠输注营养物质可增加健康大鼠的葡萄糖耐量，但不会增加 HF 大鼠的葡萄糖耐量。将从 USI 获得的健康微生物组移植到 HF 大鼠的 USI 中，通过减少 USI 和回肠中的 TCDCA 来恢复营养感知并抑制 FXR。此外，抑制 USI 和回肠 FXR 增强了 HF 大鼠的营养感知，同时抑制了移植了健康微生物组的 HF 大鼠的 USI（但不是回肠）胆汁盐水解酶，激活了 FXR，并破坏了 USI 和回肠的营养感知。

结论

我们揭示了 USI 和回肠中的 TCDCA-FXR 轴，这是上小肠微生物组控制大鼠局部营养感应葡萄糖调节途径所必需的。