肠道大麻素受体1调节酒精狂欢诱导的肠道通透性。

eGastroenterology Pub Date : 2025-02-12 eCollection Date: 2025-01-01 DOI:10.1136/egastro-2024-100173
Luca Maccioni, Szabolcs Dvorácskó, Grzegorz Godlewski, Resat Cinar, Malliga R Iyer, Bin Gao, George Kunos
{"title":"肠道大麻素受体1调节酒精狂欢诱导的肠道通透性。","authors":"Luca Maccioni, Szabolcs Dvorácskó, Grzegorz Godlewski, Resat Cinar, Malliga R Iyer, Bin Gao, George Kunos","doi":"10.1136/egastro-2024-100173","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Endocannabinoids acting via cannabinoid receptor 1 (CB1R) can elicit increased intestinal permeability (a condition also called 'leaky gut'). Alcohol binge can adversely affect digestive functions, including intestinal permeability; however, the underlying mechanisms remain incompletely understood. The current study aimed at examining whether CB1R is involved in alcohol binge-induced intestinal permeability.</p><p><strong>Methods: </strong>We developed intestinal epithelial-specific CB1R knockout (CB1<sup>IEC-/-</sup>) mice and evaluated the <i>in vivo</i> contribution of gut CB1R in alcohol binge-induced intestinal permeability.</p><p><strong>Results: </strong>Alcohol binge increased anandamide levels in the proximal small intestine in association with increased intestinal permeability. Radioligand binding and functional assays confirmed that the genetic deletion of intestinal epithelial CB1R did not alter the density or functionality of CB1R in the brain. Additionally, a peripheral CB1R antagonist, (<i>S</i>)-MRI-1891 (INV-202/monlunabant), exhibited comparable binding affinity to CB1R in brain homogenates. An acute oral administration of (<i>S</i>)-MRI-1891 (3 mg/kg) reduced alcohol binge-induced intestinal permeability in littermate control CB1<sup>f/f</sup> (CB1 floxed/floxed) mice but had no effect in CB1<sup>IEC-/-</sup> mice, underscoring the role of intestinal CB1R in this phenomenon. Mechanistically, we found that alcohol activated intestinal epithelial CB1R-ERK1/2 pathway with subsequent downregulation of tight junction proteins and reduction in villi length. In addition, targeting intestinal CB1R and downstream ERK1/2 was able to reverse this process, with subsequent upregulation of tight junction proteins and increased villi length, thus improving gut barrier function. Despite the effects on intestinal permeability, deletion of intestinal CB1R did not significantly affect metabolic parameters and liver disease.</p><p><strong>Conclusion: </strong>Our findings suggest that alcohol promotes leaky gut via the activation of gut epithelial CB1R and demonstrate that inhibition of CB1R with peripheral-restricted selective CB1R antagonists can prevent alcohol binge-induced intestinal permeability.</p>","PeriodicalId":72879,"journal":{"name":"eGastroenterology","volume":"3 1","pages":"e100173"},"PeriodicalIF":0.0000,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927431/pdf/","citationCount":"0","resultStr":"{\"title\":\"Gut cannabinoid receptor 1 regulates alcohol binge-induced intestinal permeability.\",\"authors\":\"Luca Maccioni, Szabolcs Dvorácskó, Grzegorz Godlewski, Resat Cinar, Malliga R Iyer, Bin Gao, George Kunos\",\"doi\":\"10.1136/egastro-2024-100173\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Endocannabinoids acting via cannabinoid receptor 1 (CB1R) can elicit increased intestinal permeability (a condition also called 'leaky gut'). Alcohol binge can adversely affect digestive functions, including intestinal permeability; however, the underlying mechanisms remain incompletely understood. The current study aimed at examining whether CB1R is involved in alcohol binge-induced intestinal permeability.</p><p><strong>Methods: </strong>We developed intestinal epithelial-specific CB1R knockout (CB1<sup>IEC-/-</sup>) mice and evaluated the <i>in vivo</i> contribution of gut CB1R in alcohol binge-induced intestinal permeability.</p><p><strong>Results: </strong>Alcohol binge increased anandamide levels in the proximal small intestine in association with increased intestinal permeability. Radioligand binding and functional assays confirmed that the genetic deletion of intestinal epithelial CB1R did not alter the density or functionality of CB1R in the brain. Additionally, a peripheral CB1R antagonist, (<i>S</i>)-MRI-1891 (INV-202/monlunabant), exhibited comparable binding affinity to CB1R in brain homogenates. An acute oral administration of (<i>S</i>)-MRI-1891 (3 mg/kg) reduced alcohol binge-induced intestinal permeability in littermate control CB1<sup>f/f</sup> (CB1 floxed/floxed) mice but had no effect in CB1<sup>IEC-/-</sup> mice, underscoring the role of intestinal CB1R in this phenomenon. Mechanistically, we found that alcohol activated intestinal epithelial CB1R-ERK1/2 pathway with subsequent downregulation of tight junction proteins and reduction in villi length. In addition, targeting intestinal CB1R and downstream ERK1/2 was able to reverse this process, with subsequent upregulation of tight junction proteins and increased villi length, thus improving gut barrier function. Despite the effects on intestinal permeability, deletion of intestinal CB1R did not significantly affect metabolic parameters and liver disease.</p><p><strong>Conclusion: </strong>Our findings suggest that alcohol promotes leaky gut via the activation of gut epithelial CB1R and demonstrate that inhibition of CB1R with peripheral-restricted selective CB1R antagonists can prevent alcohol binge-induced intestinal permeability.</p>\",\"PeriodicalId\":72879,\"journal\":{\"name\":\"eGastroenterology\",\"volume\":\"3 1\",\"pages\":\"e100173\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2025-02-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927431/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"eGastroenterology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1136/egastro-2024-100173\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"eGastroenterology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1136/egastro-2024-100173","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

