Pan Shaorong, Yan Han, Zhu Jing, Ma Yuanyuan, Wang Pengyuan, Liu Yucun, Chen Zeyang
Department of Gastrointestinal Surgery, Peking University First Hospital, Peking University, Beijing, China.
Animal Experiment Center, Peking University First Hospital, Peking University, Beijing, China.
Front Pharmacol. 2024 Oct 22;15:1476407. doi: 10.3389/fphar.2024.1476407. eCollection 2024.
Numerous studies have revealed that a long-term high-fat diet can raise intestinal deoxycholate acid concentration, which can harm intestinal mucosal barrier function in several ways. This study aims to verify the protective effect of GYY4137, as a slow-releasing HS donor, on microbiome disturbance and the chronic injury of the intestinal mucosal barrier function caused by sodium deoxycholate.
Caco-2 monolayer and mouse models were treated with a relatively high concentration of sodium deoxycholate (1.0 mM and 0.2%, respectively) for longer periods (32 h and 12 weeks, respectively) to understand the effects of GYY4137 on sodium deoxycholate-induced chronic intestinal barrier dysfunction and its fundamental mechanisms.
A relatively long period of sodium deoxycholate treatment can remarkably increase the intestinal barrier permeability, alter the distribution and expression of tight junction proteins and generate the production of pro-inflammatory cytokines (TNF- and IL-1) in the Caco-2 monolayers and mouse models. Moreover, it can activate the MLCK-P-MLC2 pathway in the Caco-2 monolayers, which was further confirmed using RNA sequencing. The body weight, intestinal barrier histological score, and TUNEL index of sodium deoxycholate-treated mice worsened. In addition, an induced microbiome imbalance was observed in these mice. The above variations can be reversed with the administration of GYY4137.
This study demonstrates that GYY4137 ameliorates sodium deoxycholate-induced chronic intestinal barrier injury by restricting the MLCK-P-MLC2 pathway while elevating the expression level of tight junction proteins, anti-apoptosis and maintaining the microbiome's homeostasis.
大量研究表明，长期高脂饮食会提高肠道脱氧胆酸浓度，这会通过多种方式损害肠道黏膜屏障功能。本研究旨在验证作为缓释硫化氢供体的GYY4137对脱氧胆酸钠引起的微生物群紊乱和肠道黏膜屏障功能慢性损伤的保护作用。
用相对高浓度的脱氧胆酸钠（分别为1.0 mM和0.2%）对Caco-2单层细胞和小鼠模型进行较长时间处理（分别为32小时和12周），以了解GYY4137对脱氧胆酸钠诱导的慢性肠道屏障功能障碍的影响及其基本机制。
较长时间的脱氧胆酸钠处理可显著增加Caco-2单层细胞和小鼠模型中的肠道屏障通透性，改变紧密连接蛋白的分布和表达，并产生促炎细胞因子（TNF-和IL-1）。此外，它可激活Caco-2单层细胞中的MLCK-P-MLC2途径，RNA测序进一步证实了这一点。脱氧胆酸钠处理的小鼠体重、肠道屏障组织学评分和TUNEL指数恶化。此外，在这些小鼠中观察到诱导的微生物群失衡。给予GYY4137可逆转上述变化。
本研究表明，GYY4137通过限制MLCK-P-MLC2途径，同时提高紧密连接蛋白的表达水平、抗凋亡并维持微生物群的稳态，改善脱氧胆酸钠诱导的慢性肠道屏障损伤。
