Division of Metabolism, Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan; Department of General Medicine, Asahikawa Medical University, Japan.
Department of Regional Medicine and Education, Asahikawa Medical University, Japan.
Biochem Pharmacol. 2022 Dec;206:115331. doi: 10.1016/j.bcp.2022.115331. Epub 2022 Oct 29.
Intestinal barrier dysfunction, a leaky gut, contributes to the pathophysiology of various diseases such as dementia and irritable bowel syndrome (IBS). We recently clarified that orexin, ghrelin, or adenosine A2B signaling in the brain improved leaky gut through the vagus nerve. The present study was performed to clarify whether basal forebrain cholinergic neurons (BFCNs) are implicated in the central regulation of intestinal barrier function. We activated BFCNs using benzyl quinolone carboxylic acid (BQCA), a positive muscarinic M1 allosteric modulator, and evaluated colonic permeability by quantifying the absorbed Evans blue in rat colonic tissue. Intracisternal (not intraperitoneal) injection of BQCA blocked the increased colonic permeability in response to lipopolysaccharide. Vagotomy blocked BQCA-induced improvement of colonic hyperpermeability. Intracisternally administered pirenzepine, a muscarinic M1 selective antagonist, prevented intestinal barrier function improvement by intravenously administered 2-deoxy-d-glucose, central vagal stimulant. Adenosine A2B receptor antagonist but not dopamine or opioid receptor antagonist prevented BQCA-induced blockade of colonic hyperpermeability. Additionally, intracisternal injection of pirenzepine blocked orexin- or butyrate-induced intestinal barrier function improvement. These results suggest that BFCNs improve leaky gut through adenosine A2B signaling and the vagal pathway. Furthermore, BFCNs mediate orexin- or butyrate-induced intestinal barrier function improvement. Since BFCNs play a role in cognitive function and a leaky gut is associated with dementia, the present finding may lead us to speculate that BFCNs are involved in the development of dementia by regulating intestinal barrier function.
肠屏障功能障碍，即肠道渗漏，导致各种疾病的病理生理学变化，如痴呆和肠易激综合征（IBS）。我们最近阐明，大脑中的食欲素、胃饥饿素或腺苷 A2B 信号通过迷走神经改善肠道渗漏。本研究旨在阐明基底前脑胆碱能神经元（BFCNs）是否参与肠道屏障功能的中枢调节。我们使用苯并喹诺酮羧酸（BQCA）激活 BFCNs，BQCA 是一种阳性毒蕈碱 M1 变构调节剂，并通过定量大鼠结肠组织中吸收的 Evans 蓝来评估结肠通透性。脑室内（非腹腔内）注射 BQCA 可阻断脂多糖引起的结肠通透性增加。迷走神经切断术阻断了 BQCA 诱导的结肠高通透性的改善。脑室内给予哌仑西平，一种毒蕈碱 M1 选择性拮抗剂，可预防静脉内给予 2-脱氧-d-葡萄糖（中枢迷走神经刺激物）引起的肠道屏障功能改善。腺苷 A2B 受体拮抗剂而不是多巴胺或阿片受体拮抗剂可预防 BQCA 诱导的结肠高通透性阻断。此外，脑室内注射哌仑西平可阻断食欲素或丁酸盐诱导的肠道屏障功能改善。这些结果表明，BFCNs 通过腺苷 A2B 信号和迷走神经途径改善肠道渗漏。此外，BFCNs 介导食欲素或丁酸盐诱导的肠道屏障功能改善。由于 BFCNs 在认知功能中起作用，并且肠道渗漏与痴呆有关，因此这一发现可能使我们推测 BFCNs 通过调节肠道屏障功能参与痴呆的发生。
