Bartochowski Piotr, Cortijo Irene, Bhargava Shruti, Jover Bernard, Raynaud Fabrice, Boukhaled Juliana H, Lajoix Anne-Dominique, Jankowski Vera, Jankowski Joachim, Cordaillat-Simmons Magali, Argilés Àngel, Gayrard Nathalie, Duranton Flore, Laget Jonas
RD Néphrologie SAS, Montpellier, France.
BC2M, University of Montpellier, France.
FEBS Open Bio. 2025 Aug;15(8):1219-1231. doi: 10.1002/2211-5463.70043. Epub 2025 Jun 17.
Intestinal disorders and vascular calcification (VC) are often associated with chronic kidney disease (CKD). While gut barrier alterations have been reported in CKD (such as abnormal intestinal permeability, bacterial overgrowth, and inflammation), it is not clear if vascular calcification influences these alterations. To investigate whether the bidirectional relationships between VC and gut dysfunction could be mediated by increased inflammation and uremic toxin generation, we used the SNx-VC model of uremic vascular calcification (rats undergoing subtotal 5/6th nephrectomy and fed a procalcifying high-phosphate and vitamin D diet). We confirmed the presence of CKD and VC by von Kossa staining and observed increased gut-origin uremic toxin, indoxyl sulfate (IS), in SNx-VC animals compared to controls. In SNx-VC rats, we observed decreased mucus production (Alcian blue, Mucin 2 staining) in the colon and ileum which was correlated with the level of calcification. There was no change in inflammation markers or tight junction protein expression. We assessed intestinal levels in the NOD-like receptor family pyrin domain containing 6 (NLRP6) protein, known to regulate mucus secretion, and found no change in the colon or ileum. Nlrp6 mRNA was, however, decreased in the colon of SNx-VC rats, along with other mRNA (Ly96, Sod1), while Tlr2 was increased compared to controls. Our observations of low mucus, low Nlrp6 mRNA, and high IS in SNx-VC rats confirm a link between gut barrier alterations and uremic VC. This suggests that alterations in the mucus layer could favor the generation of gut-origin uremic toxins and promote VC in CKD. Thus, improving the gut mucus barrier function in the context of uremic VC could be considered as a possible therapeutic strategy in CKD patients.
肠道疾病与血管钙化（VC）常与慢性肾脏病（CKD）相关。虽然已有报道称CKD存在肠道屏障改变（如肠道通透性异常、细菌过度生长和炎症），但血管钙化是否会影响这些改变尚不清楚。为了研究VC与肠道功能障碍之间的双向关系是否可由炎症增加和尿毒症毒素生成介导，我们使用了尿毒症性血管钙化的SNx-VC模型（大鼠接受5/6肾次全切除并喂食促钙化的高磷和维生素D饮食）。我们通过冯·科萨染色证实了CKD和VC的存在，并观察到与对照组相比，SNx-VC动物中肠道源性尿毒症毒素硫酸吲哚酚（IS）增加。在SNx-VC大鼠中，我们观察到结肠和回肠中黏液分泌减少（阿尔辛蓝、黏蛋白2染色），这与钙化水平相关。炎症标志物或紧密连接蛋白表达没有变化。我们评估了已知调节黏液分泌的含NOD样受体家族吡啉结构域蛋白6（NLRP6）在肠道中的水平，发现结肠和回肠中没有变化。然而，与对照组相比，SNx-VC大鼠结肠中的Nlrp6 mRNA减少，同时其他mRNA（Ly96、Sod1）也减少，而Tlr2增加。我们对SNx-VC大鼠中低黏液、低Nlrp6 mRNA和高IS的观察证实了肠道屏障改变与尿毒症性VC之间的联系。这表明黏液层的改变可能有利于肠道源性尿毒症毒素的生成，并促进CKD中的VC。因此，在尿毒症性VC的背景下改善肠道黏液屏障功能可被视为CKD患者的一种可能治疗策略。
