Funayama Takuya, Nozu Tsukasa, Ishioh Masatomo, Sumi Chihiro, Saito Takeshi, Hatayama Mayumi, Yamamoto Masayo, Shindo Motohiro, Takahashi Shuichiro, Okumura Toshikatsu
Division of Hematology, Department of Medicine, Asahikawa Medical University, Japan.
Department of Regional Medicine and Education, Asahikawa Medical University, Japan; Department of General Medicine, Asahikawa Medical University, Japan.
Neurosci Lett. 2025 Apr 1;854:138208. doi: 10.1016/j.neulet.2025.138208. Epub 2025 Mar 28.
Leaky gut, an increased intestinal permeability, has been described in many diseases. We have recently demonstrated that neuropeptides such as orexin in the brain improved leaky gut, suggesting that the brain is involved in maintaining intestinal barrier function. It has been suggested that AMPK in the hypothalamus play a role in food intake. Because the hypothalamus is involved in the regulation of not only feeding behavior but also gut function, the present study was performed to clarify a hypothesis that AMPK in the brain regulate gut barrier function. Colonic permeability was determined by quantifying the absorbed Evans blue within the colonic tissue in rats. Intracisternal AICAR, an AMPK activator, could reduce LPS-induced colonic hyperpermeability while peripherally administered AICAR failed to change it. The improvement of colonic hyperpermeability by intracisternal AICAR was blocked by intracisternal but not subcutaneous compound C, AMPK inhibitor, atropine or vagotomy. The improvement of colonic hyperpermeability by intracisternal AICAR was blocked by intracisternal orexin receptor antagonist but not oxytocin or GLP-1 receptor antagonist. Intracisternal compound C prevented brain oxytocin or GLP-1 but not orexin-induced improvement of colonic hyperpermeability. These results suggest that activation of brain AMPK is capable of reducing colonic hyperpermeability through brain orexin signaling and the vagus nerve. In addition, endogenous AMPK in the brain may mediate the oxytocin or GLP-induced improvement of colonic hyperpermeability. We would suggest that improvement of leaky gut by activation of brain AMPK may play a role in leaky gut-related diseases.
肠道渗漏，即肠道通透性增加，在许多疾病中都有描述。我们最近证明，大脑中的神经肽如食欲素可改善肠道渗漏，这表明大脑参与维持肠道屏障功能。有人提出，下丘脑中的AMPK在食物摄入中起作用。由于下丘脑不仅参与进食行为的调节，还参与肠道功能的调节，因此进行本研究以阐明大脑中的AMPK调节肠道屏障功能这一假说。通过定量大鼠结肠组织内吸收的伊文思蓝来测定结肠通透性。脑池内注射AICAR（一种AMPK激活剂）可降低脂多糖诱导的结肠高通透性，而外周给予AICAR则无法改变它。脑池内注射AICAR对结肠高通透性的改善作用被脑池内注射而非皮下注射的化合物C（AMPK抑制剂）、阿托品或迷走神经切断术所阻断。脑池内注射AICAR对结肠高通透性的改善作用被脑池内注射的食欲素受体拮抗剂而非催产素或胰高血糖素样肽-1受体拮抗剂所阻断。脑池内注射化合物C可阻止脑内催产素或胰高血糖素样肽-1而非食欲素诱导的结肠高通透性改善。这些结果表明，大脑中AMPK的激活能够通过大脑食欲素信号通路和迷走神经降低结肠高通透性。此外，大脑中的内源性AMPK可能介导催产素或胰高血糖素样肽诱导的结肠高通透性改善。我们认为，激活大脑AMPK对肠道渗漏的改善可能在与肠道渗漏相关的疾病中起作用。
