Allam-Ndoul Bénédicte, Pulido-Mateos Elena Cristina, Bégin Frédéric, St-Arnaud Gabrielle, Tinoco Mar Briscia Anaid, Mayer Thomas, Dumais Elizabeth, Flamand Nicolas, Raymond Frederic, Roy Denis, Desjardins Yves, Di Marzo Vincenzo, Veilleux Alain
Centre Nutrition, Santé et Société (NUTRISS), Université Laval, Québec, Québec, Canada.
Institut sur la nutrition et les aliments fonctionnels (INAF), Université Laval, Québec,Québec, Canada.
Am J Physiol Gastrointest Liver Physiol. 2025 Aug 1;329(2):G245-G260. doi: 10.1152/ajpgi.00142.2024. Epub 2025 Jun 16.
Probiotics have been suggested to ameliorate intestinal epithelial homeostasis and barrier function. They also modulate several mediators and receptors of the expanded endocannabinoid system, or endocannabinoidome (eCBome), potentially explaining their beneficial effects on intestinal function. We aimed to study the effects of probiotic strains on gut barrier functions and the possible involvement of the eCBome in these effects. We cocultured three strains of with murine small intestine epithelial organoids and explored the involvement of eCBome signaling and inflammation in mediating the beneficial effects of the probiotics on the epithelial barrier function. All three strains reduced the transepithelial permeability of organoids and increased mRNA expression of several tight junction proteins (, , , , and ) and intestinal barrier proteins (, , , and ). Concomitantly, the three strains increased the expression of genes encoding eCBome receptors while decreasing the expression of two catabolic enzymes ( and ), and increasing one anabolic enzyme (). Altogether, these changes led to an overall increase in levels of eCBome mediators, namely -acyl-ethanolamines (NAEs) and, particularly, 2-monoacylglycerols (2-MAGs), as measured by LC-MS/MS. URB 597 and JZL 184, two selective inhibitors of NAE and 2-MAG catabolism, reduced the transepithelial permeability of organoids, as observed with strains. Interestingly, both inhibitors also reversed inflammation-induced transepithelial permeability in organoids. Elevated endogenous levels of NAEs or 2-MAGs promote improvement in small intestine transepithelial permeability, and strains may exploit this mechanism to exert this same beneficial effect. strains improve transepithelial permeability and concomitantly increase the levels of eCBome mediators in murine small intestine epithelial organoids. Pharmacological elevation of NAE or 2-MAG levels enhances the expression of intestinal epithelial barrier genes and reduces the transepithelial permeability of murine small intestine epithelial organoids, suggesting that may exploit eCBome signaling to exert its beneficial effects.
益生菌已被认为可改善肠道上皮的稳态和屏障功能。它们还可调节扩展的内源性大麻素系统（或内源性大麻素组，eCBome）的多种介质和受体，这可能解释了它们对肠道功能的有益作用。我们旨在研究益生菌菌株对肠道屏障功能的影响以及eCBome在这些影响中可能的参与情况。我们将三株益生菌与小鼠小肠上皮类器官共培养，并探讨eCBome信号传导和炎症在介导益生菌对上皮屏障功能的有益作用中的作用。所有三株益生菌菌株均降低了类器官的跨上皮通透性，并增加了几种紧密连接蛋白（ZO-1、occludin、claudin-1、claudin-3和claudin-4）和肠道屏障蛋白（mucin-2、mucin-3、mucin-4和mucin-13）的mRNA表达。同时，这三株菌株增加了编码eCBome受体的基因的表达，同时降低了两种分解代谢酶（FAAH和MAGL）的表达，并增加了一种合成代谢酶（DAGLα）的表达。总体而言，通过液相色谱-串联质谱法（LC-MS/MS）测定，这些变化导致eCBome介质水平总体升高，即N-酰基乙醇胺（NAEs），尤其是2-单酰甘油（2-MAGs）。NAE和2-MAG分解代谢的两种选择性抑制剂URB 597和JZL 184降低了类器官的跨上皮通透性，这与益生菌菌株观察到的情况相同。有趣的是，这两种抑制剂还逆转了类器官中炎症诱导的跨上皮通透性。内源性NAEs或2-MAGs水平升高促进小肠跨上皮通透性的改善，而益生菌菌株可能利用这一机制发挥相同的有益作用。益生菌菌株改善了跨上皮通透性，并同时增加了小鼠小肠上皮类器官中eCBome介质的水平。NAE或2-MAG水平的药理学升高增强了肠道上皮屏障基因的表达，并降低了小鼠小肠上皮类器官的跨上皮通透性，这表明益生菌可能利用eCBome信号传导发挥其有益作用。