摘要

背景:内源性大麻素通过大麻素受体1 (CB1R)作用可引起肠道通透性增加(也称为“漏肠”)。酗酒会对消化功能产生不利影响,包括肠道通透性;然而,潜在的机制仍然不完全清楚。目前的研究旨在检查CB1R是否参与酒精暴饮暴食诱导的肠道通透性。方法:我们培育了肠道上皮特异性CB1R敲除(CB1IEC-/-)小鼠,并评估了肠道CB1R在酒精狂欢诱导的肠道通透性中的体内贡献。结果:狂饮酒精增加了小肠近端阿南达胺水平,并与肠道通透性增加有关。放射配体结合和功能分析证实,肠上皮CB1R的基因缺失不会改变大脑中CB1R的密度或功能。此外,外周CB1R拮抗剂(S)-MRI-1891 (INV-202/monlunabant)在脑匀浆中显示出与CB1R相似的结合亲和力。急性口服(S)- mri -1891 (3mg /kg)降低了酒精过量诱导的CB1f/f (CB1 floxed/floxed)小鼠的肠道通透性,但对CB1IEC-/-小鼠没有影响,强调了肠道CB1R在这一现象中的作用。在机制上,我们发现酒精激活肠上皮CB1R-ERK1/2通路,随后下调紧密连接蛋白并减少绒毛长度。此外,靶向肠道CB1R和下游ERK1/2能够逆转这一过程,随后上调紧密连接蛋白,增加绒毛长度,从而改善肠道屏障功能。尽管对肠道通透性有影响,但肠道CB1R的缺失并未显著影响代谢参数和肝脏疾病。结论:我们的研究结果表明,酒精通过激活肠道上皮CB1R促进肠道渗漏,并且表明外周限制性选择性CB1R拮抗剂抑制CB1R可以预防酒精暴饮暴食诱导的肠道通透性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Gut cannabinoid receptor 1 regulates alcohol binge-induced intestinal permeability.

Background: Endocannabinoids acting via cannabinoid receptor 1 (CB1R) can elicit increased intestinal permeability (a condition also called 'leaky gut'). Alcohol binge can adversely affect digestive functions, including intestinal permeability; however, the underlying mechanisms remain incompletely understood. The current study aimed at examining whether CB1R is involved in alcohol binge-induced intestinal permeability.

Methods: We developed intestinal epithelial-specific CB1R knockout (CB1IEC-/-) mice and evaluated the in vivo contribution of gut CB1R in alcohol binge-induced intestinal permeability.

Results: Alcohol binge increased anandamide levels in the proximal small intestine in association with increased intestinal permeability. Radioligand binding and functional assays confirmed that the genetic deletion of intestinal epithelial CB1R did not alter the density or functionality of CB1R in the brain. Additionally, a peripheral CB1R antagonist, (S)-MRI-1891 (INV-202/monlunabant), exhibited comparable binding affinity to CB1R in brain homogenates. An acute oral administration of (S)-MRI-1891 (3 mg/kg) reduced alcohol binge-induced intestinal permeability in littermate control CB1f/f (CB1 floxed/floxed) mice but had no effect in CB1IEC-/- mice, underscoring the role of intestinal CB1R in this phenomenon. Mechanistically, we found that alcohol activated intestinal epithelial CB1R-ERK1/2 pathway with subsequent downregulation of tight junction proteins and reduction in villi length. In addition, targeting intestinal CB1R and downstream ERK1/2 was able to reverse this process, with subsequent upregulation of tight junction proteins and increased villi length, thus improving gut barrier function. Despite the effects on intestinal permeability, deletion of intestinal CB1R did not significantly affect metabolic parameters and liver disease.

Conclusion: Our findings suggest that alcohol promotes leaky gut via the activation of gut epithelial CB1R and demonstrate that inhibition of CB1R with peripheral-restricted selective CB1R antagonists can prevent alcohol binge-induced intestinal permeability.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信