PDF(Pubmed)
Abstract：
Obstructive sleep apnea (OSA) can lead to intestinal injury, endotoxemia, and disturbance of intestinal flora. Additionally, as a crucial component of the endocannabinoid system, some studies have demonstrated that cannabinoid 1 (CB1) receptors are closely linked to the multiple organ dysfunction triggered by OSA. However, the role of the CB1 receptor in alleviating OSA-induced colon injury remains unclear. Here, through the construction of the OSA classic model, we found that the colon tissue of chronic intermittent hypoxia (CIH)-induced mice exhibited an overexpression of the CB1 receptor. The results of hematoxylin-eosin staining and transmission electron microscopy revealed that inhibition of the CB1 receptor could decrease the gap between the mucosa and muscularis mucosae, alleviate mitochondrial swelling, reduce microvilli shedding, and promote the recovery of tight junctions of CIH-induced mice. Furthermore, CB1 receptor inhibition reduced the levels of metabolic endotoxemia and inflammatory responses, exhibiting significant protective effects on the colon injury caused by CIH. At the molecular level, through western blotting and real-time polymerase chain reaction techniques, we found that inhibiting the CB1 receptor can significantly increase the expression of ZO-1 and Occludin proteins, which are closely related to the maintenance of intestinal mucosal barrier function. Through 16S rRNA high-throughput sequencing and short-chain fatty acid (SCFA) determination, we found that inhibition of the CB1 receptor increased the diversity of the microbial flora and controlled the makeup of intestinal flora. Moreover, butyric acid concentration and the amount of SCFA-producing bacteria, such as Ruminococcaceae and Lachnospiraceae, were both markedly elevated by CB1 receptor inhibition. The results of the spearman correlation study indicated that Lachnospiraceae showed a positive association with both ZO-1 and Occludin but was negatively correlated with the colon CB1 receptor, IL-1β, and TNF-α. According to this study, we found that inhibiting CB1 receptor can improve CIH-induced colon injury by regulating gut microbiota, reducing mucosal damage and promoting tight junction recovery. KEY POINTS: •CIH leads to overexpression of CB1 receptor in colon tissue. •CIH causes intestinal flora disorder, intestinal mucosal damage, and disruption of tight junctions. •Inhibition of CB1 receptor can alleviate the colon injury caused by CIH through regulating the gut microbiota, reducing mucosal injury, and promoting tight junction recovery.
摘要：
阻塞性睡眠呼吸暂停（OSA）可导致肠道损伤，内毒素血症,和肠道菌群紊乱。此外,作为内源性大麻素系统的重要组成部分，一些研究表明，大麻素1（CB1）受体与OSA引发的多器官功能障碍密切相关。然而,CB1受体在减轻OSA诱导的结肠损伤中的作用尚不清楚.这里,通过OSA经典模型的构建，我们发现，慢性间歇性缺氧（CIH）诱导的小鼠的结肠组织表现出CB1受体的过度表达。苏木精-伊红染色和透射电子显微镜的结果表明，抑制CB1受体可以减少粘膜和粘膜肌层之间的间隙，缓解线粒体肿胀，减少微绒毛脱落，并促进CIH诱导小鼠紧密连接的恢复。此外，CB1受体抑制降低了代谢性内毒素血症和炎症反应的水平，对CIH引起的结肠损伤表现出明显的保护作用。在分子水平上,通过蛋白质印迹和实时聚合酶链反应技术，我们发现抑制CB1受体可以显著增加ZO-1和Occludin蛋白的表达,与维持肠黏膜屏障功能密切相关。通过16SrRNA高通量测序和短链脂肪酸(SCFA)测定,我们发现CB1受体的抑制增加了微生物菌群的多样性并控制了肠道菌群的构成。此外，丁酸浓度和产生SCFA的细菌数量，如Ruminocycaceae和Lachnospileaceae，均因CB1受体抑制而显著升高。Spearman相关研究结果表明，Lachnospileaceae与ZO-1和Occludin均呈正相关，但与结肠CB1受体呈负相关，IL-1β,和TNF-α。根据这项研究,我们发现抑制CB1受体可以通过调节肠道菌群改善CIH诱导的结肠损伤,减少粘膜损伤，促进紧密连接恢复。关键点:•CIH导致结肠组织中CB1受体的过表达。•CIH导致肠道菌群紊乱，肠粘膜损伤，和紧密连接的中断。•抑制CB1受体可以通过调节肠道菌群来减轻CIH引起的结肠损伤，减少粘膜损伤，促进紧密连接恢复。
